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  • 1. Aleksandrova, Krasimira
    et al.
    Chuang, Shu-Chun
    Boeing, Heiner
    Zuo, Hui
    Tell, Grethe S
    Pischon, Tobias
    Jenab, Mazda
    Bueno-de-Mesquita, Bas
    Vollset, Stein Emil
    Midttun, Øivind
    Ueland, Per Magne
    Fedirko, Veronika
    Johansson, Mattias
    Weiderpass, Elisabete
    Severi, Gianluca
    Racine, Antoine
    Boutron-Ruault, Marie-Christine
    Kaaks, Rudolf
    Kühn, Tilman
    Tjønneland, Anne
    Overvad, Kim
    Quirós, J Ramón
    Jakszyn, Paula
    Sánchez, María-José
    Dorronsoro, Miren
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Khaw, Kay-Tee
    Wareham, Nicholas J
    Travis, Ruth C
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Palli, Domenico
    Sieri, Sabina
    Tumino, Rosario
    Panico, Salvatore
    May, Anne M
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kong, So Yeon J
    Freisling, Heinz
    Gunter, Marc J
    Lu, Yunxia
    Cross, Amanda J
    Riboli, Elio
    Vineis, Paolo
    A prospective study of the immune system activation biomarker neopterin and colorectal cancer risk2015In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 107, no 4, article id djv010Article in journal (Refereed)
    Abstract [en]

    Background: Neopterin may be relevant for colorectal cancer (CRC) development, as a biomarker of cellular immune activity exerting pleiotropic effects on cellular ageing, oxidative stress, and inflammation. So far, the association between prediagnostic neopterin and colon and rectal cancer risk has not been evaluated in human populations. Methods: A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition cohort using data on plasma concentrations of total neopterin (T-N, sum of neopterin and 7,8-dihydroneopterin) in 830 incident CRC case patients (561 colon and 269 rectal) matched within risk sets to 830 control participants. A subsequent replication study used data from the Hordaland Health Study, where 173 CRC case patients have been diagnosed among 6594 healthy participants over 12 years of follow-up. Results: After multivariable adjustment for a priori chosen CRC risk factors, a "U-shaped" association of T-N with CRC was revealed. Compared with the second quintile of the T-N distribution, the relative risks for the first, third, fourth, and fifth quintiles were 2.37 (95% CI = 1.66 to 3.39), 1.24 (95% CI = 0.87 to 1.77), 1.55 (95% CI = 1.08 to 2.22), and 2.31 (95% CI = 1.63 to 3.27), respectively. Replication of these associations within the Hordaland Health Study yielded similar results. No differences have been observed when the associations were explored by colon and rectal cancer site (two-sided P-difference = .87) and after excluding case patients diagnosed within the first four follow-up years. Conclusions: These novel findings provide evidence of the role of both suppressed and activated cell-mediated immunity as reflected by prediagnostic T-N concentrations in the development of CRC.

  • 2. Allen, Naomi E.
    et al.
    Travis, Ruth C.
    Appleby, Paul N.
    Albanes, Demetrius
    Barnett, Matt J.
    Black, Amanda
    Bueno-de-Mesquita, H. Bas
    Deschasaux, Melanie
    Galan, Pilar
    Goodman, Gary E.
    Goodman, Phyllis J.
    Gunter, Marc J.
    Heliovaara, Markku
    Helzlsouer, Kathy J.
    Henderson, Brian E.
    Hercberg, Serge
    Knekt, Paul
    Kolonel, Laurence N.
    Lasheras, Christina
    Linseisen, Jakob
    Metter, E. Jeffrey
    Neuhouser, Marian L.
    Olsen, Anja
    Pala, Valeria
    Platz, Elizabeth A.
    Rissanen, Harri
    Reid, Mary E.
    Schenk, Jeannette M.
    Stampfer, Meir J.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Tangen, Catherine M.
    Touvier, Mathilde
    Trichopoulou, Antonia
    van den Brandt, Piet A.
    Key, Timothy J.
    Selenium and Prostate Cancer: Analysis of Individual Participant Data From Fifteen Prospective Studies2016In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 108, no 11, article id djw153Article in journal (Refereed)
    Abstract [en]

    Background: Some observational studies suggest that a higher selenium status is associated with a lower risk of prostate cancer but have been generally too small to provide precise estimates of associations, particularly by disease stage and grade. Methods: Collaborating investigators from 15 prospective studies provided individual-participant records (from predominantly men of white European ancestry) on blood or toenail selenium concentrations and prostate cancer risk. Odds ratios of prostate cancer by selenium concentration were estimated using multivariable-adjusted conditional logistic regression. All statistical tests were two-sided. Results: Blood selenium was not associated with the risk of total prostate cancer (multivariable-adjusted odds ratio [OR] per 80 percentile increase = 1.01, 95% confidence interval [CI] = 0.83 to 1.23, based on 4527 case patients and 6021 control subjects). However, there was heterogeneity by disease aggressiveness (ie, advanced stage and/or prostate cancer death, P-heterogeneity = .01), with high blood selenium associated with a lower risk of aggressive disease (OR = 0.43, 95% CI = 0.21 to 0.87) but not with nonaggressive disease. Nail selenium was inversely associated with total prostate cancer (OR = 0.29, 95% CI = 0.22 to 0.40, P-trend <.001, based on 1970 case patients and 2086 control subjects), including both nonaggressive (OR = 0.33, 95% CI = 0.22 to 0.50) and aggressive disease (OR = 0.18, 95% CI = 0.11 to 0.31, P-heterogeneity =.08). Conclusions: Nail, but not blood, selenium concentration is inversely associated with risk of total prostate cancer, possibly because nails are a more reliable marker of long-term selenium exposure. Both blood and nail selenium concentrations are associated with a reduced risk of aggressive disease, which warrants further investigation.

  • 3.
    Andrae, Bengt
    et al.
    Department of Obstetrics and Gynecology, Gävle Hospital, Gävle, Sweden.
    Kemetli, Levent
    Cancer Screening Unit, Oncologic Center M8, Karolinska University Hospital, Stockholm, Sweden.
    Sparén, Pär
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Silfverdal, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Strander, Björn
    Oncologic center, Western Region, Sahlgrenska University Hospital, Göteborg, Sweden .
    Ryd, Walter
    Department of Pathology and Clinical Cytology, Sahlgrenska University Hospital, Göteborg, Sweden .
    Dillner, Joakim
    Department of Medical Microbiology, Lund University, University Hospital, Malmö, Sweden.
    Törnberg, Sven
    Cancer Screening Unit, Oncologic Center M8, Karolinska University Hospital, Stockholm, Sweden.
    Screening-preventable cervical cancer risks: evidence from a nationwide audit in Sweden2008In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 100, no 9, p. 622-629Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The effectiveness of cervical cancer screening programs differs widely in different populations. The reasons for these differences are unclear. Routine and comprehensive audits have been proposed as an ethically required component of screening. We performed a nationwide audit of the effectiveness of the Swedish cervical cancer screening program.

    METHODS: We identified all invasive cervical cancer cases that were diagnosed in Sweden from January 1, 1999, through December 31, 2001, and had been reported to the Swedish Cancer Registry (n = 1230 cases). We verified the diagnoses by histopathologic rereview and matched each case subject to five (population-based) age-matched control subjects who were identified from the National Population Register. The Pap smear screening histories for case and control subjects were reviewed for a 6-year period using the National Cervical Cancer Screening Register, which contains data on essentially all relevant cytological and histological diagnoses in Sweden. Odds ratios (ORs), and their 95% confidence intervals (CIs), of cervical cancer according to screening history were calculated in conditional logistic regression models. All statistical tests were two-sided.

    RESULTS: Women who had not had a Pap smear within the recommended screening interval had higher risk of cervical cancer than women who had been screened (OR = 2.52, 95% CI = 2.19 to 2.91). This risk was similarly increased for all age groups (P(homogeneity) = .96). The risk for non-squamous cell cervical cancers (OR = 1.59, 95% CI = 1.20 to 2.11) was also increased. Women who had not had a Pap smear within the recommended screening interval had a particularly high risk of advanced cancers (OR = 4.82, 95% CI = 3.61 to 6.44). Among women who had been screened within the recommended interval, those with abnormal Pap smears had a higher risk of cervical cancer than those with normal smears (OR = 7.55, 95% CI = 5.88 to 9.69) and constituted 11.5% of all women with cervical cancer.

    CONCLUSIONS: Nonadherence to screening intervals was the major reason for cervical cancer morbidity. The screening program was equally effective for women of all ages and was also effective against non-squamous cancers.

  • 4. Bainbridge, Matthew N
    et al.
    Armstrong, Georgina N
    Gramatges, M Monica
    Bertuch, Alison A
    Jhangiani, Shalini N
    Doddapaneni, Harsha
    Lewis, Lora
    Tombrello, Joseph
    Tsavachidis, Spyros
    Liu, Yanhong
    Jalali, Ali
    Plon, Sharon E
    Lau, Ching C
    Parsons, Donald W
    Claus, Elizabeth B
    Barnholtz-Sloan, Jill
    Il'yasova, Dora
    Schildkraut, Joellen
    Ali-Osman, Francis
    Sadetzki, Siegal
    Johansen, Christoffer
    Houlston, Richard S
    Jenkins, Robert B
    Lachance, Daniel
    Olson, Sara H
    Bernstein, Jonine L.
    Merrell, Ryan T
    Wrensch, Margaret R
    Walsh, Kyle M
    Davis, Faith G
    Lai, Rose
    Shete, Sanjay
    Aldape, Kenneth
    Amos, Christopher I
    Thompson, Patricia A
    Muzny, Donna M
    Gibbs, Richard A
    Melin, Beatrice S
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bondy, Melissa L
    Germline mutations in shelterin complex genes are associated with familial glioma2015In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 107, no 1, article id dju384Article in journal (Refereed)
    Abstract [en]

    Gliomas are the most common brain tumor, with several histological subtypes of various malignancy grade. The genetic contribution to familial glioma is not well understood. Using whole exome sequencing of 90 individuals from 55 families, we identified two families with mutations in POT1 (p.G95C, p.E450X), a member of the telomere shelterin complex, shared by both affected individuals in each family and predicted to impact DNA binding and TPP1 binding, respectively. Validation in a separate cohort of 264 individuals from 246 families identified an additional mutation in POT1 (p.D617Efs), also predicted to disrupt TPP1 binding. All families with POT1 mutations had affected members with oligodendroglioma, a specific subtype of glioma more sensitive to irradiation. These findings are important for understanding the origin of glioma and could have importance for the future diagnostics and treatment of glioma.

  • 5. Barbus, Sebastian
    et al.
    Tews, Björn
    Karra, Daniela
    Hahn, Meinhard
    Radlwimmer, Bernhard
    Delhomme, Nicolas
    Hartmann, Christian
    Felsberg, Jörg
    Krex, Dietmar
    Schackert, Gabriele
    Martinez, Ramon
    Reifenberger, Guido
    Lichter, Peter
    Differential retinoic acid signaling in tumors of long- and short-term glioblastoma survivors.2011In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 103, no 7Article in journal (Refereed)
    Abstract [en]

    Although the prognosis of most glioblastoma patients is poor, 3%-5% patients show long-term survival of 36 months or longer after diagnosis. To study the differences in activation of biochemical pathways, we performed mRNA and protein expression analyses of primary glioblastoma tissues from 11 long-term survivors (LTS; overall survival ≥ 36 months) and 12 short-term survivors (STS; overall survival ≤ 6 months). The mRNA expression ratio of the retinoic acid transporters fatty acid-binding protein 5 (FABP5) and cellular retinoic acid-binding protein 2 (CRABP2), which regulate the differential delivery of retinoic acid to either antioncogenic retinoic acid receptors or prooncogenic nuclear receptor peroxisome proliferator-activated receptor delta, was statistically significantly higher in the tumor tissues of STS than those of LTS (median ratio in STS tumors = 3.64, 10th-90th percentile = 1.43-4.54 vs median ratio in LTS tumors = 1.42, 10th-90th percentile = -0.98 to 2.59; P < .001). High FABP5 protein expression in STS tumors was associated with highly proliferating tumor cells and activation of 3-phosphoinositide-dependent protein kinase-1 and v-akt murine thymoma viral oncogene homolog. The data suggest that retinoic acid signaling activates different targets in glioblastomas from LTS and STS. All statistical tests were two-sided.

  • 6. Bethke, Lara
    et al.
    Murray, Anne
    Webb, Emily
    Schoemaker, Minouk
    Muir, Kenneth
    McKinney, Patricia
    Hepworth, Sarah
    Dimitropoulou, Polyxeni
    Lophatananon, Artitaya
    Feychting, Maria
    Lönn, Stefan
    Ahlbom, Anders
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Auvinen, Anssi
    Kiuru, Anne
    Salminen, Tiina
    Johansen, Christoffer
    Collatz Christensen, Helle
    Kosteljanetz, Michael
    Swerdlow, Anthony
    Houlston, Richard
    Comprehensive analysis of DNA repair gene variants and risk of meningioma2008In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 100, no 4, p. 270-276Article in journal (Refereed)
    Abstract [en]

    Background: Meningiomas account for up to 37% of all primary brain tumors. Genetic susceptibility to meningioma is well established, with the risk among relatives of meningioma patients being approximately threefold higher than that in the general population. A relationship between risk of meningioma and exposure to ionizing radiation is also well known and led us to examine whether variants in DNA repair genes contribute to disease susceptibility.

    Methods: We analyzed 1127 tagging single-nucleotide polymorphisms (SNPs) that were selected to capture most of the common variation in 136 DNA repair genes in five case–control series (631 case patients and 637 control subjects) from four countries in Europe. We also analyzed 388 putative functional SNPs in these genes for their association with meningioma. All statistical tests were two-sided.

    Results: The SNP rs4968451, which maps to intron 4 of the gene that encodes breast cancer susceptibility gene 1–interacting protein 1, was consistently associated with an increased risk of developing meningioma. Across the five studies, the association was highly statistically significant (trend odds ratio = 1.57, 95% confidence interval = 1.28 to 1.93; Ptrend = 8.95 × 10−6; P = .009 after adjusting for multiple testing).

    Conclusions: We have identified a novel association between rs4968451 and meningioma risk. Because approximately 28% of the European population are carriers of at-risk genotypes for rs4968451, the variant is likely to make a substantial contribution to the development of meningioma.

  • 7. Boffetta, Paolo
    et al.
    Couto, Elisabeth
    Wichmann, Janine
    Ferrari, Pietro
    Trichopoulos, Dimitrios
    Bueno-de-Mesquita, H Bas
    van Duijnhoven, Fränzel J B
    Büchner, Frederike L
    Key, Tim
    Boeing, Heiner
    Nöthlings, Ute
    Linseisen, Jakob
    Gonzalez, Carlos A
    Overvad, Kim
    Nielsen, Michael R S
    Tjønneland, Anne
    Olsen, Anja
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Morois, Sophie
    Lagiou, Pagona
    Naska, Androniki
    Benetou, Vassiliki
    Kaaks, Rudolf
    Rohrmann, Sabine
    Panico, Salvatore
    Sieri, Sabina
    Vineis, Paolo
    Palli, Domenico
    van Gils, Carla H
    Peeters, Petra H
    Lund, Eiliv
    Brustad, Magritt
    Engeset, Dagrun
    Huerta, José María
    Rodríguez, Laudina
    Sánchez, Maria-José
    Dorronsoro, Miren
    Barricarte, Aurelio
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Manjer, Jonas
    Sonestedt, Emily
    Allen, Naomi E
    Bingham, Sheila
    Khaw, Kay-Tee
    Slimani, Nadia
    Jenab, Mazda
    Mouw, Traci
    Norat, Teresa
    Riboli, Elio
    Trichopoulou, Antonia
    Fruit and vegetable intake and overall cancer risk in the European prospective investigation into cancer and nutrition (EPIC)2010In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 102, no 8, p. 529-537Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: It is widely believed that cancer can be prevented by high intake of fruits and vegetables. However, inconsistent results from many studies have not been able to conclusively establish an inverse association between fruit and vegetable intake and overall cancer risk. METHODS: We conducted a prospective analysis of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to assess relationships between intake of total fruits, total vegetables, and total fruits and vegetables combined and cancer risk during 1992-2000. Detailed information on the dietary habit and lifestyle variables of the cohort was obtained. Cancer incidence and mortality data were ascertained, and hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox regression models. Analyses were also conducted for cancers associated with tobacco and alcohol after stratification for tobacco smoking and alcohol drinking. RESULTS: Of the initial 142 605 men and 335 873 women included in the study, 9604 men and 21 000 women were identified with cancer after a median follow-up of 8.7 years. The crude cancer incidence rates were 7.9 per 1000 person-years in men and 7.1 per 1000 person-years in women. Associations between reduced cancer risk and increased intake of total fruits and vegetables combined and total vegetables for the entire cohort were similar (200 g/d increased intake of fruits and vegetables combined, HR = 0.97, 95% CI = 0.96 to 0.99; 100 g/d increased intake of total vegetables, HR = 0.98, 95% CI = 0.97 to 0.99); intake of fruits showed a weaker inverse association (100 g/d increased intake of total fruits, HR = 0.99, 95% CI = 0.98 to 1.00). The reduced risk of cancer associated with high vegetable intake was restricted to women (HR = 0.98, 95% CI = 0.97 to 0.99). Stratification by alcohol intake suggested a stronger reduction in risk in heavy drinkers and was confined to cancers caused by smoking and alcohol. CONCLUSIONS: A very small inverse association between intake of total fruits and vegetables and cancer risk was observed in this study. Given the small magnitude of the observed associations, caution should be applied in their interpretation.

  • 8. Bratt, Ola
    et al.
    Drevin, Linda
    Akre, Olof
    Garmo, Hans
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Family History and Probability of Prostate Cancer, Differentiated by Risk Category: A Nationwide Population-Based Study2016In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 108, no 10, article id djw110Article in journal (Refereed)
    Abstract [en]

    Background: Familial prostate cancer risk estimates are inflated by clinically insignificant low-risk cancer, diagnosed after prostate-specific antigen testing. We provide age-specific probabilities of non-low-and high-risk prostate cancer. Methods: Fifty-one thousand, eight hundred ninety-seven brothers of 32 807 men with prostate cancer were identified in Prostate Cancer data Base Sweden (PCBaSe). Nelson-Aalen estimates with 95% confidence intervals (CIs) were calculated for cumulative, family history-stratified probabilities of any, non-low-(any of Gleason score >= 7, prostate-specific antigen [PSA] >= 10 ng/mL, T3-4, N1, and/or M1) and high-risk prostate cancer (Gleason score >= 8 and/or T3-4 and/or PSA >= 20 ng/mL and/or N1 and/or M1). Results: The population probability of any prostate cancer was 4.8% (95% CI = 4.8% to 4.9%) at age 65 years and 12.9% (95% CI = 12.8% to 12.9%) at age 75 years, of non-low-risk prostate cancer 2.8% (95% CI = 2.7% to 2.8%) at age 65 years and 8.9% (95% CI = 8.8% to 8.9%) at age 75 years, and of high-risk prostate cancer 1.4% (95% CI = 1.3% to 1.4%) at age 65 years and 5.2% (95% CI = 5.1% to 5.2%) at age 75 years. For men with one affected brother, probabilities of any prostate cancer were 14.9% (95% CI = 14.1% to 15.8%) at age 65 years and 30.3% (95% CI = 29.3% to 31.3%) at age 75 years, of non-low-risk prostate cancer 7.3% (95% CI = 6.7% to 7.9%) at age 65 years and 18.8% (95% CI = 17.9% to 19.6%) at age 75 years, and of high-risk prostate cancer 3.0% (95% CI = 2.6% to 3.4%) at age 65 years and 8.9% (95% CI = 8.2% to 9.5%) at age 75 years. Probabilities were higher for men with a stronger family history. For example, men with two affected brothers had a 13.6% (95% CI = 9.9% to 17.6 %) probability of high-risk cancer at age 75 years. Conclusions: The age-specific probabilities of non-low-and high-risk cancer presented here are more informative than relative risks of any prostate cancer and more suitable to use for counseling men with a family history of prostate cancer.

  • 9. Bratt, Ola
    et al.
    Garmo, Hans
    Adolfsson, Jan
    Bill-Axelson, Anna
    Holmberg, Lars
    Lambe, Mats
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Effects of prostate-specific antigen testing on familial prostate cancer risk estimates2010In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 102, no 17, p. 1336-1343Article in journal (Refereed)
    Abstract [en]

    Background Family history is a strong risk factor for prostate cancer. The aim of this study was to investigate whether increased diagnostic activity is related to the incidence of prostate cancer among brothers of men with prostate cancer.

    Methods Data were from the nationwide population-based Prostate Cancer Database Sweden (PCBaSe Sweden), which includes data from the National Prostate Cancer Register, the Swedish Cancer Register, the Register of the Total Population, the Multi-Generation Register, and the Census database. We investigated the relationship of tumor characteristics, time from diagnosis of the index patient (ie, prostate cancer patients in the National Prostate Cancer Register for whom at least one brother and their father could be identified), calendar period, geographic factors, and socioeconomic status to standardized incidence ratios (SIRs) for prostate cancer among 22 511 brothers of 13 975 index patients in PCBaSe Sweden.

    Results Brothers of index patients with prostate cancer were at increased risk for a diagnosis of prostate cancer (SIR = 3.1, 95% confidence interval [CI] = 2.9 to 3.3). Risk was higher for T1c tumors (SIR = 3.4, 95% CI = 3.2 to 3.8) than for metastatic tumors (SIR = 2.0, 95% CI = 1.5 to 2.6), and risk of T1c tumors was especially high during the first year after the diagnosis of the index patient (SIR = 4.3, 95% CI = 3.8 to 4.9), compared with the following years (SIR range = 2.8–3.3), and for brothers of index patients who had a higher socioeconomic status (SIR = 4.2, 95% CI = 3.7 to 4.7), compared with brothers of index patients with lower socioeconomic status (SIR = 2.8, 95% CI = 2.4 to 3.2).

    Conclusions Increased diagnostic activity among men with a family history of prostate cancer appears to contribute to their increased risk of prostate cancer and to lead to detection bias in epidemiological and genetic studies of familial prostate cancer.

  • 10. Campa, Daniele
    et al.
    Kaaks, Rudolf
    Le Marchand, Loic
    Haiman, Christopher A.
    Travis, Ruth C.
    Berg, Christine D.
    Buring, Julie E.
    Chanock, Stephen J.
    Diver, W. Ryan
    Dostal, Lucie
    Fournier, Agnes
    Hankinson, Susan E.
    Henderson, Brian E.
    Hoover, Robert N.
    Isaacs, Claudine
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. International Agency for Research on Cancer (IARC), Lyon, France.
    Kolonel, Laurence N.
    Kraft, Peter
    Lee, I-Min
    McCarty, Catherine A.
    Overvad, Kim
    Panico, Salvatore
    Peeters, Petra H. M.
    Riboli, Elio
    Jose Sanchez, Maria
    Schumacher, Fredrick R.
    Skeie, Guri
    Stram, Daniel O.
    Thun, Michael J.
    Trichopoulos, Dimitrios
    Zhang, Shumin
    Ziegler, Regina G.
    Hunter, David J.
    Lindstroem, Sara
    Canzian, Federico
    Interactions Between Genetic Variants and Breast Cancer Risk Factors in the Breast and Prostate Cancer Cohort Consortium2011In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 103, no 16, p. 1252-1263Article in journal (Refereed)
    Abstract [en]

    Background Recently, several genome-wide association studies have identified various genetic susceptibility loci for breast cancer. Relatively little is known about the possible interactions between these loci and the established risk factors for breast cancer. Methods To assess interactions between single-nucleotide polymorphisms (SNPs) and established risk factors, we prospectively collected DNA samples and questionnaire data from 8576 breast cancer case subjects and 11 892 control subjects nested within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). We genotyped 17 germline SNPs (FGFR2-rs2981582, FGFR2-rs3750817, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, CASP8-rs1045485, LSP1-rs3817198, COL1A1-rs2075555, COX11-rs6504950, RNF146-rs2180341, 6q25-rs2046210, SLC4A7-rs4973768, NOTCH2-rs11249433, 5p12-rs4415084, 5p12-rs10941679, RAD51L1-rs999737), and odds ratios were estimated by logistic regression to confirm previously reported associations with breast cancer risk. We performed likelihood ratio test to assess interactions between 17 SNPs and nine established risk factors (age at menarche, parity, age at menopause, use of hormone replacement therapy, family history, height, body mass index, smoking status, and alcohol consumption), and a correction for multiple testing of 153 tests (adjusted P value threshold = .05/153 = 3 x 10(-4)) was done. Casecase comparisons were performed for possible differential associations of polymorphisms by subgroups of tumor stage, estrogen and progesterone receptor status, and age at diagnosis. All statistical tests were two-sided. Results We confirmed the association of 14 SNPs with breast cancer risk (P(trend) = 2.57 x 10(-3) -3.96 x 10(-19)). Three SNPs (LSP1-rs3817198, COL1A1-rs2075555, and RNF146-rs2180341) did not show association with breast cancer risk. After accounting for multiple testing, no statistically significant interactions were detected between the 17 SNPs and the nine risk factors. We also confirmed that SNPs in FGFR2 and TNRC9 were associated with greater risk of estrogen receptor-positive than estrogen receptor-negative breast cancer (P(heterogeneity) = .0016 for FGFR2-rs2981582 and P(heterogeneity) = .0053 for TNRC9-rs3803662). SNP 5p12-rs10941679 was statistically significantly associated with greater risk of progesterone receptor-positive than progesterone receptor-negative breast cancer (P(heterogeneity) = .0028). Conclusion This study does not support the hypothesis that known common breast cancer susceptibility loci strongly modify the associations between established risk factors and breast cancer.

  • 11. Cao, Yin
    et al.
    Lindström, Sara
    Schumacher, Fredrick
    Stevens, Victoria L.
    Albanes, Demetrius
    Berndt, Sonja I.
    Boeing, Heiner
    Bueno-de-Mesquita, H. Bas
    Canzian, Federico
    Chamosa, Saioa
    Chanock, Stephen J.
    Diver, W. Ryan
    Gapstur, Susan M.
    Gaziano, J. Michael
    Giovannucci, Edward L.
    Haiman, Christopher A.
    Henderson, Brian
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer, Lyon, France.
    Le Marchand, Loïc
    Palli, Domenico
    Rosner, Bernard
    Siddiq, Afshan
    Stampfer, Meir
    Stram, Daniel O.
    Tamimi, Rulla
    Travis, Ruth C.
    Trichopoulos, Dimitrios
    Willett, Walter C.
    Yeager, Meredith
    Kraft, Peter
    Hsing, Ann W.
    Pollak, Michael
    Lin, Xihong
    Ma, Jing
    Insulin-like growth factor pathway genetic polymorphisms, circulating IGF1 and IGFBP3, and prostate cancer survival2014In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 106, no 5, article id dju218Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown.

    METHODS: Among 5887 PCa patients (704 PCa deaths) of European ancestry from seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, we conducted Cox kernel machine pathway analysis to evaluate whether 530 tagging single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes were collectively associated with PCa mortality. We also conducted SNP-specific analysis using stratified Cox models adjusting for multiple testing. In 2424 patients (313 PCa deaths), we evaluated the association of prediagnostic circulating IGF1 and IGFBP3 levels and PCa mortality. All statistical tests were two-sided.

    RESULTS: The IGF signaling pathway was associated with PCa mortality (P = .03), and IGF2-AS and SSTR2 were the main contributors (both P = .04). In SNP-specific analysis, 36 SNPs were associated with PCa mortality with P-trend less than .05, but only three SNPs in the IGF2-AS remained statistically significant after gene-based corrections. Two were in linkage disequilibrium (r(2) = 1 for rs1004446 and rs3741211), whereas the third, rs4366464, was independent (r(2) = 0.03). The hazard ratios (HRs) per each additional risk allele were 1.19 (95% confidence interval [CI] = 1.06 to 1.34; P-trend = .003) for rs3741211 and 1.44 (95% CI = 1.20 to 1.73; P-trend < .001) for rs4366464. rs4366464 remained statistically significant after correction for all SNPs (P-trend.corr = .04). Prediagnostic IGF1 (HRhighest (vs lowest quartile) = 0.71; 95% CI = 0.48 to 1.04) and IGFBP3 (HR = 0.93; 95% Cl = 0.65 to 1.34) levels were not associated with PCa mortality.

    CONCLUSIONS: The IGF signaling pathway, primarily IGF2-AS and SSTR2 genes, may be important in PCa survival.

  • 12. Crowe, Francesca L.
    et al.
    Appleby, Paul N.
    Travis, Ruth C.
    Barnett, Matt
    Brasky, Theodore M.
    Bueno-de-Mesquita, H. Bas
    Chajes, Veronique
    Chavarro, Jorge E.
    Chirlaque, Maria-Dolores
    English, Dallas R.
    Gibson, Robert A.
    Giles, Graham G.
    Goodman, Gary E.
    Henning, Susanne M.
    Kaaks, Rudolf
    King, Irena B.
    Kolonel, Lawrence N.
    Kristal, Alan R.
    Neuhouser, Marian L.
    Park, Song-Yi
    Severi, Gianluca
    Siddiq, Afshan
    Stampfer, Meir J.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Tangen, Catherine M.
    Tjonneland, Anne
    Trichopoulos, Dimitrios
    Tumino, Rosario
    Wilkens, Lynne R.
    Key, Timothy J.
    Allen, Naomi E.
    Circulating Fatty Acids and Prostate Cancer Risk: Individual Participant Meta-Analysis of Prospective Studies2014In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 106, no 9, p. dju240-Article, review/survey (Refereed)
    Abstract [en]

    Background

    Individual studies have suggested that some circulating fatty acids are associated with prostate cancer risk, but have not been large enough to provide precise estimates of associations, particularly by stage and grade of disease.

    Methods

    Principal investigators of prospective studies on circulating fatty acids and prostate cancer were invited to collaborate. Investigators provided individual participant data on circulating fatty acids (weight percent) and other characteristics of prostate cancer cases and controls. Prostate cancer risk by study-specific fifths of 14 fatty acids was estimated using multivariable-adjusted conditional logistic regression. All statistical tests were two-sided.

    Results

    Five thousand and ninety-eight case patients and 6649 control patients from seven studies with an average follow-up of 5.1 (SD = 3.3) years were included. Stearic acid (18: 0) was inversely associated with total prostate cancer (odds ratio [OR] Q5 vs Q1 = 0.88, 95% confidence interval [CI] = 0.78 to 1.00, P-trend = .043). Prostate cancer risk was, respectively, 14% and 16% greater in the highest fifth of eicosapentaenoic acid (20:5n-3) (OR = 1.14, 95% CI = 1.01 to 1.29, P-trend = .001) and docosapentaenoic acid (22: 5n-3) (OR = 1.16, 95% CI = 1.02 to 1.33, P-trend = .003), but in each case there was heterogeneity between studies (P = .022 and P < .001, respectively). There was heterogeneity in the association between docosapentaenoic acid and prostate cancer by grade of disease (P = .006); the association was statistically significant for low-grade disease but not high-grade disease. The remaining 11 fatty acids were not statistically associated with total prostate cancer risk.

    Conclusion

    There was no strong evidence that circulating fatty acids are important predictors of prostate cancer risk. It is not clear whether the modest associations of stearic, eicosapentaenoic, and docosapentaenoic acid are causal.

  • 13. de Batlle, J.
    et al.
    Ferrari, P.
    Chajes, V.
    Park, J. Y.
    Slimani, N.
    McKenzie, F.
    Overvad, K.
    Roswall, N.
    Tjønneland, A.
    Boutron-Ruault, M. C.
    Clavel-Chapelon, F.
    Fagherazzi, G.
    Katzke, V.
    Kaaks, R.
    Bergmann, M. M.
    Trichopoulou, A.
    Lagiou, P.
    Trichopoulos, D.
    Palli, D.
    Sieri, S.
    Panico, S.
    Tumino, R.
    Vineis, P.
    Bueno-de-Mesquita, H. B.
    Peeters, P. H.
    Hjartåker, A.
    Engeset, D.
    Weiderpass, E.
    Sánchez, S.
    Travier, N.
    Sanchez, M. J.
    Amiano, P.
    Chirlaque, M. D.
    Barricarte Gurrea, A.
    Khaw, K. T.
    Key, T. J.
    Bradbury, K. E.
    Ericson, U.
    Sonestedt, E.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Riboli, E.
    Romieu, I.
    Dietary folate intake and breast cancer risk: European prospective investigation into cancer and nutrition2015In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 107, no 1, article id dju367Article in journal (Refereed)
    Abstract [en]

    There is limited evidence on the association between dietary folate intake and the risk of breast cancer (BC) by hormone receptor expression in the tumors. We investigated the relationship between dietary folate and BC risk using data from the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 367993 women age 35 to 70 years were recruited in 10 European countries. During a median follow-up of 11.5 years, 11575 women with BC were identified. Dietary folate intake was estimated from country-specific dietary questionnaires. Cox proportional hazards regression models were used to quantify the association between dietary variables and BC risk. BC tumors were classified by receptor status. Subgroup analyses were performed by menopausal status and alcohol intake. Intake of other B vitamins was considered. All statistical tests were two-sided. A borderline inverse association was observed between dietary folate and BC risk (hazard ratio comparing top vs bottom quintile [HRQ5-Q1] = 0.92, 95% CI = 0.83 to 1.01, P (trend) = .037). In premenopausal women, we observed a statistically significant trend towards lower risk in estrogen receptor-negative BC (HRQ5-Q1 = 0.66, 95% CI = 0.45 to 0.96, P (trend) = .042) and progesterone receptor-negative BC (HRQ5-Q1 = 0.70, 95% CI = 0.51 to 0.97, P (trend) = .021). No associations were found in postmenopausal women. A 14% reduction in BC risk was observed when comparing the highest with the lowest dietary folate tertiles in women having a high (> 12 alcoholic drinks/week) alcohol intake (HRT3-T1 = 0.86, 95% CI = 0.75 to 0.98, P (interaction) = .035). Higher dietary folate intake may be associated with a lower risk of sex hormone receptor-negative BC in premenopausal women.

  • 14. Eliassen, A. Heather
    et al.
    Hendrickson, Sara J.
    Brinton, Louise A.
    Buring, Julie E.
    Campos, Hannia
    Dai, Qi
    Dorgan, Joanne F.
    Franke, Adrian A.
    Gao, Yu-tang
    Goodman, Marc T.
    Hallmans, Goeran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Helzlsouer, Kathy J.
    Hoffman-Bolton, Judy
    Hulten, Kerstin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sesso, Howard D.
    Sowell, Anne L.
    Tamimi, Rulla M.
    Toniolo, Paolo
    Wilkens, Lynne R.
    Winkvist, Anna
    Zeleniuch-Jacquotte, Anne
    Zheng, Wei
    Hankinson, Susan E.
    Circulating Carotenoids and Risk of Breast Cancer: Pooled Analysis of Eight Prospective Studies2012In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 104, no 24, p. 1905-1916Article in journal (Refereed)
    Abstract [en]

    Carotenoids, micronutrients in fruits and vegetables, may reduce breast cancer risk. Most, but not all, past studies of circulating carotenoids and breast cancer have found an inverse association with at least one carotenoid, although the specific carotenoid has varied across studies. We conducted a pooled analysis of eight cohort studies comprising more than 80% of the world's published prospective data on plasma or serum carotenoids and breast cancer, including 3055 case subjects and 3956 matched control subjects. To account for laboratory differences and examine population differences across studies, we recalibrated participant carotenoid levels to a common standard by reassaying 20 plasma or serum samples from each cohort together at the same laboratory. Using conditional logistic regression, adjusting for several breast cancer risk factors, we calculated relative risks (RRs) and 95% confidence intervals (CIs) using quintiles defined among the control subjects from all studies. All P values are two-sided. Statistically significant inverse associations with breast cancer were observed for -carotene (top vs bottom quintile RR 0.87, 95% CI 0.71 to 1.05, Ptrend .04), -carotene (RR 0.83, 95% CI 0.70 to 0.98, Ptrend .02), luteinzeaxanthin (RR 0.84, 95% CI 0.70 to 1.01, Ptrend .05), lycopene (RR 0.78, 95% CI 0.62 to 0.99, Ptrend .02), and total carotenoids (RR 0.81, 95% CI 0.68 to 0.96, Ptrend .01). -Cryptoxanthin was not statistically significantly associated with risk. Tests for heterogeneity across studies were not statistically significant. For several carotenoids, associations appeared stronger for estrogen receptor negative (ER) than for ER tumors (eg, -carotene: ER: top vs bottom quintile RR 0.52, 95% CI 0.36 to 0.77, Ptrend .001; ER: RR 0.83, 95% CI 0.66 to 1.04, Ptrend .06; Pheterogeneity .01). This comprehensive prospective analysis suggests women with higher circulating levels of -carotene, -carotene, luteinzeaxanthin, lycopene, and total carotenoids may be at reduced risk of breast cancer. 

  • 15. Fanidi, Anouar
    et al.
    Muller, David C
    Yuan, Jian-Min
    Stevens, Victoria L
    Weinstein, Stephanie J
    Albanes, Demetrius
    Prentice, Ross
    Thomsen, Cynthia A
    Pettinger, Mary
    Cai, Qiuyin
    Blot, William J
    Wu, Jie
    Arslan, Alan A
    Zeleniuch-Jacquotte, Anne
    McCullough, Marjorie L
    Le Marchand, Loic
    Wilkens, Lynne R
    Haiman, Christopher A
    Zhang, Xuehong
    Han, Jiali
    Stampfer, Meir J
    Smith-Warner, Stephanie A
    Giovannucci, Edward
    Giles, Graham G
    Hodge, Allison M
    Severi, Gianluca
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Langhammer, Arnulf
    Krokstad, Steinar
    Næss, Marit
    Wang, Renwei
    Gao, Yu-Tang
    Butler, Lesley M
    Koh, Woon-Puay
    Shu, Xiao-Ou
    Xiang, Yong-Bing
    Li, Honglan
    Zheng, Wei
    Lan, Qing
    Visvanathan, Kala
    Bolton, Judith Hoffman
    Ueland, Per Magne
    Midttun, Øivind
    Ulvik, Arve
    Caporaso, Neil E
    Purdue, Mark
    Ziegler, Regina G
    Freedman, Neal D
    Buring, Julie E
    Lee, I-Min
    Sesso, Howard D
    Gaziano, J Michael
    Manjer, Jonas
    Ericson, Ulrika
    Relton, Caroline
    Brennan, Paul
    Johansson, Mattias
    Circulating Folate, Vitamin B6, and Methionine in Relation to Lung Cancer Risk in the Lung Cancer Cohort Consortium (LC3)2018In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 110, no 1, article id djx119Article in journal (Refereed)
    Abstract [en]

    Background: Circulating concentrations of B vitamins and factors related to one-carbon metabolism have been found to be strongly inversely associated with lung cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The extent to which these associations are present in other study populations is unknown.

    Methods: Within 20 prospective cohorts from the National Cancer Institute Cohort Consortium, a nested case-control study was designed including 5364 incident lung cancer case patients and 5364 control subjects who were individually matched to case patients by age, sex, cohort, and smoking status. Centralized biochemical analyses were performed to measure circulating concentrations of vitamin B6, folate, and methionine, as well as cotinine as an indicator of recent tobacco exposure. The association between these biomarkers and lung cancer risk was evaluated using conditional logistic regression models.

    Results: Participants with higher circulating concentrations of vitamin B6 and folate had a modestly decreased risk of lung cancer risk overall, the odds ratios when comparing the top and bottom fourths (OR 4vs1 ) being 0.88 (95% confidence interval [CI] = 0.78 to 1.00) and 0.86 (95% CI = 0.74 to 0.99), respectively. We found stronger associations among men (vitamin B6: OR 4vs1 = 0.74, 95% CI = 0.62 to 0.89; folate: OR 4vs1 = 0.75, 95% CI = 0.61 to 0.93) and ever smokers (vitamin B6: OR 4vs1 = 0.78, 95% CI = 0.67 to 0.91; folate: OR 4vs1 = 0.87, 95% CI = 0.73 to 1.03). We further noted that the association of folate was restricted to Europe/Australia and Asia, whereas no clear association was observed for the United States. Circulating concentrations of methionine were not associated with lung cancer risk overall or in important subgroups.

    Conclusions: Although confounding by tobacco exposure or reverse causation cannot be ruled out, these study results are compatible with a small decrease in lung cancer risk in ever smokers who avoid low concentrations of circulating folate and vitamin B6.

  • 16. Hardell, Lennart
    et al.
    Carlberg, Michael
    Söderqvist, Fredrik
    Hansson Mild, Kjell
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Re: time trends in brain tumor incidence rates in Denmark, Finland, Norway, and Sweden, 1974-20032010In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 102, no 10, p. 740-742Article in journal (Refereed)
  • 17. Hellberg, Victoria
    et al.
    Wallin, Inger
    Eriksson, Sofi
    Hernlund, Emma
    Jerremalm, Elin
    Berndtsson, Maria
    Eksborg, Staffan
    Arnér, Elias SJ
    Shoshan, Maria
    Ehrsson, Hans
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Cisplatin and oxaliplatin toxicity: importance of cochlear kinetics as a determinant for ototoxicity2009In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 101, no 1, p. 37-47Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cisplatin is a cornerstone anticancer drug with pronounced ototoxicity, whereas oxaliplatin, a platinum derivative with a different clinical profile, is rarely ototoxic. This difference has not been explained.

    METHODS: In HCT-116 cells, cisplatin (20 microM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold), to 3.1-fold induction (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging from 9.3-fold (95% CI = 8.8- to 9.8-fold), to 5.1-fold (95% CI = 4.4- to 5.8-fold). A guinea pig model (n = 23) was used to examine pharmacokinetics. Drug concentrations were determined by liquid chromatography with post-column derivatization. The total platinum concentration in cochlear tissue was determined by inductively coupled plasma mass spectrometry. Drug pharmacokinetics was assessed by determining the area under the concentration-time curve (AUC). Statistical tests were two-sided.

    RESULTS: In HCT-116 cells, cisplatin (20 microM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold to 3.1-fold induction) (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging (from 9.3-fold, 95% CI = 8.8- to 9.8-fold, to 5.1-fold, 95% CI = 4.4- to 5.8-fold). Oxaliplatin (20 microM)-induced apoptosis was unaffected by calcium chelation (from 7.1- to 6.2-fold induction) and by superoxide scavenging (from 5.9- to 5.6-fold induction). In guinea pig cochlea, total platinum concentration (0.12 vs 0.63 microg/kg, respectively, P = .008) and perilymphatic drug concentrations (238 vs 515 microM x minute, respectively, P < .001) were lower after intravenous oxaliplatin treatment (16.6 mg/kg) than after equimolar cisplatin treatment (12.5 mg/kg). However, after a non-ototoxic cisplatin dose (5 mg/kg) or the same oxaliplatin dose (16.6 mg/kg), the AUC for perilymphatic concentrations was similar, indicating that the two drugs have different cochlear pharmacokinetics.

    CONCLUSION: Cisplatin- but not oxaliplatin-induced apoptosis involved superoxide-related pathways. Lower cochlear uptake of oxaliplatin than cisplatin appears to be a major explanation for its lower ototoxicity.

  • 18. Hjalgrim, Lisa Lyngsie
    et al.
    Rostgaard, Klaus
    Hjalgrim, Henrik
    Westergaard, Tine
    Thomassen, Harald
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Gustafsson, Göran
    Kristinsson, Jon
    Melbye, Mads
    Schmiegelow, Kjeld
    Birth weight and risk for childhood leukemia in Denmark, Sweden, Norway, and Iceland2004In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 96, no 20, p. 1549-1556Article in journal (Refereed)
    Abstract [en]

    Background: Compelling evidence suggests that childhood leukemia often originates in utero. Birth weight is one of the few pregnancy-related risk factors that has been associated with leukemia risk, but the association has remained poorly characterized. We conducted a population-based case-control stud-v in Denmark, Sweden, Norway, and Iceland to investigate the association between birth weight (and other birth characteristics) and the risk of childhood leukemia.

    Methods: Overall, 1905 children (aged 0-14 years) with acute lymphoblastic leukemia (ALL) and 299 children with acute myeloid leukemia (AML) diagnosed between January 1, 1984, and December 31, 1999, were identified in the Nordic Society of Paediatric Haematology and Oncology acute leukemia database. Each case patient was matched to five population control subjects (n = 1.0 745) on nationality, age, and sex. All live-born siblings of case patients (n = 3812) and control subjects (n = 17 937) were also identified in population registers. Information on birth weight and gestational age at birth was ascertained from the national Medical Birth Registers. The association between various birth characteristics and leukemia risk was assessed by conditional logistic regression. All statistical tests were two-sided.

    Results: Risk of ALL overall was statistically significantly associated with birth weight (odds ratio [OR] = 1.26 per 1-kg increase in birth weight, 95% confidence interval [CI] = 1.13 to 1.41). The association was similar for B- and T-lineage ALL and across all diagnostic ages (0-14 years). However, children with ALL did not weigh more at birth than their siblings. Statistically significantly reduced risks of B-precursor ALL were observed with increasing position in the birth order (OR = 0.90 per position increase, 95% CI = 0.84 to 0.96) and increasing gestational age (OR = 0.87 per 2-week increase in gestational age, 95% CI = 0.81 to 0.94). Risk of AML did not vary monotonically with birth weight, and low birth weight (<1500 g [i.e., 3.3 pounds]) was associated with the highest risk.

    Conclusion: Our results are compatible with the hypothesis that a high birth weight is associated with an increased risk of ALL.

  • 19.
    Johansson, Mattias
    et al.
    International Agency for Research on Cancer, Lyon, France.
    Fanidi, Anouar
    Muller, David C.
    Bassett, Julie K.
    Midttun, Oivind
    Vollset, Stein Emil
    Travis, Ruth C.
    Palli, Domenico
    Mattiello, Amalia
    Sieri, Sabina
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Weiderpass, Elisabete
    Skeie, Guri
    Gonzalez, Carlos A.
    Dorronsoro, Miren
    Peeters, Petra H.
    Bueno-de-Mesquita, H. B(as).
    Ros, Martine M.
    Ruault, Marie-Christine Boutron
    Fagherazzi, Guy
    Clavel, Francoise
    Sanchez, Maria-Jose
    Barricarte Gurrea, Aurelio
    Navarro, Carmen
    Ramon Quiros, J.
    Overvad, Kim
    Tjonneland, Anne
    Aleksandrova, Krassimira
    Vineis, Paolo
    Gunter, Marc J.
    Kaaks, Rudolf
    Giles, Graham
    Relton, Caroline
    Riboli, Elio
    Boeing, Heiner
    Ueland, Per Magne
    Severi, Gianluca
    Brennan, Paul
    Circulating Biomarkers of One-Carbon Metabolism in Relation to Renal Cell Carcinoma Incidence and Survival2014In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 106, no 12, article id dju327Article in journal (Refereed)
    Abstract [en]

    Background: The etiology of renal cell carcinoma (RCC) is only partially understood, but a metabolic component appears likely. We investigated biomarkers of one-carbon metabolism and RCC onset and survival. Methods: The European Prospective Investigation into Cancer and Nutrition (EPIC) recruited 385 747 participants with blood samples between 1992 and 2000, and this analysis included 556 RCC case-control pairs. A subsequent replication study included 144 case-control pairs nested within the Melbourne Collaborative Cohort Study (MCCS). Plasma concentrations of vitamin B2, vitamin B6, folate, vitamin B12, methionine and homocysteine were measured in prediagnostic samples and evaluated with respect to RCC risk using conditional and unconditional logistic regression models, and to all-cause mortality in RCC cases using Cox regression models. All statistical tests were two-sided. Results: EPIC participants with higher plasma concentrations of vitamin B6 had lower risk of RCC, the odds ratio comparing the 4th and 1st quartiles (OR4vs1) being 0.40 95% confidence interval [CI] = 0.28 to 0.57, P-trend < .001. We found similar results after adjusting for potential confounders (adjusted P-trend < .001). In survival analysis, the hazard ratio for all-cause mortality in RCC cases when comparing the 4th and 1st quartiles (HR4vs1) of vitamin B6 was 0.57 (95% CI = 0.37 to 0.87, P-trend < .001). Subsequent replication of these associations within the MCCS yielded very similar results for both RCC risk (OR4vs1 = 0.47, 95% CI = 0.23 to 0.99, P-trend = .07) and all-cause mortality (HR4vs1 = 0.56, 95% CI = 0.27 to 1.17, P-trend = .02). No association was evident for the other measured biomarkers. Conclusion: Study participants with higher circulating concentrations of vitamin B6 had lower risk of RCC and improved survival following diagnosis in two independent cohorts.

  • 20. Kaaks, R
    et al.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hallmans, G
    Stattin, P
    Plasma insulin-like growth factor-I, insulin-like growth factor-binding proteins, and prostate cancer risk: a prospective study - Response.2001In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 93, no 8, p. 650-651Article in journal (Refereed)
  • 21. Kyro, Cecilie
    et al.
    Olsen, Anja
    Landberg, Rikard
    Skeie, Guri
    Loft, Steffen
    Aman, Per
    Leenders, Max
    Dik, Vincent K.
    Siersema, Peter D.
    Pischon, Tobias
    Christensen, Jane
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Fagherazzi, Guy
    Cottet, Vanessa
    Kuehn, Tilman
    Chang-Claude, Jenny
    Boeing, Heiner
    Trichopoulou, Antonia
    Bamia, Christina
    Trichopoulos, Dimitrios
    Palli, Domenico
    Krogh, Vittorio
    Tumino, Rosario
    Vineis, Paolo
    Panico, Salvatore
    Peeters, Petra H.
    Weiderpass, Elisabete
    Bakken, Toril
    Asli, Lene Angell
    Argueelles, Marcial
    Jakszyn, Paula
    Sanchez, Maria-Jose
    Amiano, Pilar
    Huerta, Jose Maria
    Barricarte, Aurelio
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Khaw, Kay-Tee
    Wareham, Nick
    Key, Timothy J.
    Travis, Ruth C.
    Ferrari, Pietro
    Freisling, Heinz
    Jenab, Mazda
    Gunter, Marc J.
    Murphy, Neil
    Riboli, Eilo
    Tjonneland, Anne
    Bueno-de-Mesquita, H. B(as)
    Plasma Alkylresorcinols, Biomarkers of Whole-Grain Wheat and Rye Intake, and Incidence of Colorectal Cancer2014In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 106, no 1, p. djt352-Article in journal (Refereed)
    Abstract [en]

    Background Few studies have investigated the association between whole-grain intake and colorectal cancer. Because whole-grain intake estimation might be prone to measurement errors, more objective measures (eg, biomarkers) could assist in investigating such associations. Methods The association between alkylresorcinols, biomarkers of whole-grain rye and wheat intake, and colorectal cancer incidence were investigated using prediagnostic plasma samples from colorectal cancer case patients and matched control subjects nested within the European Prospective Investigation into Cancer and Nutrition. We included 1372 incident colorectal cancer case patients and 1372 individual matched control subjects and calculated the incidence rate ratios (IRRs) for overall and anatomical subsites of colorectal cancer using conditional logistic regression adjusted for potential confounders. Regional differences (Scandinavia, the Mediterranean, Central Europe) were also explored. Results High plasma total alkylresorcinol concentration was associated with lower incidence of distal colon cancer; the adjusted incidence rate ratio of distal colon cancer for the highest vs lowest quartile of plasma total alkylresorcinols was 0.48 (95% confidence interval [CI] = 0.28 to 0.83). An inverse association between plasma total alkylresorcinol concentrations and colon cancer was found for Scandinavian participants (IRR per doubling = 0.83; 95% CI = 0.70 to 0.98). However, plasma total alkylresorcinol concentrations were not associated with overall colorectal cancer, proximal colon cancer, or rectal cancer. Plasma alkylresorcinols concentrations were associated with colon and distal colon cancer only in Central Europe and Scandinavia (ie, areas where alkylresorcinol levels were higher). Conclusions High concentrations of plasma alkylresorcinols were associated with a lower incidence of distal colon cancer but not with overall colorectal cancer, proximal colon cancer, and rectal cancer.

  • 22.
    Lindmark, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Zheng, S Lilly
    Wiklund, Fredrik
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Bensen, Jeannette
    Augustsson Bälter, Katarina
    Chang, Baoli
    Hedelin, Maria
    Clark, Jonathan
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Meyers, Deborah A
    Adami, Hans-Olov
    Isaacs, William
    Grönberg, Henrik
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Xu, Jianfeng
    H6D polymorphism in macrophage-inhibitory cytokine-1 gene associated with prostate cancer2004In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 96, no 16, p. 1248-1254Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Accumulating epidemiologic and molecular evidence suggest that inflammation is an important component in the etiology of prostate cancer. Macrophage-inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor beta superfamily, is thought to play an important role in inflammation by regulating macrophage activity. We examined whether sequence variants in the MIC-1 gene are associated with the risk of prostate cancer. METHODS: The study population, a population-based case-control study in Sweden, consisted of 1383 prostate cancer case patients and 780 control subjects. From 94 of the control subjects, we constructed gene-specific haplotypes of MIC-1 and identified four haplotype-tagging single-nucleotide polymorphisms (SNPs): Exon1+25 (V9L), Exon1+142 (S48T), IVS1+1809, and Exon2+2423 (H6D). All study subjects were genotyped for the four SNPs, and conditional logistic regression analysis was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: A statistically significant difference (P =.006) in genotype frequency was observed for the nonsynonymous change H6D (histidine to aspartic acid at position 6) between prostate cancer patients and control subjects. Carriers of the GC genotype, which results in the H6D change, experienced a lower risk of sporadic prostate cancer (OR = 0.80, 95% CI = 0.66 to 0.97) and of familial prostate cancer (OR = 0.61, 95% CI = 0.42 to 0.89) than the CC genotype carriers. In the study population, the proportion of prostate cancer cases attributable to the CC genotype was 7.2% for sporadic cancer and 19.2% for familial cancer. None of the other SNPs or haplotypes was associated with prostate cancer. CONCLUSION: This study shows an association between a nonsynonymous change (H6D) in the MIC-1 gene and prostate cancer. This finding supports the hypothesis that genetic variation in the inflammatory process contributes to prostate cancer susceptibility.

  • 23. Loeb, Stacy
    et al.
    Ventimiglia, Eugenio
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Division of Experimental Oncology, Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy; Universita Vita-Salute San Raffaele, Milan, Italy.
    Salonia, Andrea
    Folkvaljon, Yasin
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden .
    Meta-Analysis of the Association Between Phosphodiesterase Inhibitors (PDE5Is) and Risk of Melanoma2017In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 109, no 8, article id djx086Article in journal (Refereed)
    Abstract [en]

    The US Food and Drug Administration recently announced the need to evaluate the association between PDE5is and melanoma. We performed a meta-analysis on the association between PDE5i and melanoma using random effects models and examined whether it met Hill's criteria for causality. A systematic search of Medline, EMBASE, and the Cochrane Library from 1998 to 2016 identified three case-control studies and two cohort studies, including a total of 866 049 men, of whom 41 874 were diagnosed with melanoma. We found a summary estimate indicating an increased risk of melanoma in PDE5i users (relative risk = 1.12, 95% confidence interval = 1.02 to 1.23). However, there was no difference in risk between men with low and high exposure to PDE5i, and risk was higher for in situ melanoma than localized and high-risk melanoma, suggesting a lack of dose response and biological gradient. PDE5i use was also associated with basal cell cancer, suggesting a lack of specificity and likely confounding by ultraviolet exposure. Thus, although this meta-analysis found a statistically significant association between PDE5i and melanoma, it did not satisfy Hill's criteria for causality.

  • 24. Makarov, Danil V.
    et al.
    Loeb, Stacy
    Ulmert, David
    Drevin, Linda
    Lambe, Mats
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Prostate Cancer Imaging Trends After a Nationwide Effort to Discourage Inappropriate Prostate Cancer Imaging2013In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 105, no 17, p. 1306-1313Article in journal (Refereed)
    Abstract [en]

    Background: Reducing inappropriate use of imaging to stage incident prostate cancer is a challenging problem highlighted recently as a Physician Quality Reporting System quality measure and by the American Society of Clinical Oncology and the American Urological Association in the Choosing Wisely campaign. Since 2000, the National Prostate Cancer Register (NPCR) of Sweden has led an effort to decrease national rates of inappropriate prostate cancer imaging by disseminating utilization data along with the latest imaging guidelines to urologists in Sweden. We sought to determine the temporal and regional effects of this effort on prostate cancer imaging rates.

    Methods: We performed a retrospective cohort study among men diagnosed with prostate cancer from the NPCR from 1998 to 2009 (n = 99 879). We analyzed imaging use over time stratified by clinical risk category (low, intermediate, high) and geographic region. Generalized linear models with a logit link were used to test for time trend.

    Results: Thirty-six percent of men underwent imaging within 6 months of prostate cancer diagnosis. Overall, imaging use decreased over time, particularly in the low-risk category, among whom the imaging rate decreased from 45% to 3% (P < .001), but also in the high-risk category, among whom the rate decreased from 63% to 47% (P < .001). Despite substantial regional variation, all regions experienced clinically and statistically (P < .001) significant decreases in prostate cancer imaging.

    Conclusions: A Swedish effort to provide data on prostate cancer imaging use and imaging guidelines to clinicians was associated with a reduction in inappropriate imaging over a 10-year period, as well as slightly decreased appropriate imaging in high-risk patients. These results may inform current efforts to promote guideline-concordant imaging in the United States and internationally.

  • 25. Naucler, Pontus
    et al.
    Ryd, Walter
    Törnberg, Sven
    Strand, Anders
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Elfgren, Kristina
    Rådberg, Thomas
    Strander, Björn
    Forslund, Ola
    Hansson, Bengt-Göran
    Hagmar, Björn
    Johansson, Bo
    Rylander, Eva
    Dillner, Joakim
    Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening.2009In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 101, no 2, p. 88-99Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Primary cervical screening with both human papillomavirus (HPV) DNA testing and cytological examination of cervical cells with a Pap test (cytology) has been evaluated in randomized clinical trials. Because the vast majority of women with positive cytology are also HPV DNA positive, screening strategies that use HPV DNA testing as the primary screening test may be more effective. METHODS: We used the database from the intervention arm (n = 6,257 women) of a population-based randomized trial of double screening with cytology and HPV DNA testing to evaluate the efficacy of 11 possible cervical screening strategies that are based on HPV DNA testing alone, cytology alone, and HPV DNA testing combined with cytology among women aged 32-38 years. The main outcome measures were sensitivity for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) within 6 months of enrollment or at colposcopy for women with a persistent type-specific HPV infection and the number of screening tests and positive predictive value (PPV) for each screening strategy. All statistical tests were two-sided. RESULTS: Compared with screening by cytology alone, double testing with cytology and for type-specific HPV persistence resulted in a 35% (95% confidence interval [CI] = 15% to 60%) increase in sensitivity to detect CIN3+, without a statistically significant reduction in the PPV (relative PPV = 0.76, 95% CI = 0.52 to 1.10), but with more than twice as many screening tests needed. Several strategies that incorporated screening for high-risk HPV subtypes were explored, but they resulted in reduced PPV compared with cytology. Compared with cytology, primary screening with HPV DNA testing followed by cytological triage and repeat HPV DNA testing of HPV DNA-positive women with normal cytology increased the CIN3+ sensitivity by 30% (95% CI = 9% to 54%), maintained a high PPV (relative PPV = 0.87, 95% CI = 0.60 to 1.26), and resulted in a mere 12% increase in the number of screening tests (from 6,257 to 7,019 tests). CONCLUSIONS: Primary HPV DNA-based screening with cytology triage and repeat HPV DNA testing of cytology-negative women appears to be the most feasible cervical screening strategy.

  • 26. Rinaldi, Sabina
    et al.
    Plummer, Martyn
    Biessy, Carine
    Tsilidis, Konstantinos K.
    Nautrup Østergaard, Jane
    Overvad, Kim
    Tjønneland, Anne
    Halkjaer, Jytte
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Dossus, Laure
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Boeing, Heiner
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Palli, Domenico
    Agnoli, Claudia
    Tumino, Rosario
    Vineis, Paolo
    Panico, Salvatore
    Bueno-de-Mesquita, H. Bas
    Peeters, Petra H.
    Weiderpass, Elisabete
    Lund, Eiliv
    Quirós, J. Ramón
    Agudo, Antonio
    Molina, Esther
    Larrañaga, Nerea
    Navarro, Carmen
    Ardanaz, Eva
    Manjer, Jonas
    Almquist, Martin
    Sandström, Maria
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hennings, Joakim
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Khaw, Kay-Tee
    Schmidt, Julie
    Travis, Ruth C.
    Byrnes, Graham
    Scalbert, Augustin
    Romieu, Isabelle
    Gunter, Marc
    Riboli, Elio
    Franceschi, Silvia
    Thyroid-stimulating hormone, thyroglobulin, and thyroid hormones and risk of differentiated thyroid carcinoma: the EPIC study2014In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 106, no 6, p. dju097-Article in journal (Refereed)
    Abstract [en]

    Background Increased levels of thyroglobulin (Tg) and thyroid-stimulating hormone (TSH) are associated with differentiated thyroid carcinoma (TC) risk, but strong epidemiological evidence is lacking. Methods Three hundred fifty-seven incident TC case patients (n = 300 women and 57 men; mean age at blood collection = 51.5 years) were identified in the EPIC cohort study and matched with 2 (women) or 3 (men) control subjects using incidence density sampling. Matching included study center, sex, age, date, time, and fasting status at blood collection. Levels of total and free (f) thyroxine (T4) and triiodo-thyronine (T3), TSH, Tg, and anti-Tg antibodies (TgAb) were measured by commercially available immunoassays. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using conditional logistic regression. All statistical tests were two-sided. Results TC risk was positively associated with Tg (OR for the highest vs lowest quartile = 9.15; 95% CI = 5.28 to 15.90; P < .001) and negatively associated with TSH level (OR = 0.56; 95% CI = 0.38 to 0.81; P = .001). Odds ratios were not modified by adjustment for weight and height and were consistent across sexes, age groups, and countries. The association with Tg was stronger in follicular than papillary TC. The odds ratio for TgAb-positivity was 1.50 (95% CI = 1.05 to 2.15; P = .03). Among case patients, TSH level was stable over time, whereas Tg level was higher in proximity to TC diagnosis. Areas under the receiver operating characteristic curve were 57% and 74% for TSH and Tg level, respectively. Conclusions High Tg levels precede by up to 8 years the detection of TC, pointing to a long sojourn time of the disease. Low TSH levels may predispose to TC onset. Neither marker has sufficient accuracy to be a screening test.

  • 27. Sampson, Joshua N.
    et al.
    Wheeler, William A.
    Yeager, Meredith
    Panagiotou, Orestis
    Wang, Zhaoming
    Berndt, Sonja I.
    Lan, Qing
    Abnet, Christian C.
    Amundadottir, Laufey T.
    Figueroa, Jonine D.
    Landi, Maria Teresa
    Mirabello, Lisa
    Savage, Sharon A.
    Taylor, Philip R.
    De Vivo, Immaculata
    McGlynn, Katherine A.
    Purdue, Mark P.
    Rajaraman, Preetha
    Adami, Hans-Olov
    Ahlbom, Anders
    Albanes, Demetrius
    Amary, Maria Fernanda
    An, She-Juan
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andriole, Gerald, Jr.
    Andrulis, Irene L.
    Angelucci, Emanuele
    Ansell, Stephen M.
    Arici, Cecilia
    Armstrong, Bruce K.
    Arslan, Alan A.
    Austin, Melissa A.
    Baris, Dalsu
    Barkauskas, Donald A.
    Bassig, Bryan A.
    Becker, Nikolaus
    Benavente, Yolanda
    Benhamou, Simone
    Berg, Christine
    Van Den Berg, David
    Bernstein, Leslie
    Bertrand, Kimberly A.
    Birmann, Brenda M.
    Black, Amanda
    Boeing, Heiner
    Boffetta, Paolo
    Boutron-Ruault, Marie-Christine
    Bracci, Paige M.
    Brinton, Louise
    Brooks-Wilson, Angela R.
    Bueno-de-Mesquita, H. Bas
    Burdett, Laurie
    Buring, Julie
    Butler, Mary Ann
    Cai, Qiuyin
    Cancel-Tassin, Geraldine
    Canzian, Federico
    Carrato, Alfredo
    Carreon, Tania
    Carta, Angela
    Chan, John K. C.
    Chang, Ellen T.
    Chang, Gee-Chen
    Chang, I-Shou
    Chang, Jiang
    Chang-Claude, Jenny
    Chen, Chien-Jen
    Chen, Chih-Yi
    Chen, Chu
    Chen, Chung-Hsing
    Chen, Constance
    Chen, Hongyan
    Chen, Kexin
    Chen, Kuan-Yu
    Chen, Kun-Chieh
    Chen, Ying
    Chen, Ying-Hsiang
    Chen, Yi-Song
    Chen, Yuh-Min
    Chien, Li-Hsin
    Chirlaque, Maria-Dolores
    Choi, Jin Eun
    Choi, Yi Young
    Chow, Wong-Ho
    Chung, Charles C.
    Clavel, Jacqueline
    Clavel-Chapelon, Franoise
    Cocco, Pierluigi
    Colt, Joanne S.
    Comperat, Eva
    Conde, Lucia
    Connors, Joseph M.
    Conti, David
    Cortessis, Victoria K.
    Cotterchio, Michelle
    Cozen, Wendy
    Crouch, Simon
    Crous-Bou, Marta
    Cussenot, Olivier
    Davis, Faith G.
    Ding, Ti
    Diver, W. Ryan
    Dorronsoro, Miren
    Dossus, Laure
    Duell, Eric J.
    Ennas, Maria Grazia
    Erickson, Ralph L.
    Feychting, Maria
    Flanagan, Adrienne M.
    Foretova, Lenka
    Fraumeni, Joseph F., Jr.
    Freedman, Neal D.
    Freeman, Laura E. Beane
    Fuchs, Charles
    Gago-Dominguez, Manuela
    Gallinger, Steven
    Gao, Yu-Tang
    Gapstur, Susan M.
    Garcia-Closas, Montserrat
    Garcia-Closas, Reina
    Gascoyne, Randy D.
    Gastier-Foster, Julie
    Gaudet, Mia M.
    Gaziano, J. Michael
    Giffen, Carol
    Giles, Graham G.
    Giovannucci, Edward
    Glimelius, Bengt
    Goggins, Michael
    Gokgoz, Nalan
    Goldstein, Alisa M.
    Gorlick, Richard
    Gross, Myron
    Grubb, Robert, III
    Gu, Jian
    Guan, Peng
    Gunter, Marc
    Guo, Huan
    Habermann, Thomas M.
    Haiman, Christopher A.
    Halai, Dina
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hassan, Manal
    Hattinger, Claudia
    He, Qincheng
    He, Xingzhou
    Helzlsouer, Kathy
    Henderson, Brian
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hjalgrim, Henrik
    Hoffman-Bolton, Judith
    Hohensee, Chancellor
    Holford, Theodore R.
    Holly, Elizabeth A.
    Hong, Yun-Chul
    Hoover, Robert N.
    Horn-Ross, Pamela L.
    Hosain, G. M. Monawar
    Hosgood, H. Dean, III
    Hsiao, Chin-Fu
    Hu, Nan
    Hu, Wei
    Hu, Zhibin
    Huang, Ming-Shyan
    Huerta, Jose-Maria
    Hung, Jen-Yu
    Hutchinson, Amy
    Inskip, Peter D.
    Jackson, Rebecca D.
    Jacobs, Eric J.
    Jenab, Mazda
    Jeon, Hyo-Sung
    Ji, Bu-Tian
    Jin, Guangfu
    Jin, Li
    Johansen, Christoffer
    Johnson, Alison
    Jung, Yoo Jin
    Kaaks, Rudolph
    Kamineni, Aruna
    Kane, Eleanor
    Kang, Chang Hyun
    Karagas, Margaret R.
    Kelly, Rachel S.
    Khaw, Kay-Tee
    Kim, Christopher
    Kim, Hee Nam
    Kim, Jin Hee
    Kim, Jun Suk
    Kim, Yeul Hong
    Kim, Young Tae
    Kim, Young-Chul
    Kitahara, Cari M.
    Klein, Alison P.
    Klein, Robert J.
    Kogevinas, Manolis
    Kohno, Takashi
    Kolonel, Laurence N.
    Kooperberg, Charles
    Kricker, Anne
    Krogh, Vittorio
    Kunitoh, Hideo
    Kurtz, Robert C.
    Kweon, Sun-Seog
    LaCroix, Andrea
    Lawrence, Charles
    Lecanda, Fernando
    Lee, Victor Ho Fun
    Li, Donghui
    Li, Haixin
    Li, Jihua
    Li, Yao-Jen
    Li, Yuqing
    Liao, Linda M.
    Liebow, Mark
    Lightfoot, Tracy
    Lim, Wei-Yen
    Lin, Chien-Chung
    Lin, Dongxin
    Lindstrom, Sara
    Linet, Martha S.
    Link, Brian K.
    Liu, Chenwei
    Liu, Jianjun
    Liu, Li
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lloreta, Josep
    Di Lollo, Simonetta
    Lu, Daru
    Lund, Eiluv
    Malats, Nuria
    Mannisto, Satu
    Le Marchand, Loic
    Marina, Neyssa
    Masala, Giovanna
    Mastrangelo, Giuseppe
    Matsuo, Keitaro
    Maynadie, Marc
    Mckay, James
    McKean-Cowdin, Roberta
    Melbye, Mads
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Michaud, Dominique S.
    Mitsudomi, Tetsuya
    Monnereau, Alain
    Montalvan, Rebecca
    Moore, Lee E.
    Mortensen, Lotte Maxild
    Nieters, Alexandra
    North, Kari E.
    Novak, Anne J.
    Oberg, Ann L.
    Offit, Kenneth
    Oh, In-Jae
    Olson, Sara H.
    Palli, Domenico
    Pao, William
    Park, In Kyu
    Park, Jae Yong
    Park, Kyong Hwa
    Patino-Garcia, Ana
    Pavanello, Sofia
    Peeters, Petra H. M.
    Perng, Reury-Perng
    Peters, Ulrike
    Petersen, Gloria M.
    Picci, Piero
    Pike, Malcolm C.
    Porru, Stefano
    Prescott, Jennifer
    Prokunina-Olsson, Ludmila
    Qian, Biyun
    Qiao, You-Lin
    Rais, Marco
    Riboli, Elio
    Riby, Jacques
    Risch, Harvey A.
    Rizzato, Cosmeri
    Rodabough, Rebecca
    Roman, Eve
    Roupret, Morgan
    Ruder, Avima M.
    de Sanjose, Silvia
    Scelo, Ghislaine
    Schned, Alan
    Schumacher, Fredrick
    Schwartz, Kendra
    Schwenn, Molly
    Scotlandi, Katia
    Seow, Adeline
    Serra, Consol
    Serra, Massimo
    Sesso, Howard D.
    Setiawan, Veronica Wendy
    Severi, Gianluca
    Severson, Richard K.
    Shanafelt, Tait D.
    Shen, Hongbing
    Shen, Wei
    Shin, Min-Ho
    Shiraishi, Kouya
    Shu, Xiao-Ou
    Siddiq, Afshan
    Sierrasesumaga, Luis
    Sihoe, Alan Dart Loon
    Skibola, Christine F.
    Smith, Alex
    Smith, Martyn T.
    Southey, Melissa C.
    Spinelli, John J.
    Staines, Anthony
    Stampfer, Meir
    Stern, Marianna C.
    Stevens, Victoria L.
    Stolzenberg-Solomon, Rachael S.
    Su, Jian
    Su, Wu-Chou
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sung, Jae Sook
    Sung, Sook Whan
    Tan, Wen
    Tang, Wei
    Tardon, Adonina
    Thomas, David
    Thompson, Carrie A.
    Tinker, Lesley F.
    Tirabosco, Roberto
    Tjonneland, Anne
    Travis, Ruth C.
    Trichopoulos, Dimitrios
    Tsai, Fang-Yu
    Tsai, Ying-Huang
    Tucker, Margaret
    Turner, Jenny
    Vajdic, Claire M.
    Vermeulen, Roel C. H.
    Villano, Danylo J.
    Vineis, Paolo
    Virtamo, Jarmo
    Visvanathan, Kala
    Wactawski-Wende, Jean
    Wang, Chaoyu
    Wang, Chih-Liang
    Wang, Jiu-Cun
    Wang, Junwen
    Wei, Fusheng
    Weiderpass, Elisabete
    Weiner, George J.
    Weinstein, Stephanie
    Wentzensen, Nicolas
    White, Emily
    Witzig, Thomas E.
    Wolpin, Brian M.
    Wong, Maria Pik
    Wu, Chen
    Wu, Guoping
    Wu, Junjie
    Wu, Tangchun
    Wu, Wei
    Wu, Xifeng
    Wu, Yi-Long
    Wunder, Jay S.
    Xiang, Yong-Bing
    Xu, Jun
    Xu, Ping
    Yang, Pan-Chyr
    Yang, Tsung-Ying
    Ye, Yuanqing
    Yin, Zhihua
    Yokota, Jun
    Yoon, Ho-Il
    Yu, Chong-Jen
    Yu, Herbert
    Yu, Kai
    Yuan, Jian-Min
    Zelenetz, Andrew
    Zeleniuch-Jacquotte, Anne
    Zhang, Xu-Chao
    Zhang, Yawei
    Zhao, Xueying
    Zhao, Zhenhong
    Zheng, Hong
    Zheng, Tongzhang
    Zheng, Wei
    Zhou, Baosen
    Zhu, Meng
    Zucca, Mariagrazia
    Boca, Simina M.
    Cerhan, James R.
    Ferri, Giovanni M.
    Hartge, Patricia
    Hsiung, Chao Agnes
    Magnani, Corrado
    Miligi, Lucia
    Morton, Lindsay M.
    Smedby, Karin E.
    Teras, Lauren R.
    Vijai, Joseph
    Wang, Sophia S.
    Brennan, Paul
    Caporaso, Neil E.
    Hunter, David J.
    Kraft, Peter
    Rothman, Nathaniel
    Silverman, Debra T.
    Slager, Susan L.
    Chanock, Stephen J.
    Chatterjee, Nilanjan
    Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types2015In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 107, no 12, article id djv279Article in journal (Refereed)
    Abstract [en]

    Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.

    Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.

    Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.

    Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

  • 28. Schmit, Stephanie L.
    et al.
    Edlund, Christopher K.
    Schumacher, Fredrick R.
    Gong, Jian
    Harrison, Tabitha A.
    Huyghe, Jeroen R.
    Qu, Chenxu
    Melas, Marilena
    Van den Berg, David J.
    Wang, Hansong
    Tring, Stephanie
    Plummer, Sarah J.
    Albanes, Demetrius
    Alonso, M. Henar
    Amos, Christopher I.
    Anton, Kristen
    Aragaki, Aaron K.
    Arndt, Volker
    Barry, Elizabeth L.
    Berndt, Sonja I.
    Bezieau, Stephane
    Bien, Stephanie
    Bloomer, Amanda
    Boehm, Juergen
    Boutron-Ruault, Marie-Christine
    Brenner, Hermann
    Brezina, Stefanie
    Buchanan, Daniel D.
    Butterbach, Katja
    Caan, Bette J.
    Campbell, Peter T.
    Carlson, Christopher S.
    Castelao, Jose E.
    Chan, Andrew T.
    Chang-Claude, Jenny
    Chanock, Stephen J.
    Cheng, Iona
    Cheng, Ya-Wen
    Chin, Lee Soo
    Church, James M.
    Church, Timothy
    Coetzee, Gerhard A.
    Cotterchio, Michelle
    Correa, Marcia Cruz
    Curtis, Keith R.
    Duggan, David
    Easton, Douglas F.
    English, Dallas
    Feskens, Edith J. M.
    Fischer, Rocky
    FitzGerald, Liesel M.
    Fortini, Barbara K.
    Fritsche, Lars G.
    Fuchs, Charles S.
    Gago-Dominguez, Manuela
    Gala, Manish
    Gallinger, Steven J.
    Gauderman, W. James
    Giles, Graham G.
    Giovannucci, Edward L.
    Gogarten, Stephanie M.
    Gonzalez-Villalpando, Clicerio
    Gonzalez-Villalpando, Elena M.
    Grady, William M.
    Greenson, Joel K.
    Gsur, Andrea
    Gunter, Marc
    Haiman, Christopher A.
    Hampe, Jochen
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Harju, John F.
    Hayes, Richard B.
    Hofer, Philipp
    Hoffmeister, Michael
    Hopper, John L.
    Huang, Shu-Chen
    Huerta, Jose Maria
    Hudson, Thomas J.
    Hunter, David J.
    Idos, Gregory E.
    Iwasaki, Motoki
    Jackson, Rebecca D.
    Jacobs, Eric J.
    Jee, Sun Ha
    Jenkins, Mark A.
    Jia, Wei-Hua
    Jiao, Shuo
    Joshi, Amit D.
    Kolonel, Laurence N.
    Kono, Suminori
    Kooperberg, Charles
    Krogh, Vittorio
    Kuehn, Tilman
    Kury, Sebastien
    LaCroix, Andrea
    Laurie, Cecelia A.
    Lejbkowicz, Flavio
    Lemire, Mathieu
    Lenz, Heinz-Josef
    Levine, David
    Li, Christopher I.
    Li, Li
    Lieb, Wolfgang
    Lin, Yi
    Lindor, Noralane M.
    Liu, Yun-Ru
    Loupakis, Fotios
    Lu, Yingchang
    Luh, Frank
    Ma, Jing
    Mancao, Christoph
    Manion, Frank J.
    Markowitz, Sanford D.
    Martin, Vicente
    Matsuda, Koichi
    Matsuo, Keitaro
    McDonnell, Kevin J.
    McNeil, Caroline E.
    Milne, Roger
    Molina, Antonio J.
    Mukherjee, Bhramar
    Murphy, Neil
    Newcomb, Polly A.
    Offit, Kenneth
    Omichessan, Hanane
    Palli, Domenico
    Cotore, Jesus P. Paredes
    Perez-Mayoral, Julyann
    Pharoah, Paul D.
    Potter, John D.
    Qu, Conghui
    Raskin, Leon
    Rennert, Gad
    Rennert, Hedy S.
    Riggs, Bridget M.
    Schafmayer, Clemens
    Schoen, Robert E.
    Sellers, Thomas A.
    Seminara, Daniela
    Severi, Gianluca
    Shi, Wei
    Shibata, David
    Shu, Xiao-Ou
    Siegel, Erin M.
    Slattery, Martha L.
    Southey, Melissa
    Stadler, Zsofia K.
    Stern, Mariana C.
    Stintzing, Sebastian
    Taverna, Darin
    Thibodeau, Stephen N.
    Thomas, Duncan C.
    Trichopoulou, Antonia
    Tsugane, Shoichiro
    Ulrich, Cornelia M.
    van Duijnhoven, Franzel J. B.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Vijai, Joseph
    Virtamo, Jarmo
    Weinstein, Stephanie J.
    White, Emily
    Win, Aung Ko
    Wolk, Alicja
    Woods, Michael
    Wu, Anna H.
    Wu, Kana
    Xiang, Yong-Bing
    Yen, Yun
    Zanke, Brent W.
    Zeng, Yi-Xin
    Zhang, Ben
    Zubair, Niha
    Kweon, Sun-Seog
    Figueiredo, Jane C.
    Zheng, Wei
    Le Marchand, Loic
    Lindblom, Annika
    Moreno, Victor
    Peters, Ulrike
    Casey, Graham
    Hsu, Li
    Conti, David V.
    Gruber, Stephen B.
    Novel Common Genetic Susceptibility Loci for Colorectal Cancer2019In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 111, no 2, p. 146-157Article in journal (Refereed)
    Abstract [en]

    Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5x10(-8)) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.

    Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5x10(-8)) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.

    Results: The discovery GWAS identified 11 variants associated with CRC at P < 5x10(-8), of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.

    Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

  • 29. Sieri, Sabina
    et al.
    Chiodini, Paolo
    Agnoli, Claudia
    Pala, Valeria
    Berrino, Franco
    Trichopoulou, Antonia
    Benetou, Vassiliki
    Vasilopoulou, Effie
    Sánchez, María-José
    Chirlaque, Maria-Dolores
    Amiano, Pilar
    Quirós, J Ramón
    Ardanaz, Eva
    Buckland, Genevieve
    Masala, Giovanna
    Panico, Salvatore
    Grioni, Sara
    Sacerdote, Carlotta
    Tumino, Rosario
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Fagherazzi, Guy
    Peeters, Petra H M
    van Gils, Carla H
    Bueno-de-Mesquita, H Bas
    van Kranen, Henk J
    Key, Timothy J
    Travis, Ruth C
    Khaw, Kay Tee
    Wareham, Nicholas J
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Boeing, Heiner
    Schütze, Madlen
    Sonestedt, Emily
    Wirfält, Elisabeth
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Andersson, Anne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Chajes, Veronique
    Rinaldi, Sabina
    Romieu, Isabelle
    Weiderpass, Elisabete
    Skeie, Guri
    Dagrun, Engeset
    Tjønneland, Anne
    Halkjær, Jytte
    Overvard, Kim
    Merritt, Melissa A
    Cox, David
    Riboli, Elio
    Krogh, Vittorio
    Dietary fat intake and development of specific breast cancer subtypes2014In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 106, no 5, p. dju068-Article in journal (Refereed)
    Abstract [en]

    We prospectively evaluated fat intake as predictor of developing breast cancer (BC) subtypes defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 receptor (HER2), in a large (n = 337327) heterogeneous cohort of women, with 10062 BC case patients after 11.5 years, estimating BC hazard ratios (HRs) by Cox proportional hazard modeling. High total and saturated fat were associated with greater risk of ER(+)PR(+) disease (HR = 1.20, 95% confidence interval [CI] = 1.00 to 1.45; HR = 1.28, 95% CI = 1.09 to 1.52; highest vs lowest quintiles) but not ER(-)PR(-) disease. High saturated fat was statistically significantly associated with greater risk of HER2(-) disease. High saturated fat intake particularly increases risk of receptor-positive disease, suggesting saturated fat involvement in the etiology of this BC subtype.

  • 30.
    Stattin, Pär
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgery, Urology Service, Memorial Sloan-Kettering Cancer Center, New York, NY.
    Carlsson, Sigrid
    Holmström, Benny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Vickers, Andrew
    Hugosson, Jonas
    Lilja, Hans
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Prostate cancer mortality in areas with high and low prostate cancer incidence2014In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 106, no 3, p. dju007-Article in journal (Refereed)
    Abstract [en]

    The effect of prostate-specific antigen (PSA) screening on prostate cancer mortality remains debated, despite evidence from randomized trials. We investigated the association between prostate cancer incidence, reflecting uptake of PSA testing, and prostate cancer mortality. The study population consisted of all men aged 50 to 74 years residing in eight counties in Sweden with an early increase in prostate cancer incidence and six counties with a late increase during two time periods. Incidence of metastatic prostate cancer was investigated in the period from 2000 to 2009, and prostate cancerspecific mortality and excess mortality were investigated in the period from 1990 to 1999 and the period from 2000 to 2009 by calculating rate ratios for high- vs low-incidence counties and rate ratios for the period from 2000 to 2009 vs the period from 1990 to 1999 within these two groups. All statistical tests were two-sided. There were 4528134 person-years at risk, 1577 deaths from prostate cancer, and 1210 excess deaths in men with prostate cancer in high-incidence counties and 2471373 person-years at risk, 985 prostate cancer deaths, and 878 excess deaths in low-incidence counties in the period from 2000 to 2009. Rate ratios in counties with high vs low incidence adjusted for time period were 0.81 (95% confidence interval [CI] 0.73 to 0.90) for prostate cancer specific mortality and 0.74 (95% CI 0.64 to 0.86) for excess mortality, and the rate ratio of metastatic prostate cancer was 0.85 (95% CI 0.79 to 0.92). The lower prostate cancer mortality in high-incidence counties reflecting a high PSA uptake suggests that more-intense as compared with less-intense opportunistic PSA screening reduces prostate cancer mortality.

  • 31.
    Stattin, Pär
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Carlsson, Sigrid
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    RE: Prostate Cancer Mortality in Areas With High and Low Prostate Cancer Incidence Response2014In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 106, no 10, p. dju293-Article in journal (Refereed)
  • 32.
    Stattin, Pär
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Garmo, H
    Steineck, G
    Bill-Axelson, A
    Re: Immediate risk of suicide and cardiovascular death after a prostate cancer diagnosis2010In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 102, no 18, p. 1447-1448; author reply 1448Article in journal (Other academic)
  • 33.
    Stattin, Pär
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Holmberg, Erik
    Johansson, Jan-Erik
    Holmberg, Lars
    Adolfsson, Jan
    Hugosson, Jonas
    Outcomes in localized prostate cancer: National Prostate Cancer Register of Sweden follow-up study2010In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 102, no 13, p. 950-958Article in journal (Refereed)
    Abstract [en]

    Background Treatment for localized prostate cancer remains controversial. To our knowledge, there are no outcome studies from contemporary population-based cohorts that include data on stage, Gleason score, and serum levels of prostate-specific antigen (PSA).

    Methods In the National Prostate Cancer Register of Sweden Follow-up Study, a nationwide cohort, we identified 6849 patients aged 70 years or younger. Inclusion criteria were diagnosis with local clinical stage T1–2 prostate cancer from January 1, 1997, through December 31, 2002, a Gleason score of 7 or less, a serum PSA level of less than 20 ng/mL, and treatment with surveillance (including active surveillance and watchful waiting, n = 2021) or curative intent (including radical prostatectomy, n = 3399, and radiation therapy, n = 1429). Among the 6849 patients, 2686 had low-risk prostate cancer (ie, clinical stage T1, Gleason score 2-6, and serum PSA level of <10 ng/mL). The study cohort was linked to the Cause of Death Register, and cumulative incidence of death from prostate cancer and competing causes was calculated.

    Results For the combination of low- and intermediate-risk prostate cancers, calculated cumulative 10-year prostate cancer–specific mortality was 3.6% (95% confidence interval [CI] = 2.7% to 4.8%) in the surveillance group and 2.7% (95% CI = 2.1% to 3.45) in the curative intent group. For those with low-risk disease, the corresponding values were 2.4% (95% CI = 1.2% to 4.1%) among the 1085 patients in the surveillance group and 0.7% (95% CI = 0.3% to 1.4%) among the 1601 patients in the curative intent group. The 10-year risk of dying from competing causes was 19.2% (95% CI = 17.2% to 21.3%) in the surveillance group and 10.2% (95% CI = 9.0% to 11.4%) in the curative intent group.

    Conclusion A 10-year prostate cancer–specific mortality of 2.4% among patients with low-risk prostate cancer in the surveillance group indicates that surveillance may be a suitable treatment option for many patients with low-risk disease.

  • 34. Tannous, Bakhos A.
    et al.
    Kerami, Mariam
    Van der Stoop, Petra M.
    Kwiatkowski, Nicholas
    Wang, Jinhua
    Zhou, Wenjun
    Kessler, Almuth F.
    Lewandrowski, Grant
    Hiddingh, Lotte
    Sol, Nik
    Lagerweij, Tonny
    Wedekind, Laurine
    Niers, Johanna M.
    Barazas, Marco
    Nilsson, R. Jonas A.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Geerts, Dirk
    Hamer, Philip C. De Witt
    Hagemann, Carsten
    Vandertop, W. Peter
    Van Tellingen, Olaf
    Noske, David P.
    Gray, Nathanael S.
    Wuerdinger, Thomas
    Effects of the Selective MPS1 Inhibitor MPS1-IN-3 on Glioblastoma Sensitivity to Antimitotic Drugs2013In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 105, no 17, p. 1322-1331Article in journal (Refereed)
    Abstract [en]

    Background Glioblastomas exhibit a high level of chemotherapeutic resistance, including to the antimitotic agents vincristine and taxol. During the mitotic agent-induced arrest, glioblastoma cells are able to perform damage-control and self-repair to continue proliferation. Monopolar spindle 1 (MPS1/TTK) is a checkpoint kinase and a gatekeeper of the mitotic arrest.

    Methods We used glioblastoma cells to determine the expression of MPS1 and to determine the effects of MPS1 inhibition on mitotic errors and cell viability in combination with vincristine and taxol. The effect of MPS1 inhibition was assessed in different orthotopic glioblastoma mouse models (n = 3-7 mice/group). MPS1 expression levels were examined in relation to patient survival.

    Results Using publicly available gene expression data, we determined that MPS1 overexpression corresponds positively with tumor grade and negatively with patient survival (two-sided t test, P < .001). Patients with high MPS1 expression (n = 203) had a median and mean survival of 487 and 913 days (95% confidence intervals [CI] = 751 to 1075), respectively, and a 2-year survival rate of 35%, whereas patients with intermediate MPS1 expression (n = 140) had a median and mean survival of 858 and 1183 days (95% CI = 1177 to 1189), respectively, and a 2-year survival rate of 56%. We demonstrate that MPS1 inhibition by RNAi results in sensitization to antimitotic agents. We developed a selective small-molecule inhibitor of MPS1, MPS1-IN-3, which caused mitotic aberrancies in glioblastoma cells and, in combination with vincristine, induced mitotic checkpoint override, increased aneuploidy, and augmented cell death. MPS1-IN-3 sensitizes glioblastoma cells to vincristine in orthotopic mouse models (two-sided log-rank test, P < .01), resulting in prolonged survival without toxicity.

    Conclusions Our results collectively demonstrate that MPS1, a putative therapeutic target in glioblastoma, can be selectively inhibited by MPS1-IN-3 sensitizing glioblastoma cells to antimitotic drugs.

  • 35. Trabert, Britton
    et al.
    Waterboer, Tim
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Brenner, Nicole
    Brinton, Louise A.
    Butt, Julia
    Coburn, Sally B.
    Hartge, Patricia
    Hufnagel, Katrin
    Inturrisi, Federica
    Lissowska, Jolanta
    Mentzer, Alexander
    Peplonska, Beata
    Sherman, Mark E.
    Wills, Gillian S.
    Woodhall, Sarah C.
    Pawlita, Michael
    Wentzensen, Nicolas
    Antibodies Against Chlamydia trachomatis and Ovarian Cancer Risk in Two Independent Populations2019In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 111, no 2, p. 129-136Article in journal (Refereed)
    Abstract [en]

    Background: Pelvic inflammatory disease (PID) has been associated with ovarian cancer risk. To clarify the role of Chlamydia trachomatis and other infectious agents in the development of ovarian cancer, we evaluated the association of serologic markers with incident ovarian cancer using a staged approach in two independent populations.

    Methods: Studies included: 1) a case-control study in Poland (244 ovarian cancers/556 control subjects) and 2) a prospective nested case-control study in the PLCO Cancer Screening Trial (160 ovarian cancers/159 control subjects). Associations of serologic marker levels with ovarian cancer risk at diagnostic as well as higher thresholds, identified in Poland and independently evaluated in PLCO, were estimated using multivariable adjusted logistic regression.

    Results: In the Polish study, antibodies (based on laboratory cut-point) against the chlamydia plasmid-encoded Pgp3 protein (serological gold standard) were associated with increased ovarian cancer risk (adjusted odds ratio [OR] = 1.63, 95% confidence interval [CI] = 1.20 to 2.22); when a positive result was redefined at higher levels, ovarian cancer risk was increased (cut-point 2: OR = 2.00, 95% CI = 1.38 to 2.89; cut-point 3 [max OR]: OR = 2.19, 95% CI = 1.29 to 3.73). In the prospective PLCO study, Pgp3 antibodies were associated with elevated risk at the laboratory cut-point (OR = 1.43, 95% CI = 0.78 to 2.63) and more stringent cut-points (cut-point 2: OR = 2.25, 95% CI = 1.07 to 4.71); cut-point 3: OR = 2.53, 95% CI = 0.63 to 10.08). In both studies, antibodies against other infectious agents measured were not associated with risk.

    Conclusions: In two independent populations, antibodies against prior/current C. trachomatis (Pgp3) were associated with a doubling in ovarian cancer risk, whereas markers of other infectious agents were unrelated. These findings lend support for an association between PID and ovarian cancer.

  • 36. Trichopoulos, Dimitrios
    et al.
    Bamia, Christina
    Lagiou, Pagona
    Fedirko, Veronika
    Trepo, Elisabeth
    Jenab, Mazda
    Pischon, Tobias
    Noethlings, Ute
    Overved, Kim
    Tjonneland, Anne
    Outzen, Malene
    Clavel-Chapelon, Francoise
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Boeing, Heiner
    Aleksandrova, Krasimira
    Benetou, Vassiliki
    Zylis, Dimosthenis
    Palli, Domenico
    Pala, Valeria
    Panico, Salvatore
    Tumino, Rosario
    Sacerdote, Carlotta
    Bueno-De-Mesquita, H. Bas
    Van Kranen, Henk J.
    Peeters, Petra H. M.
    Lund, Eiliv
    Ramon Quiros, J.
    Gonzalez, Carlos A.
    Sanchez Perez, Maria-Jose
    Navarro, Carmen
    Dorronsoro, Miren
    Barricarte, Aurelio
    Lindkvist, Bjorn
    Regner, Sara
    Werner, Mårten
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Khaw, Kay-Tee
    Wareham, Nick
    Key, Timothy
    Romieu, Isabelle
    Chuang, Shu-Chun
    Murphy, Neil
    Boffetta, Paolo
    Trichopoulou, Antonia
    Riboli, Elio
    Hepatocellular carcinoma risk factors and disease burden in a European cohort: a nested case-control study2011In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 103, no 22, p. 1686-1695Article in journal (Refereed)
    Abstract [en]

    Background: To date, no attempt has been made to systematically determine the apportionment of the hepatocellular carcinoma burden in Europe or North America among established risk factors.

    Methods: Using data collected from 1992 to 2006, which included 4 409 809 person-years in the European Prospective Investigation into Cancer and nutrition (EPIC), we identified 125 case patients with hepatocellular carcinoma, of whom 115 were matched to 229 control subjects. We calculated odds ratios (ORs) for the association of documented risk factors for hepatocellular carcinoma with incidence of this disease and estimated their importance in this European cohort.

    Results: Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (OR = 9.10, 95% confidence interval [CI] = 2.10 to 39.50 and OR = 13.36, 95% CI = 4.11 to 43.45, respectively), obesity (OR = 2.13, 95% CI = 1.06 to 4.29), former or current smoking (OR = 1.98, 95% CI = 0.90 to 4.39 and OR = 4.55, 95% CI = 1.90 to 10.91, respectively), and heavy alcohol intake (OR = 1.77, 95% CI = 0.73 to 4.27) were associated with hepatocellular carcinoma. Smoking contributed to almost half of all hepatocellular carcinomas (47.6%), whereas 13.2% and 20.9% were attributable to chronic HBV and HCV infection, respectively. Obesity and heavy alcohol intake contributed 16.1% and 10.2%, respectively. Almost two-thirds (65.7%, 95% CI = 50.6% to 79.3%) of hepatocellular carcinomas can be accounted for by exposure to at least one of these documented risk factors.

    Conclusions: Smoking contributed to more hepatocellular carcinomas in this Europe-wide cohort than chronic HBV and HCV infections. Heavy alcohol consumption and obesity also contributed to sizeable fractions of this disease burden. These contributions may be underestimates because EPIC volunteers are likely to be more health conscious than the general population.

  • 37. Trichopoulos, Dimitrios
    et al.
    Bamia, Christina
    Lagiou, Pagona
    Fedirko, Veronika
    Trepo, Elisabeth
    Jenab, Mazda
    Pischon, Tobias
    Nthlings, Ute
    Overvad, Kim
    Tjonneland, Anne
    Outzen, Malene
    Clavel-Chapelon, Francoise
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Boeing, Heiner
    Aleksandrova, Krasimira
    Benetou, Vassiliki
    Zylis, Dimosthenis
    Palli, Domenico
    Pala, Valeria
    Panico, Salvatore
    Tumino, Rosario
    Sacerdote, Carlotta
    Bueno-De-Mesquita, H. Bas
    Van Kranen, Henk J.
    Peeters, Petra H. M.
    Lund, Eiliv
    Ramon Quiros, J.
    Gonzalez, Carlos A.
    Sanchez Perez, Maria-Jose
    Navarro, Carmen
    Dorronsoro, Miren
    Barricarte, Aurelio
    Lindkvist, Bjoern
    Regner, Sara
    Werner, Mårten
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Khaw, Kay-Tee
    Wareham, Nick
    Key, Timothy
    Romieu, Isabelle
    Chuang, Shu-Chun
    Murphy, Neil
    Boffetta, Paolo
    Trichopoulou, Antonia
    Riboli, Elio
    Re: Hepatocellular Carcinoma Risk factors and Disease Burden in a European Cohort: A Nested Case-Control Study Response2012In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 104, no 21, p. 1683-1684Article in journal (Refereed)
  • 38. Tsilidis, Konstantinos K
    et al.
    Papadimitriou, Nikos
    Capothanassi, Despoina
    Bamia, Christina
    Benetou, Vassiliki
    Jenab, Mazda
    Freisling, Heinz
    Kee, Frank
    Nelen, Annemarie
    O'Doherty, Mark G
    Scott, Angela
    Soerjomataram, Isabelle
    Tjønneland, Anne
    May, Anne M
    Ramón Quirós, J
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Brenner, Hermann
    Schöttker, Ben
    Ordóñez-Mena, José M
    Karina Dieffenbach, Aida
    Eriksson, Sture
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Bøgeberg Mathiesen, Ellisiv
    Njølstad, Inger
    Siganos, Galatios
    Wilsgaard, Tom
    Boffetta, Paolo
    Trichopoulos, Dimitrios
    Trichopoulou, Antonia
    Burden of Cancer in a Large Consortium of Prospective Cohorts in Europe2016In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 108, no 10, article id djw127Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Disability-adjusted life-years (DALYs) are an indicator of mortality, morbidity, and disability. We calculated DALYs for cancer in middle-aged and older adults participating in the Consortium on Health and Ageing Network of Cohorts in Europe and the United States (CHANCES) consortium.

    METHODS: A total of 90 199 participants from five European cohorts with 10 455 incident cancers and 4399 deaths were included in this study. DALYs were calculated as the sum of the years of life lost because of premature mortality (YLLs) and the years lost because of disability (YLDs). Population-attributable fractions (PAFs) were also estimated for five cancer risk factors, ie, smoking, adiposity, physical inactivity, alcohol intake, and type II diabetes.

    RESULTS: After a median follow-up of 12 years, the total number of DALYs lost from cancer was 34 474 (382 per 1000 individuals) with a similar distribution by sex. Lung cancer was responsible for the largest number of lost DALYs (22.9%), followed by colorectal (15.3%), prostate (10.2%), and breast cancer (8.7%). Mortality (81.6% of DALYs) predominated over disability. Ever cigarette smoking was the risk factor responsible for the greatest total cancer burden (24.0%, 95% confidence interval [CI] = 22.2% to 26.0%), followed by physical inactivity (4.9%, 95% CI = 0.8% to 8.1%) and adiposity (1.8%, 95% CI = 0.2% to 2.8%).

    CONCLUSIONS: DALYs lost from cancer were substantial in this large European sample of middle-aged and older adults. Even if the burden of disease because of cancer is predominantly caused by mortality, some cancers have sizeable consequences for disability. Smoking remained the predominant risk factor for total cancer burden.

  • 39. Urayama, Kevin Y
    et al.
    Jarrett, Ruth F
    Hjalgrim, Henrik
    Diepstra, Arjan
    Kamatani, Yoichiro
    Chabrier, Amelie
    Gaborieau, Valerie
    Boland, Anne
    Nieters, Alexandra
    Becker, Nikolaus
    Foretova, Lenka
    Benavente, Yolanda
    Maynadié, Marc
    Staines, Anthony
    Shield, Lesley
    Lake, Annette
    Montgomery, Dorothy
    Taylor, Malcolm
    Smedby Ekström, Karin
    Amini, Rose-Marie
    Adami, Hans-Olov
    Glimelius, Bengt
    Feenstra, Bjarke
    Nolte, Ilja M
    Visser, Lydia
    van Imhoff, Gustaaf W
    Lightfoot, Tracy
    Cocco, Pierluigi
    Kiemeney, Lambertus
    Vermeulen, Sita H
    Holcatova, Ivana
    Vatten, Lars
    Macfarlane, Gary J
    Thomson, Peter
    Conway, David I
    Benhamou, Simone
    Agudo, Antonio
    Healy, Claire M
    Overvad, Kim
    Tjønneland, Anne
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Canzian, Federico
    Khaw, Kay-Tee
    Travis, Ruth C
    Peeters, Petra H M
    González, Carlos A
    Quirós, José Ramón
    Sánchez, María-José
    Huerta, José María
    Ardanaz, Eva
    Dorronsoro, Miren
    Clavel-Chapelon, Françoise
    Bueno-de-Mesquita, H Bas
    Riboli, Elio
    Roman, Eve
    Boffetta, Paolo
    de Sanjosé, Silvia
    Zelenika, Diana
    Melbye, Mads
    van den Berg, Anke
    Lathrop, Mark
    Brennan, Paul
    McKay, James D
    Genome-wide association study of classical hodgkin lymphoma and epstein-barr virus status-defined subgroups2012In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 104, no 3, p. 240-253Article in journal (Refereed)
    Abstract [en]

    Background Accumulating evidence suggests that risk factors for classical Hodgkin lymphoma (cHL) differ by tumor Epstein-Barr virus (EBV) status. This potential etiological heterogeneity is not recognized in current disease classification. Methods We conducted a genome-wide association study of 1200 cHL patients and 6417 control subjects, with validation in an independent replication series, to identify common genetic variants associated with total cHL and subtypes defined by tumor EBV status. Multiple logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) assuming a log-additive genetic model for the variants. All statistical tests were two-sided. Results Two novel loci associated with total cHL irrespective of EBV status were identified in the major histocompatibility complex region; one resides adjacent to MICB (rs2248462: OR = 0.61, 95% CI = 0.53 to 0.69, P = 1.3 × 10(-13)) and the other at HLA-DRA (rs2395185: OR = 0.56, 95% CI = 0.50 to 0.62, P = 8.3 × 10(-25)) with both results confirmed in an independent replication series. Consistent with previous reports, associations were found between EBV-positive cHL and genetic variants within the class I region (rs2734986, HLA-A: OR = 2.45, 95% CI = 2.00 to 3.00, P = 1.2 × 10(-15); rs6904029, HCG9: OR = 0.46, 95% CI = 0.36 to 0.59, P = 5.5 × 10(-10)) and between EBV-negative cHL and rs6903608 within the class II region (rs6903608, HLA-DRA: OR = 2.08, 95% CI = 1.84 to 2.35, P = 6.1 × 10(-31)). The association between rs6903608 and EBV-negative cHL was confined to the nodular sclerosis histological subtype. Evidence for an association between EBV-negative cHL and rs20541 (5q31, IL13: OR = 1.53, 95% CI = 1.32 to 1.76, P = 5.4 x 10(-9)), a variant previously linked to psoriasis and asthma, was observed; however, the evidence for replication was less clear. Notably, one additional psoriasis-associated variant, rs27524 (5q15, ERAP1), showed evidence of an association with cHL in the genome-wide association study (OR = 1.21, 95% CI = 1.10 to 1.33, P = 1.5 × 10(-4)) and replication series (P = .03). Conclusion Overall, these results provide strong evidence that EBV status is an etiologically important classification of cHL and also suggest that some components of the pathological process are common to both EBV-positive and EBV-negative patients.

  • 40. Walsh, Naomi
    et al.
    Zhang, Han
    Hyland, Paula L
    Yang, Qi
    Mocci, Evelina
    Zhang, Mingfeng
    Childs, Erica J
    Collins, Irene
    Wang, Zhaoming
    Arslan, Alan A
    Beane-Freeman, Laura
    Bracci, Paige M
    Brennan, Paul
    Canzian, Federico
    Duell, Eric J
    Gallinger, Steven
    Giles, Graham G
    Goggins, Michael
    Goodman, Gary E
    Goodman, Phyllis J
    Hung, Rayjean J
    Kooperberg, Charles
    Kurtz, Robert C
    Malats, Núria
    LeMarchand, Loic
    Neale, Rachel E
    Olson, Sara H
    Scelo, Ghislaine
    Shu, Xiao O
    Van Den Eeden, Stephen K
    Visvanathan, Kala
    White, Emily
    Zheng, Wei
    Albanes, Demetrius
    Andreotti, Gabriella
    Babic, Ana
    Bamlet, William R
    Berndt, Sonja I
    Borgida, Ayelet
    Boutron-Ruault, Marie-Christine
    Brais, Lauren
    Brennan, Paul
    Bueno-de-Mesquita, Bas
    Buring, Julie
    Chaffee, Kari G
    Chanock, Stephen
    Cleary, Sean
    Cotterchio, Michelle
    Foretova, Lenka
    Fuchs, Charles
    M Gaziano, J Michael
    Giovannucci, Edward
    Goggins, Michael
    Hackert, Thilo
    Haiman, Christopher
    Hartge, Patricia
    Hasan, Manal
    Helzlsouer, Kathy J
    Herman, Joseph
    Holcatova, Ivana
    Holly, Elizabeth A
    Hoover, Robert
    Hung, Rayjean J
    Janout, Vladimir
    Klein, Eric A
    Kurtz, Robert C
    Laheru, Daniel
    Lee, I-Min
    Lu, Lingeng
    Malats, Núria
    Mannisto, Satu
    Milne, Roger L
    Oberg, Ann L
    Orlow, Irene
    Patel, Alpa V
    Peters, Ulrike
    Porta, Miquel
    Real, Francisco X
    Rothman, Nathaniel
    Sesso, Howard D
    Severi, Gianluca
    Silverman, Debra
    Strobel, Oliver
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Thornquist, Mark D
    Tobias, Geoffrey S
    Wactawski-Wende, Jean
    Wareham, Nick
    Weiderpass, Elisabete
    Wentzensen, Nicolas
    Wheeler, William
    Yu, Herbert
    Zeleniuch-Jacquotte, Anne
    Kraft, Peter
    Li, Donghui
    Jacobs, Eric J
    Petersen, Gloria M
    Wolpin, Brian M
    Risch, Harvey A
    Amundadottir, Laufey T
    Yu, Kai
    Klein, Alison P
    Stolzenberg-Solomon, Rachael Z
    Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer2019In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 111, no 6, article id djy155Article in journal (Refereed)
    Abstract [en]

    Background: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes.

    Methods: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided.

    Results: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets.

    Conclusion: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.

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