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  • 1. Agudo, Antonio
    et al.
    Sala, Naría
    Pera, Guillem
    Capella, Gabriel
    Berenguer, Antonio
    García, Nadia
    Palli, Domenico
    Boeing, Heiner
    Del Giudice, Giuseppe
    Saieva, Calogero
    Carneiro, Fatima
    Berrino, Franco
    Sacerdote, Carlotta
    Tumino, Rosario
    Panico, Salvatore
    Berglund, Göran
    Siman, Henrik
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Martínez, Carmen
    Bilbao, Roberto
    Barricarte, Aurelio
    Navarro, Carmen
    Quiros, José
    Allen, Naomi
    Key, Tim
    Bingham, Sheila
    Khaw, Kay-Tee
    Linseisen, Jakob
    Nagel, Gabriele
    Overvad, Kim
    Tjonneland, Anne
    Olsen, Anja
    Bueno-de-Mesquita, H Bas
    Boshuizen, Hendriek C
    Peeters, Petra H
    Numans, Mattijs E
    Clavel-Chapelon, Francoíse
    Boutron-Ruault, Marie-Christine
    Trichopoulou, Antonia
    Lund, Eiliv
    Offerhaus, Johan
    Jenab, Mazda
    Ferrari, Pietro
    Norat, Teresa
    Riboli, Elio
    González, Carlos A
    Polymorphisms in metabolic genes related to tobacco smoke and the risk of gastric cancer in the European prospective investigation into cancer and nutrition.2006In: Cancer Epidemiology Biomarkers & Prevention, ISSN 1055-9965, Vol. 15, no 12, p. 2427-34Article in journal (Refereed)
  • 2. Agudo, Antonio
    et al.
    Sala, Nária
    Pera, Guillem
    Capella, Gabriel
    Berenguer, Antonio
    García, Nadia
    Palli, Domenico
    Boeing, Heiner
    Del Giudice, Giuseppe
    Saieva, Calogero
    Carneiro, Fatima
    Berrino, Franco
    Sacerdote, Carlotta
    Tumino, Rosario
    Panico, Salvatore
    Berglund, Göran
    Siman, Henrik
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Martínez, Carmen
    Amiano, Pilar
    Barricarte, Aurelio
    Navarro, Carmen
    Qui, Jose R
    Allen, Naomi
    Key, Tim
    Bingham, Sheila
    Khaw, Kay-Tee
    Linseisen, Jakob
    Nagel, Gabriele
    Overvad, Kim
    Tjonneland, Anne
    Olsen, Anja
    Bueno-de-Mesquita, H Bas
    Boshuizen, Hendriek C
    Peeters, Petra H
    Numans, Mattijs E
    Clavel-Chapelon, Francoíse
    Boutron-Ruault, Marie-Christine
    Trichopoulou, Antonia
    Lund, Eiliv
    Báker, Hendrik
    Jenab, Mazda
    Ferrari, Pietro
    Norat, Teresa
    Riboli, Elio
    González, Carlos A
    No association between polymorphisms in CYP2E1, GSTM1, NAT1, NAT2 and the risk of gastric adenocarcinoma in the European prospective investigation into cancer and nutrition.2006In: Cancer Epidemiology Biomarkers & Prevention, ISSN 1055-9965, Vol. 15, no 5, p. 1043-5Article in journal (Refereed)
  • 3. Balassiano, Karen
    et al.
    Lima, Sheila
    Jenab, Mazda
    Overvad, Kim
    Tjonneland, Anne
    Boutron-Ruault, Marie Christine
    Clavel-Chapelon, Francoise
    Canzian, Federico
    Kaaks, Rudolf
    Boeing, Heiner
    Meidtner, Karina
    Trichopoulou, Antonia
    Laglou, Pagona
    Vineis, Paolo
    Panico, Salvatore
    Palli, Domenico
    Grioni, Sara
    Tumino, Rosario
    Lund, Eiliv
    Bueno-de-Mesquita, H. Bas
    Numans, Mattjis E.
    Peeters, Petra H. M.
    Ramon Quiros, J.
    Sanchez, Maria-Jose
    Navarro, Carmen
    Ardanaz, Eva
    Dorronsoro, Miren
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Ehrnstrom, Roy
    Regner, Sara
    Allen, Naomi E.
    Travis, Ruth C.
    Khaw, Kay-Tee
    Offerhaus, G. Johan A.
    Sala, Nuria
    Riboli, Elio
    Hainaut, Pierre
    Scoazec, Jean-Yves
    Sylla, Bakary S.
    Gonzalez, Carlos A.
    Herceg, Zdenko
    Aberrant DNA methylation of cancer-associated genes in gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST)2011In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 311, no 1, p. 85-95Article in journal (Refereed)
    Abstract [en]

    Epigenetic events have emerged as key mechanisms in the regulation of critical biological processes and in the development of a wide variety of human malignancies, including gastric cancer (GC), however precise gene targets of aberrant DNA methylation in GC remain largely unknown. Here, we have combined pyrosequencing-based quantitative analysis of DNA methylation in 98 GC cases and 64 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort and in cancer tissue and non-tumorigenic adjacent tissue of an independent series of GC samples. A panel of 10 cancer-associated genes (CHRNA3, DOK1, MGMT, RASSF1A, p14ARF, CDH1, MLH1, ALDH2, GNMT and MTHFR) and LINE-1 repetitive elements were included in the analysis and their association with clinicopathological characteristics (sex, age at diagnosis, anatomical sub-site, histological sub-type) was examined. Three out of the 10 genes analyzed exhibited a marked hypermethylation, whereas two genes (ALDH2 and MTHFR) showed significant hypomethylation, in gastric tumors. Among differentially methylated genes, we identified new genes (CHRNA3 and DOK1) as targets of aberrant hypermethylation in GC, suggesting that epigenetic deregulation of these genes and their corresponding cellular pathways may promote the development and progression of GC. We also found that global demethylation of tumor cell genomes occurs in GC, consistent with the notion that abnormal hypermethylation of specific genes occurs concomitantly with genome-wide hypomethylation. Age and gender had no significant influence on methylation states, but an association was observed between LINE-1 and MLH1 methylation levels with histological subtype and anatomical sub-site. This study identifies aberrant methylation patters in specific genes in GC thus providing information that could be exploited as novel biomarkers in clinics and molecular epidemiology of GC.

  • 4. Buckland, Genevieve
    et al.
    Agudo, Antonio
    Luján, Leila
    Jakszyn, Paula
    Bueno-de-Mesquita, H Bas
    Palli, Domenico
    Boeing, Heiner
    Carneiro, Fátima
    Krogh, Vittorio
    Sacerdote, Carlotta
    Tumino, Rosario
    Panico, Salvatore
    Nesi, Gabriella
    Manjer, Jonas
    Regnér, Sara
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sanchez, María-José
    Dorronsoro, Miren
    Barricarte, Aurelio
    Navarro, Carmen
    Quirós, J Ramón
    Allen, Naomi E
    Key, Timothy J
    Bingham, Sheila
    Kaaks, Rudolf
    Overvad, Kim
    Jensen, Majken
    Olsen, Anja
    Tjønneland, Anne
    Peeters, Petra H M
    Numans, Mattijs E
    Ocké, Marga C
    Clavel-Chapelon, Françoise
    Morois, Sophie
    Boutron-Ruault, Marie-Christine
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Lund, Eiliv
    Couto, Elisabeth
    Boffeta, Paolo
    Jenab, Mazda
    Riboli, Elio
    Romaguera, Dora
    Mouw, Traci
    González, Carlos A
    Adherence to a Mediterranean diet and risk of gastric adenocarcinoma within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort study2010In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 91, no 2, p. 381-390Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The Mediterranean dietary pattern is believed to protect against cancer, although evidence from cohort studies that have examined particular cancer sites is limited.

    OBJECTIVE: We aimed to explore the association between adherence to a relative Mediterranean diet (rMED) and incident gastric adenocarcinoma (GC) within the European Prospective Investigation into Cancer and Nutrition study.

    DESIGN: The study included 485,044 subjects (144,577 men) aged 35-70 y from 10 European countries. At recruitment, dietary and lifestyle information was collected. An 18-unit rMED score, incorporating 9 key components of the Mediterranean diet, was used to estimate rMED adherence. The association between rMED and GC with respect to anatomic location (cardia and noncardia) and histologic types (diffuse and intestinal) was investigated. A calibration study in a subsample was used to control for dietary measurement error.

    RESULTS: After a mean follow-up of 8.9 y, 449 validated incident GC cases were identified and used in the analysis. After stratification by center and age and adjustment for recognized cancer risk factors, high compared with low rMED adherence was associated with a significant reduction in GC risk (hazard ratio: 0.67; 95% CI: 0.47, 0.94). A 1-unit increase in the rMED score was associated with a decreased risk of GC of 5% (95% CI: 0.91, 0.99). There was no evidence of heterogeneity between different anatomic locations or histologic types. The calibrated results showed similar trends (overall hazard ratio for GC: 0.93; 95% CI: 0.89, 0.99).

    CONCLUSION: Greater adherence to an rMED is associated with a significant reduction in the risk of incident GC.

  • 5. Carneiro, Fátima
    et al.
    Moutinho, Cátia
    Pera, Guillem
    Caldas, Carlos
    Fenger, Claus
    Offerhaus, Johan
    Save, Vicki
    Stenling, Roger
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Nesi, Gabriella
    Mahlke, U
    Bläker, Hendrik
    Torrado, Julio
    Roukos, Dimitrios H
    Sabourin, Jean-Christophe
    Boeing, Heiner
    Palli, Domenico
    Bueno-de-Mesquita, H Bas
    Overvad, Kim
    Bingham, Sheila
    Clavel-Chapelon, Françoise
    Lund, Eiliv
    Trichopoulou, Antonia
    Manjer, Jonas
    Riboli, Elio
    Gonzalez, Carlos A
    Pathology findings and validation of gastric and esophageal cancer cases in a European cohort (EPIC/EUR-GAST).2007In: Scand J Gastroenterol, ISSN 0036-5521, Vol. 42, no 5, p. 618-27Article in journal (Refereed)
  • 6. Crusius, J B A
    et al.
    Canzian, F
    Capellá, G
    Peña, A S
    Pera, G
    Sala, N
    Agudo, A
    Rico, F
    Del Giudice, G
    Palli, D
    Plebani, M
    Boeing, H
    Bueno-de-Mesquita, H B
    Carneiro, F
    Pala, V
    Save, V E
    Vineis, P
    Tumino, R
    Panico, S
    Berglund, G
    Manjer, J
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Martínez, C
    Dorronsoro, M
    Barricarte, A
    Navarro, C
    Quirós, J R
    Allen, N
    Key, T J
    Binghan, S
    Caldas, C
    Linseisen, J
    Kaaks, R
    Overvad, K
    Tjønneland, A
    Büchner, F C
    Peeters, P H M
    Numans, M E
    Clavel-Chapelon, F
    Trichopoulou, A
    Lundin, Eva
    Jenab, M
    Rinaldi, S
    Ferrari, P
    Riboli, E
    González, C A
    Cytokine gene polymorphisms and the risk of adenocarcinoma of the stomach in the European prospective investigation into cancer and nutrition (EPIC-EURGAST).2008In: Ann Oncol, ISSN 1569-8041, Vol. 19, no 11, p. 1894-1902Article in journal (Refereed)
  • 7.
    Dahlin, Anna M
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor2011In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 24, p. 671-682Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to relate the density of tumor infiltrating T cells to cancer-specific survival in colorectal cancer, taking into consideration the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) screening status. The T-cell marker CD3 was stained by immunohistochemistry in 484 archival tumor tissue samples. T-cell density was semiquantitatively estimated and scored 1-4 in the tumor front and center (T cells in stroma), and intraepithelially (T cells infiltrating tumor cell nests). Total CD3 score was calculated as the sum of the three CD3 scores (range 3-12). MSI screening status was assessed by immunohistochemistry. CIMP status was determined by quantitative real-time PCR (MethyLight) using an eight-gene panel. We found that patients whose tumors were highly infiltrated by T cells (total CD3 score ≥7) had longer survival compared with patients with poorly infiltrated tumors (total CD3 score ≤4). This finding was statistically significant in multivariate analyses (multivariate hazard ratio, 0.57; 95% confidence interval, 0.31-1.00). Importantly, the finding was consistent in rectal cancer patients treated with preoperative radiotherapy. Although microsatellite unstable tumor patients are generally considered to have better prognosis, we found no difference in survival between microsatellite unstable and microsatellite stable (MSS) colorectal cancer patients with similar total CD3 scores. Patients with MSS tumors highly infiltrated by T cells had better prognosis compared with intermediately or poorly infiltrated microsatellite unstable tumors (log rank P=0.013). Regarding CIMP status, CIMP-low was associated with particularly poor prognosis in patients with poorly infiltrated tumors (multivariate hazard ratio for CIMP-low versus CIMP-negative, 3.07; 95% confidence interval, 1.53-6.15). However, some subset analyses suffered from low power and are in need of confirmation by independent studies. In conclusion, patients whose tumors are highly infiltrated by T cells have a beneficial prognosis, regardless of MSI, whereas the role of CIMP status in this context is less clear.

  • 8. Duell, Eric J
    et al.
    Lujan-Barroso, Leila
    Llivina, Claudia
    Muñoz, Xavier
    Jenab, Mazda
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Racine, Antoine
    Boeing, Heiner
    Buijsse, Brian
    Canzian, Federico
    Johnson, Theron
    Dalgård, Christine
    Overvad, Kim
    Tjønneland, Anne
    Olsen, Anja
    Sánchez, Soledad C
    Sánchez-Cantalejo, Emilio
    Huerta, José-María
    Ardanaz, Eva
    Dorronsoro, Miren
    Khaw, Kay-Tee
    Travis, Ruth C
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Rafnsson, Snorri
    Palli, Domenico
    Sacerdote, Carlotta
    Tumino, Rosario
    Panico, Salvatore
    Grioni, Sara
    Bueno-de-Mesquita, H Bas
    Ros, Martine M
    Numans, Mattijs E
    Peeters, Petra H
    Johansen, Dorthe
    Lindkvist, Björn
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic Epidemiology Group, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Skeie, Guri
    Weiderpass, Elisabete
    Duarte-Salles, Talita
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Riboli, Elio
    Sala, Núria
    González, Carlos A
    Vitamin C transporter gene (SLC23A1 and SLC23A2) polymorphisms, plasma vitamin C levels, and gastric cancer risk in the EPIC cohort2013In: Genes & Nutrition, ISSN 1555-8932, E-ISSN 1865-3499, Vol. 8, no 6, p. 549-560Article in journal (Refereed)
    Abstract [en]

    Vitamin C is known to protect mucosal tissues from oxidative stress and inhibit nitrosamine formation in the stomach. High consumption of fruits, particularly citrus, and higher circulating vitamin C concentrations may be inversely associated with gastric cancer (GC) risk. We investigated 20 polymorphisms in vitamin C transporter genes SCL23A1 and SCL23A2 and GC risk in 365 cases and 1,284 controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. We also evaluated the association between these polymorphisms and baseline plasma vitamin C levels in a subset of participants. Four SNPs were predictors of plasma vitamin C levels (SLC23A1 rs11950646 and rs33972313; SLC23A2 rs6053005 and rs6133175) in multivariable linear regression models. One SNP (SLC23A2 rs6116569) was associated with GC risk, in particular non-cardia GC (OR = 1.63, 95 % CI = 1.11-2.39, based on 178 non-cardia cases), but this association was attenuated when plasma vitamin C was included in the logistic regression model. Haplotype analysis of SLC23A1 yielded no associations with GC. In SLC23A2, one haplotype was associated with both overall and non-cardia GC, another haplotype was associated with GC overall, and a third was associated with intestinal-type GC. Common variants in SLC23A1 and SLC23A2 may influence plasma vitamin C concentration independent of dietary intake, and variation in SLC23A2 may influence GC risk. Additional prospective studies in large populations and consortia are recommended. Investigation of variation in vitamin C transporter genes may shed light on the preventative properties of vitamin C in gastric carcinogenesis.

  • 9. Duell, Eric J.
    et al.
    Sala, Nuria
    Travier, Noemie
    Munoz, Xavier
    Christine Boutron-Ruault, Marie
    Clavel-Chapelon, Francoise
    Barricarte, Aurelio
    Arriola, Larraitz
    Navarro, Carmen
    Sanchez-Cantalejo, Emilio
    Ramon Quiros, J.
    Krogh, Vittorio
    Vineis, Paolo
    Mattiello, Amalia
    Tumino, Rosario
    Khaw, Kay-Tee
    Wareham, Nicholas
    Allen, Naomi E.
    Peeters, Petra H.
    Numans, Mattijs E.
    Bueno-de-Mesquita, H. B.
    van Oijen, M. G. H.
    Bamia, Christina
    Benetou, Vassiliki
    Trichopoulos, Dimitrios
    Canzian, Federico
    Kaaks, Rudolf
    Boeing, Heiner
    Bergmann, Manuela M.
    Lund, Eiliv
    Ehrnstrom, Roy
    Johansen, Dorthe
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tjonneland, Anne
    Overvad, Kim
    Ostergaard, Jane Nautrup
    Ferrari, Pietro
    Fedirko, Veronika
    Jenab, Mazda
    Nesi, Gabriella
    Riboli, Elio
    Gonzalez, Carlos A.
    Genetic variation in alcohol dehydrogenase (ADH1A, ADH1B, ADH1C, ADH7) and aldehyde dehydrogenase (ALDH2), alcohol consumption and gastric cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort2012In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 33, no 2, p. 361-367Article in journal (Refereed)
    Abstract [en]

    Studies that have examined the association between alcohol consumption and gastric cancer (GC) risk have been inconsistent. We conducted an investigation of 29 genetic variants in alcohol metabolism loci (alcohol dehydrogenase, ADH1 gene cluster: ADH1A, ADH1B and ADH1C; ADH7 and aldehyde dehydrogenase, ALDH2), alcohol intake and GC risk. We analyzed data from a nested case-control study (364 cases and 1272 controls) within the European Prospective Investigation into Cancer and Nutrition cohort. Single nucleotide polymorphisms (SNPs) were genotyped using a customized array. We observed a statistically significant association between a common 3'-flanking SNP near ADH1A (rs1230025) and GC risk [allelic odds ratio (OR)(A v T) = 1.30, 95% confidence interval (CI) = 1.07-1.59]. Two intronic variants, one in ADH1C (rs283411) and one in ALDH2 (rs16941667), also were associated with GC risk (ORT v C = 0.59; 95% CI = 0.38-0.91 and ORT v C = 1.34; 95% CI = 1.00-1.79, respectively). Individuals carrying variant alleles at both ADH1 (rs1230025) and ALDH2 (rs16941667) were twice as likely to develop GC (ORA+T = 2.0; 95% CI = 1.25-3.20) as those not carrying variant alleles. The association between rs1230025 and GC was modified by alcohol intake (< 5 g/day: ORA = 0.89, 95% CI = 0.57-1.39; >= 5 g/day: ORA = 1.45, 95% CI = 1.08-1.94, P-value = 0.05). The association was also modified by ethanol intake from beer. A known functional SNP in ADH1B (rs1229984) was associated with alcohol intake (P-value = 0.04) but not GC risk. Variants in ADH7 were not associated with alcohol intake or GC risk. In conclusion, genetic variants at ADH1 and ALDH2 loci may influence GC risk, and alcohol intake may further modify the effect of ADH1 rs1230025. Additional population-based studies are needed to confirm our results.

  • 10. Duell, Eric J
    et al.
    Travier, Noémie
    Lujan-Barroso, Leila
    Boutron-Ruault, MC
    Clavel-Chapelon, F
    Palli, Domenico
    Krogh, Vittorio
    Mattiello, Amalia
    Tumino, Rosario
    Sacerdote, Carlotta
    Rodriguez, Laudina
    Sanchez-Cantalejo, Emilio
    Navarro, Carmen
    Barricarte, Aurelio
    Dorronsoro, Miren
    Khaw, Kay-Tee
    Wareham, Nicholas
    Allen, Naomi E
    Tsilidis, Konstantinos K
    Bueno-de-Mesquita, H Bas
    Jeurnink, Suzanne M
    Numans, ME
    Peeters, Petra HM
    Lagiou, Pagona
    Valanou, Elisabeth
    Trichopoulou, Antonia
    Kaaks, Rudolf
    Lukanova-McGregor, Annekatrin
    Bergman, Manuela M
    Boeing, Heiner
    Manjer, Jonas
    Lindkvist, Björn
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Dahm, Christina C
    Overvad, Kim
    Olsen, Anja
    Tjonneland, Anne
    Bakken, Kjersti
    Lund, Eiliv
    Jenab, Mazda
    McCormack, Valerie
    Rinaldi, Sabina
    Michaud, Dominique
    Mouw, Traci
    Nesi, Gabriella
    Carneiro, Fatima
    Riboli, Elio
    González, Carlos A
    Menstrual and reproductive factors, exogenous hormone use, and gastric cancer risk in a cohort of women from the European Prospective Investigation Into Cancer and Nutrition2010In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 172, no 12, p. 1384-1393Article in journal (Refereed)
    Abstract [en]

    The worldwide incidence of gastric adenocarcinoma (GC) is lower in women than in men. Furthermore, cancer patients treated with estrogens have been reported to have a lower subsequent risk of GC. The authors conducted a prospective analysis of menstrual and reproductive factors, exogenous hormone use, and GC in 335,216 women from the European Prospective Investigation Into Cancer and Nutrition, a cohort study of individuals aged 35-70 years from 10 European countries. After a mean follow-up of 8.7 years (through 2004), 181 women for whom complete exposure data were available developed GC. Adjusted hazard ratios and 95% confidence intervals were estimated using Cox proportional hazards models. All statistical tests were 2-sided. Women who had ovariectomy had a 79% increased risk of GC (based on 25 cases) compared with women who did not (hazard ratio = 1.79, 95% confidence interval: 1.15, 2.78). Total cumulative years of menstrual cycling was inversely associated with GC risk (fifth vs. first quintile: hazard ratio = 0.55, 95% confidence interval: 0.31, 0.98; P(trend) = 0.06). No other reproductive factors analyzed were associated with risk of GC. The results of this analysis provide some support for the hypothesis that endogenous ovarian sex hormones lower GC incidence in women.

  • 11. Duell, Eric J
    et al.
    Travier, Noémie
    Lujan-Barroso, Leila
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Morois, Sophie
    Palli, Domenico
    Krogh, Vittorio
    Panico, Salvatore
    Tumino, Rosario
    Sacerdote, Carlotta
    Quirós, J Ramón
    Sánchez-Cantalejo, Emilio
    Navarro, Carmen
    Gurrea, Aurelio Barricarte
    Dorronsoro, Miren
    Khaw, Kay-Tee
    Allen, Naomi E
    Key, Timothy J
    Bueno-de-Mesquita, H Bas
    Ros, Martine M
    Numans, Mattijs E
    Peeters, Petra Hm
    Trichopoulou, Antonia
    Naska, Androniki
    Dilis, Vardis
    Teucher, Birgit
    Kaaks, Rudolf
    Boeing, Heiner
    Schütze, Madlen
    Regner, Sara
    Lindkvist, Björn
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Overvad, Kim
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Egeberg, Rikke
    Tjønneland, Anne
    Lund, Eiliv
    Weiderpass, Elisabete
    Braaten, Tonje
    Romieu, Isabelle
    Ferrari, Pietro
    Jenab, Mazda
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Aune, Dagfinn
    Norat, Teresa
    Riboli, Elio
    González, Carlos A
    Alcohol consumption and gastric cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.2011In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 94, no 5, p. 1266-75Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Gastric cancer (GC) is the second leading cause of cancer death worldwide. The association between alcohol consumption and GC has been investigated in numerous epidemiologic studies with inconsistent results.

    OBJECTIVE: We evaluated the association between alcohol consumption and GC risk.

    DESIGN: We conducted a prospective analysis in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, which included 444 cases of first primary gastric adenocarcinoma. HRs and 95% CIs for GC were estimated by using multivariable Cox proportional hazards regression for consumption of pure ethanol in grams per day, with stratification by smoking status, anatomic subsite (cardia, noncardia), and histologic subtype (diffuse, intestinal). In a subset of participants, results were further adjusted for baseline Helicobacter pylori serostatus.

    RESULTS: Heavy (compared with very light) alcohol consumption (≥60 compared with 0.1-4.9 g/d) at baseline was positively associated with GC risk (HR: 1.65; 95% CI: 1.06, 2.58), whereas lower consumption amounts (<60 g/d) were not. When we analyzed GC risk by type of alcoholic beverage, there was a positive association for beer (≥30 g/d; HR: 1.75; 95% CI: 1.13, 2.73) but not for wine or liquor. Associations were primarily observed at the highest amounts of drinking in men and limited to noncardia subsite and intestinal histology; no statistically significant linear dose-response trends with GC risk were observed.

    CONCLUSION: Heavy (but not light or moderate) consumption of alcohol at baseline (mainly from beer) is associated with intestinal-type noncardia GC risk in men from the EPIC cohort.

  • 12. Eussen, Simone J P M
    et al.
    Vollset, Stein Emil
    Hustad, Steinar
    Midttun, Øivind
    Meyer, Klaus
    Fredriksen, Ase
    Ueland, Per Magne
    Jenab, Mazda
    Slimani, Nadia
    Ferrari, Pietro
    Agudo, Antonio
    Sala, Núria
    Capellá, Gabriel
    Del Giudice, Giuseppe
    Palli, Domenico
    Boeing, Heiner
    Weikert, Cornelia
    Bueno-de-Mesquita, H Bas
    Büchner, Frederike L
    Carneiro, Fátima
    Berrino, Franco
    Vineis, Paolo
    Tumino, Rosario
    Panico, Salvatore
    Berglund, Göran
    Manjer, Jonas
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Martínez, Carmen
    Arrizola, Larraitz
    Barricarte, Aurelio
    Navarro, Carmen
    Rodriguez, Laudina
    Bingham, Sheila
    Linseisen, Jakob
    Kaaks, Rudolf
    Overvad, Kim
    Tjønneland, Anne
    Peeters, Petra H M
    Numans, Mattijs E
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Morois, Sophie
    Trichopoulou, Antonia
    Lund, Eiliv
    Plebani, Mario
    Riboli, Elio
    González, Carlos A
    Vitamins B2 and B6 and genetic polymorphisms related to one-carbon metabolism as risk factors for gastric adenocarcinoma in the European prospective investigation into cancer and nutrition.2010In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 19, no 1, p. 28-38Article in journal (Refereed)
    Abstract [en]

    B vitamins and polymorphisms in genes coding for enzymes involved in one-carbon metabolism may affect DNA synthesis and methylation and thereby be implicated in carcinogenesis. Previous data on vitamins B2 and B6 and genetic polymorphisms other than those involving MTHFR as risk factors for gastric cancer (GC) are sparse and inconsistent. In this case-control study nested within the European Prospective Investigation into Cancer and Nutrition cohort, cases (n = 235) and controls (n = 601) were matched for study center, age, sex, and time of blood sampling. B2 and B6 species were measured in plasma, and the sum of riboflavin and flavin mononucleotide was used as the main exposure variable for vitamin B2 status, whereas the sum of pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid was used to define vitamin B6 status. In addition, we determined eight polymorphisms related to one-carbon metabolism. Relative risks for GC risk were calculated with conditional logistic regression, adjusted for Helicobacter pylori infection status and smoking status. Adjusted relative risks per quartile (95% confidence interval, P(trend)) were 0.85 (0.72-1.01, 0.06) for vitamin B2 and 0.78 (0.65-0.93, <0.01) for vitamin B6. Both relations were stronger in individuals with severe chronic atrophic gastritis. The polymorphisms were not associated with GC risk and did not modify the observed vitamin-cancer associations. In summary, results from this large European cohort study showed an inverse association between vitamin B2 and GC risk, which is borderline significant, and a significant inverse association between vitamin B6 and GC risk.

  • 13.
    Forssell, Johan
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Jung, Andreas
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    High macrophage infiltration along the tumor front correlates with improved survival in colon cancer.2007In: Clin Cancer Res, ISSN 1078-0432, Vol. 13, no 5, p. 1472-1479Article in journal (Refereed)
  • 14. Glimelius, Bengt
    et al.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Enblad, Gunilla
    Alafuzoff, Irina
    Beskow, Anna
    Ahlström, Håkan
    Bill-Axelson, Anna
    Birgisson, Helgi
    Björ, Ove
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Edqvist, Per-Henrik
    Hansson, Tony
    Helleday, Thomas
    Hellman, Per
    Henriksson, Kerstin
    Hesselager, Göran
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Häggman, Michael
    Höglund, Martin
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Larsson, Chatarina
    Lindman, Henrik
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Mindus, Stephanie
    Nygren, Peter
    Pontén, Fredrik
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Rosenquist, Richard
    Sandin, Fredrik
    Schwenk, Jochen M.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stålberg, Karin
    Stålberg, Peter
    Sundström, Christer
    Thellenberg Karlsson, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Westermark, Bengt
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Claesson-Welsh, Lena
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sjöblom, Tobias
    U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden2018In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 2, p. 187-194Article in journal (Refereed)
    Abstract [en]

    Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umea Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.

    Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.

    Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.

    Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.

  • 15. Gonzalez, C. A.
    et al.
    Megraud, F.
    Buissonniere, A.
    Lujan Barroso, L.
    Agudo, A.
    Duell, E. J.
    Boutron-Ruault, M. C.
    Clavel-Chapelon, F.
    Palli, D.
    Krogh, V.
    Mattiello, A.
    Tumino, R.
    Sacerdote, C.
    Quiros, J. R.
    Sanchez-Cantalejo, E.
    Navarro, C.
    Barricarte, A.
    Dorronsoro, M.
    Khaw, K. -T
    Wareham, N.
    Allen, N. E.
    Tsilidis, K. K.
    Bueno-de-Mesquita, H. Bas
    Jeurnink, S. M.
    Numans, M. E.
    Peeters, P. H. M.
    Lagiou, P.
    Valanou, E.
    Trichopoulou, A.
    Kaaks, R.
    Lukanova-McGregor, A.
    Bergman, M. M.
    Boeing, H.
    Manjer, J.
    Lindkvist, B.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Mortensen, L. M.
    Overvad, K.
    Olsen, A.
    Tjonneland, A.
    Bakken, K.
    Dumeaux, V.
    Lund, E.
    Jenab, M.
    Romieu, I.
    Michaud, D.
    Mouw, T.
    Carneiro, F.
    Fenge, C.
    Riboli, E.
    Helicobacter pylori infection assessed by ELISA and by immunoblot and noncardia gastric cancer risk in a prospective study: the Eurgast-EPIC project2012In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 23, no 5, p. 1320-1324Article in journal (Refereed)
    Abstract [en]

    In epidemiological studies, Helicobacter pylori infection is usually detected by enzyme-linked immunosorbent assay (ELISA). However, infection can spontaneously clear from the mucosa during the progression of atrophy and could lead to substantial under-detection of infection and underestimation of its effect on gastric cancer (GC) risk. Antibodies detected by western blot are known to persist longer after the loss of the infection. In a nested case-control study from the Eurogast-EPIC cohort, including 88 noncardia GC cases and 338 controls, we assessed the association between noncardia GC and H. pylori infection comparing antibodies detected by western blot (HELICOBLOT2.1) to those detected by ELISA (Pyloriset EIA-GIII((R))). By immunoblot, 82 cases (93.2%) were H. pylori positive, 10 of these cases (11.4%) were negative by ELISA and only 6 cases (6.8%) were negative by both ELISA and immunoblot. Multivariable odds ratio (OR) for noncardia GC comparing immunoglobulin G positive versus negative by ELISA was 6.8 [95% confidence interval (CI) 3.0-15.1], and by immunoblot, the OR was 21.4 (95% CI 7.1-64.4). Using a western blot assay, nearly all noncardia GC were classified as H. pylori positive and the OR was more than threefold higher than the OR assessed by ELISA, supporting the hypothesis that H. pylori infection is a necessary condition for noncardia GC.

  • 16. Gonzalez, Carlos A
    et al.
    Pera, Guillem
    Agudo, Antonio
    Bueno-de-Mesquita, H Bas
    Ceroti, Marco
    Boeing, Heiner
    Schulz, Mandy
    Del Giudice, Giuseppe
    Plebani, Mario
    Carneiro, Fátima
    Berrino, Franco
    Sacerdote, Carlotta
    Tumino, Rosario
    Panico, Salvatore
    Berglund, Göran
    Simane, Henrik
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Martinez, Carmen
    Dorronsoro, Miren
    Barricarte, Aurelio
    Navarro, Carmen
    Quiros, José R
    Allen, Naomi
    Key, Timothy J
    Bingham, Sheila
    Day, Nicholas E
    Linseisen, Jakob
    Nagel, Gabriele
    Overvad, Kim
    Jensen, Majken K
    Olsen, Anja
    Tjänneland, Anne
    Bächner, Frederike L
    Peeters, Petra H M
    Numans, Mattijs E
    Clavel-Chapelon, Francoise
    Boutron-Ruault, Marie-Christine
    Roukos, Dimitrios
    Trichopoulou, Antonia
    Psaltopoulou, Theodora
    Lund, Eiliv
    Casagrande, Corinne
    Slimani, Nadia
    Jenab, Mazda
    Riboli, Elio
    Fruit and vegetable intake and the risk of stomach and oesophagus adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST).2006In: International Journal of Cancer, ISSN 0020-7136, Vol. 118, no 10, p. 2559-66Article in journal (Refereed)
  • 17.
    Henriksson, Maria L
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Colorectal Cancer Cells Activate Adjacent Fibroblasts Resulting in FGF1/FGFR3 Signaling and Increased Invasion.2011In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 178, no 3, p. 1387-1394Article in journal (Refereed)
    Abstract [en]

    Cancer-associated fibroblasts expressing fibroblast activation protein (FAP) have been implicated in the invasive behavior of colorectal cancer. In this study, we use FAP expression as a marker of fibroblast activation and analyze the effect of activated fibroblasts on colorectal cancer migration and invasion in experimental cell studies. We also investigated the expression pattern of FAP in cancer-associated fibroblasts during transformation from benign to malignant colorectal tumors. In immunohistochemical analyses, FAP was expressed in fibroblasts in all colorectal cancer samples examined, whereas all normal colon, hyperplastic polyps, or adenoma samples were negative. In in vitro studies, conditioned medium from colon cancer cells, but not adenoma cells, activated fibroblasts by inducing FAP expression. These activated fibroblasts increased the migration and invasion of colon cancer cells in Boyden chamber experiments and in a three-dimensional cell culture model. We identify fibroblast growth factor 1/fibroblast growth factor receptor 3 (FGF1/FGFR-3) signaling as mediators leading to the increased migration and invasion. Activated fibroblasts increase their expression of FGF1, and by adding a fibroblast growth factor receptor inhibitor, as well as an FGF1-neutralizing antibody, we reduced the migration of colon cancer cells. Our findings provide evidence of a possible molecular mechanism involved in the cross talk between cancer cells and fibroblasts leading to cancer cell invasion.

  • 18. Huerta, José María
    et al.
    Navarro, Carmen
    Chirlaque, María-Dolores
    Tormo, María-José
    Steindorf, Karen
    Buckland, Genevieve
    Carneiro, Fátima
    Johnsen, Nina Føns
    Overvad, Kim
    Stegger, Jakob
    Tjønneland, Anne
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Morois, Sophie
    Boeing, Heiner
    Kaaks, Rudolf
    Rohrmann, Sabine
    Vigl, Matthäus
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Trichopoulou, Antonia
    Bas Bueno-de-Mesquita, H
    Monninkhof, Evelyn M
    Numans, Mattijs E
    Peeters, Petra H
    Mattiello, Amalia
    Pala, Valeria
    Palli, Domenico
    Tumino, Rosario
    Vineis, Paolo
    Agudo, Antonio
    Ardanaz, Eva
    Arriola, Larraitz
    Molina-Montes, Esther
    Rodríguez, Laudina
    Lindkvist, Björn
    Manjer, Jonas
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lund, Eiliv
    Crowe, Francesca L
    Key, Timothy J
    Khaw, Kay-Tee
    Wareham, Nicholas J
    Jenab, Mazda
    Norat, Teresa
    Romaguera, Dora
    Riboli, Elio
    González, Carlos A
    Prospective study of physical activity and risk of primary adenocarcinomas of the oesophagus and stomach in the EPIC (European Prospective Investigation into Cancer and nutrition) cohort.2010In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 21, no 5, p. 657-669Article in journal (Refereed)
    Abstract [en]

    Overall and distal (non-cardia) gastric tumours were inversely associated with time spent on cycling and sports and a total PA index. No association was found for any type of PA and risk of cardia cancers of the stomach.

  • 19. Isaksson-Mettavainio, Martin
    et al.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Forssell, Johan
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    SMAD4/DPC4 expression and prognosis in human colorectal cancer.2006In: Anticancer Res, ISSN 0250-7005, Vol. 26, no 1B, p. 507-10Article in journal (Refereed)
  • 20.
    Isaksson-Mettävainio, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    c-Met expression in primary tumors and their corresponding distant metastases2009In: Molecular Medicine Reports, ISSN 1791-2997, Vol. 1, no 6, p. 787-790Article in journal (Refereed)
    Abstract [en]

    c-Met is a receptor tyrosine kinase that has beenimplicated in the pathogenesis and growth of a wide variety ofhuman malignancies, including CRC, but its role in metastasisis largely unknown. We compared c-Met expression in primaryhuman colorectal carcinomas and distant metastases from thesame patients. Formalin-fixed paraffin-embedded tissuesamples from 69 colorectal cancer patients were obtained. Theprotein expression of c-Met was evaluated immunohistochemicallyusing a commercial antibody. The difference inexpression between primary tumors and their correspondingdistant metastases was analyzed using the Wilcoxon signedranktest. c-Met expression was statistically significantlylower in the distant metastases compared to their correspondingprimary tumors (p<0.001), whereas no difference was foundbetween lymph node metastases and their correspondingprimary tumors (p=0.957). The degree of c-Met expressionwas not related to clinicopathological characteristics such astumor grade and Dukes' stage at the time of primary tumordiagnosis, or to the location of the distant metastases. Wedemonstrated that c-Met expression is often reduced in distantmetastases compared to their corresponding primary colorectaltumors. Additional studies of c-Met activation and signaltransduction will increase our knowledge about the role ofc-Met in colorectal cancer metastasis.

  • 21. Jakszyn, Paula
    et al.
    Agudo, Antonio
    Lujan-Barroso, Leila
    Bueno-de-Mesquita, H. Bas
    Jenab, Mazda
    Navarro, Carmen
    Palli, Domenico
    Boeing, Heiner
    Manjer, Jonas
    Numans, Mattijs E.
    Igali, Laszlo
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Francoise
    Morois, Sophie
    Grioni, Sara
    Panico, CSalvatore
    Tumino, Rosario
    Sacerdote, Carlotta
    Ramon Quiros, J.
    Molina-Montes, Esther
    Huerta Castano, Jose Ma
    Barricarte, Aurelio
    Amiano, Pilar
    Khaw, Kay-Tee
    Wareham, Nicholas
    Allen, Naomi E.
    Key, Timothy J.
    Jeurnink, Suzanne M.
    Peeters, Petra H. M
    Bamia, Christina
    Valanou, Elisabeth
    Trichopoulou, Antonia
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Bergmann, Manuela M.
    Lindkvist, Bjorn
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Dahm, Christina C.
    Overvad, Kim
    Olsen, Anja
    Tjonneland, Anne
    Skeie, Guri
    Ragnhild Broderstad, Ann
    Lund, Eiliv
    Michaud, Dominique S.
    Mouw, Traci
    Riboli, Elio
    Gonzalez, Carlos A.
    Dietary intake of heme iron and risk of gastric cancer in the European prospective investigation into cancer and nutrition study2012In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 130, no 11, p. 2654-2663Article in journal (Refereed)
    Abstract [en]

    Even though recent studies suggest that a high intake of heme iron is associated with several types of cancer, epidemiological studies in relation to gastric cancer (GC) are lacking. Our previous results show a positive association between red and processed meat and non cardia gastric cancer, especially in Helicobacter pylori infected subjects. The aim of the study is to investigate the association between heme iron intake and GC risk in the European prospective investigation into cancer and nutrition (EURGAST-EPIC). Dietary intake was assessed by validated center-specific questionnaires. Heme iron was calculated as a type-specific percentage of the total iron content in meat intake, derived from the literature. Antibodies of H. pylori infection and vitamin C levels were measured in a sub-sample of cases and matched controls included in a nested case-control study within the cohort. The study included 481,419 individuals and 444 incident cases of GC that occurred during an average of 8.7 years of followup. We observed a statistically significant association between heme iron intake and GC risk (HR 1.13 95% CI: 1.011.26 for a doubling of intake) adjusted by sex, age, BMI, education level, tobacco smoking and energy intake. The positive association between heme iron and the risk of GC was statistically significant in subjects with plasma vitamin C <39 mmol/l only (log2 HR 1.54 95% CI (1.012.35). We found a positive association between heme iron intake and gastric cancer risk.

  • 22. Jakszyn, Paula
    et al.
    Bingham, Sheila
    Pera, Guillem
    Agudo, Antonio
    Luben, Robert
    Welch, Ailsa
    Boeing, Heiner
    Del Giudice, Giuseppe
    Palli, Domenico
    Saieva, Calogero
    Krogh, Vittorio
    Sacerdote, Carlotta
    Tumino, Rosario
    Panico, Salvatore
    Berglund, Göran
    Siman, Henrik
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Sanchez, María José
    Larranaga, Nerea
    Barricarte, Aurelio
    Chirlaque, María Dolores
    Quiros, José R
    Key, Timothy J
    Allen, Naomi
    Lund, Eiliv
    Carneiro, Fátima
    Linseisen, Jakob
    Nagel, Gabriele
    Overvad, Kim
    Tjonneland, Anne
    Olsen, Anja
    Bueno-de-Mesquita, H Bas
    Ocké, Marga O
    Peeters, Petra Hm
    Numans, Mattijs E
    Clavel-Chapelon, Francois
    Trichopoulou, Antonia
    Fenger, Claus
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ferrari, Pietro
    Jenab, Mazda
    Norat, Teresa
    Riboli, Elio
    Gonzalez, Carlos A
    Endogenous versus exogenous exposure to N-nitroso compounds and gastric cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST) study.2006In: Carcinogenesis, ISSN 0143-3334, Vol. 27, no 7, p. 1497-501Article in journal (Refereed)
  • 23. Jenab, Mazda
    et al.
    McKay, James D
    Ferrari, Pietro
    Biessy, Carine
    Laing, Stewart
    Munar, Gabriel Maria Capella
    Sala, Núria
    Peña, Salvador
    Crusius, J B A
    Overvad, Kim
    Jensen, Majken K
    Olsen, Anja
    Tjonneland, Anne
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Kaaks, Rudolf
    Linseisen, Jakob
    Boeing, Heiner
    Bergmann, Manuela M
    Trichopoulou, Antonia
    Georgila, Christina
    Psaltopoulou, Theodora
    Mattiello, Amalia
    Vineis, Paolo
    Pala, Valeria
    Palli, Domenico
    Tumino, Rosario
    Numans, Mattijs E
    Peeters, Petra H M
    Bueno-de-Mesquita, H Bas
    Lund, Eiliv
    Ardanaz, Eva
    Sánchez, Maria-Jose
    Dorronsoro, Miren
    Sanchez, Carmen Navarro
    Quirós, José Ramón
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Manjer, Jonas
    Régner, Sara
    Key, Tim
    Bingham, Sheila
    Khaw, Kay-tee
    Slimani, Nadia
    Rinaldi, Sabina
    Boffetta, Paolo
    Carneiro, Fátima
    Riboli, Elio
    Gonzalez, Carlos
    CDH1 gene polymorphisms, smoking, Helicobacter pylori infection and the risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST).2008In: Eur J Cancer, ISSN 0959-8049, Vol. 44, no 6, p. 774-780Article in journal (Refereed)
  • 24. Jenab, Mazda
    et al.
    Riboli, Elio
    Ferrari, Pietro
    Sabate, Joan
    Slimani, Nadia
    Norat, Teresa
    Friesen, Marlin
    Tjänneland, Anne
    Olsen, Anja
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Francois
    Touvier, Mathilde
    Boeing, Heiner
    Schulz, Mandy
    Linseisen, Jakob
    Nagel, Gabriele
    Trichopoulou, Antonia
    Naska, Androniki
    Oikonomou, Eleni
    Krogh, Vittorio
    Panico, Salvatore
    Masala, Giovanna
    Sacerdote, Carlotta
    Tumino, Rosario
    Peeters, Petra H
    Numans, Mattijs E
    Bueno-de-Mesquita, Hendrik B
    Büchner, Frederike L
    Lund, Eiliv
    Pera, Guillem
    Sanchez, Carmen Navarro
    Sanchez, Maria-Jose
    Arriola, Larraitz
    Barricarte, Aurelio
    Quiros, José R
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Berglund, Göran
    Bingham, Sheila
    Khaw, Kay-Tee
    Key, Timothy
    Allen, Naomi
    Carneiro, Fatima
    Mahlke, U
    Del Giudice, Guiseppe
    Palli, Domenico
    Kaaks, Rudolf
    Gonzalez, Carlos A
    Plasma and dietary vitamin C levels and risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST).2006In: Carcinogenesis, ISSN 0143-3334, Vol. 27, no 11, p. 2250-7Article in journal (Refereed)
  • 25.
    Lindberg, J
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery. Kirurgi.
    Surgery for neoplastic changes in ulcerative colitis - can limited resection be justified? Outcome for patients who underwent limited surgery.2006In: Colorectal Disease, ISSN 1462-8910, E-ISSN 1463-1318, Vol. 8, no 7, p. 551-556Article in journal (Refereed)
  • 26.
    Lindberg, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Early onset of ulcerative colitis: long-term follow-up with special reference to colorectal cancer and primary sclerosing cholangitis.2008In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 46, no 5, p. 534-538Article in journal (Refereed)
  • 27.
    Lindberg, Jan
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery. Kirurgi.
    Efficiency of colorectal cancer surveillance in patients with ulcerative colitis: 26 years' experience in a patient cohort from a defined population area.2005In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 40, no 9, p. 1076-1080Article in journal (Refereed)
  • 28.
    Ling, Agnes
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Löfgren-Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Larsson, Pär
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Li, Xingru
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    TAP1 down-regulation elicits immune escape and poor prognosis in colorectal cancer2017In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 6, no 11, article id e1356143Article in journal (Refereed)
    Abstract [en]

    The anti-tumor immune response has been shown to be of great prognostic importance in colorectal cancer (CRC) and so has the tumors ability for immune evasion. Our aim of this study was to investigate tumor factors that influence immunity. We used a gene expression array to search for potential mechanisms of tumor immune escape. One candidate gene identified was TAP1, involved in antigen presentation by MHC class I. TAP1 protein expression was evaluated by immunohistochemistry in 436 CRC patients of the Colorectal Cancer in Umeå Study cohort. We found a significant association between a downregulated expression of TAP1 and low infiltration of various subtypes of lymphocytes as well as macrophages. A downregulated expression of TAP1 was further found to be independent of molecular characteristics, suggesting TAP1 down-regulation to reach beyond the well described highly immunogenic MSI CRCs. A low expression of TAP1 was also significantly associated with poor prognosis in patients with CRC, a result that stayed significant in tumor front of early stage tumors (stage I-II) through multivariable analyses. Furthermore, we found that TAP1 expression was inversely correlated with methylation at sites in close proximity to the promoter region. In summary, our results show down-regulation of TAP1 to be a general mechanism of tumor immune escape in CRC and a poor prognostic factor in stage I-II CRC patients. We also suggest that methylation of the TAP1 gene may be a putative mechanism for TAP1 downregulation.

  • 29.
    Ljuslinder, Ingrid
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Jonsson, Yvonne
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    LRIG1 expression in colorectal cancer2007In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 46, no 8, p. 1118-1122Article in journal (Refereed)
  • 30.
    Ljuslinder, Ingrid
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Isaksson-Mettävainio, Martin
    Öberg, Åke
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    ErbB 1-4 expression alterations in primary colorectal cancers and their corresponding metastases2009In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 29, no 5, p. 1489-1494Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: EGFR (epidermal growth factor receptor) targeted therapies are important new tools in colorectal cancer treatment. EGFR analysis of the primary tumour was previously recommended to identify patients who will benefit from the EGFR targeted therapy. Previous studies have displayed diverging results regarding the expression of EGFR in the primary tumour compared to the metastases. The present study was performed to investigate whether EGFR and ErbB2-4 expression differed between 64 primary tumours and their corresponding metastases.

    PATIENTS AND METHODS: EGFR and ErbB2-4 expression were analysed in the primary tumour and in the corresponding metastases using immunohistochemistry (IHC).

    RESULTS: In 49/64 samples (76%), the primary tumours were EGFR positive; in 33% (16/49) of EGFR positive samples, the tumours lost the EGFR expression in the metastasis compared to the primary tumour. From the primary tumours, 15/64 (23%) were negative and 5 of these (33%) developed EGFR expression in the metastasis. ErbB2, ErbB3, and ErbB4 expression was evident in 54%, 67%, and 81%, respectively. There was no significant difference between ErbB2, ErbB3, and ErbB4 expression in primary tumours and metastases. The co-expression of the ErbB family members was also analysed, with a significant increase of ErbB3/ErbB4 co-expression in late stage tumours.

    CONCLUSION: The EGFR expression was lost in 33% of metastasising primary colorectal cancer tumours, a finding that agrees with at least one previous study. Thus, the present results clearly implicate the need for EGFR analysis of both the primary tumour and metastases to accurately determine EGFR status when considering the use of EGFR targeted therapies.

  • 31.
    Lundberg, Ida V
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Löfgren Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Eklöf, Vincy
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    SOX2 expression is regulated by BRAF and contributes to poor patient prognosis in colorectal cancer2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, article id e101957Article in journal (Refereed)
    Abstract [en]

    Sporadic colorectal cancer (CRC) is a common malignancy and also one of the main causes of cancer deaths worldwide. Aberrant expression of the transcription factor SOX2 has recently been observed in several cancer types, but its role in CRC has not been fully elucidated. Here we studied the expression of SOX2 in 441 CRC patients by immunohistochemistry and related the expression to clinicopathological and molecular variables and patient prognosis. SOX2 was expressed in 11% of the tumors and was significantly associated to BRAF(V600E) mutation, but not to KRAS mutations (codon 12 and 13). SOX2 positivity was correlated to poor patient survival, especially in BRAF(V600E) mutated cases. In vitro studies showed that cells expressing the constitutively active BRAF(V600E) had increased SOX2 expression, a finding not found in cells expressing KRAS(G12V). Furthermore, blocking downstream BRAF signalling using a MEK-inhibitor resulted in a decreased expression of SOX2. Since SOX2 overexpression has been correlated to increased migration and invasion, we investigated the SOX2 expression in human CRC liver metastasis and found that a SOX2 positive primary CRC also had SOX2 expression in corresponding liver metastases. Finally we found that cells overexpressing SOX2 in vitro showed enhanced expression of FGFR1, which has been reported to correlate with liver metastasis in CRC. Our novel findings suggest that SOX2 expression is partly regulated by BRAF signalling, and an increased SOX2 expression may promote CRC metastasis and mediate a poor patient prognosis.

  • 32. Mendez, M A
    et al.
    Pera, G
    Agudo, A
    Bueno-de-Mesquita, HB
    Palli, D
    Boeing, H
    Carneiro, F
    Berrino, F
    Sacerdote, C
    Tumino, R
    Panico, S
    Berglund, G
    Manjer, J
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Odontology, Cariology.
    Stenling, R
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Martinez, C
    Dorronsoro, M
    Barricarte, A
    Tormo, MJ
    Quiros, JR
    Allen, N
    Key, TJ
    Bingham, S
    Linseisen, J
    Kaaks, R
    Overvad, K
    Jensen, M
    Olsen, A
    Tjonneland, A
    Peeters, PH
    Numans, ME
    Ocké, MC
    Clavel-Chapelon, F
    Boutron-Ruault, MC
    Trichopoulou, A
    Lund, E
    Slimani, N
    Jenab, M
    Ferrari, P
    Riboli, E
    González, CA
    Cereal fiber intake may reduce risk of gastric adenocarcinomas: the EPIC-EURGAST study.2007In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 121, no 7, p. 1618-1623Article in journal (Refereed)
    Abstract [en]

    Numerous case-control studies suggest dietary fiber may reduce risk of gastric cancer, but this has not been confirmed prospectively. A previous case-control study reported reduced risk of gastric cardia adenocarcinomas associated with cereal fiber, but not with fruit or vegetable fiber. To date, different food sources of fiber have not been examined with respect to noncardia tumors or diverse histologic sub-types. This study prospectively examines associations between fiber from different food sources and incident gastric adenocarcinomas (GC) among more than 435,000 subjects from 10 countries participating in the European Prospective Investigation into Cancer and Nutrition study. Subjects aged 25-70 years completed dietary questionnaires in 1992-98, and were followed up for a median of 6.7 years. About 312 incident GCs were observed. The relative risk of GC was estimated based on cohort-wide sex-specific fiber intake quartiles using proportional hazards models to estimate hazards ratios (HRs) and 95% confidence intervals (CIs). Intakes of cereal fiber, but not total, fruit or vegetable fiber, were associated with reduced GC risk [adjusted HR for the highest vs. lowest quartile of cereal fiber 0.69, 0.48-0.99]. There was a strong inverse association for diffuse [HR 0.43, 0.22-0.86], but not intestinal type [HR 0.98, 0.54-1.80] tumors. Associations for cardia vs. noncardia tumors were similar to those for overall GC, although cardia associations did not reach significance. Cereal fiber consumption may help to reduce risk of GC, particularly diffuse type tumors. Further study on different food sources of fiber in relation to GC risk is warranted to confirm these relationships.

  • 33. Mårtensson, Ann
    et al.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Jung, Andreas
    Cederquist, Kristina
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Beta-catenin expression in relation to genetic instability and prognosis in colorectal cancer.2007In: Oncol Rep, ISSN 1021-335X, Vol. 17, no 2, p. 447-52Article in journal (Refereed)
  • 34. Nagel, Gabriele
    et al.
    Linseisen, Jakob
    Boshuizen, Hendriek C
    Pera, Guillem
    Del Giudice, Giuseppe
    Westert, Gert P
    Bueno-de-Mesquita, H Bas
    Allen, Naomi E
    Key, Timothy J
    Numans, Mattijs E
    Peeters, Petra Hm
    Sieri, Sabina
    Siman, Henrik
    Berglund, Goran
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Martinez, Carmen
    Arriola, Larraitz
    Barricarte, Aurelio
    Chirlaque, M Dolores
    Quiros, Jose R
    Vineis, Paolo
    Masala, Giovanna
    Palli, Domenico
    Panico, Salvatore
    Tumino, Rosario
    Bingham, Sheila
    Boeing, Heiner
    Bergmann, Manuela M
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Francoise
    Olsen, Anja
    Tjonneland, Anne
    Trichopoulou, Antonia
    Bamia, Christina
    Soukara, Stavroula
    Sabourin, Jean-Christoph
    Carneiro, Fatima
    Slimani, Nadia
    Jenab, Mazda
    Norat, Teresa
    Riboli, Elio
    González, Carlos A
    Socioeconomic position and the risk of gastric and oesophageal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST).2007In: International Journal of Epidemiology, ISSN 0300-5771, Vol. 36, no 1, p. 66-76Article in journal (Refereed)
  • 35.
    Palmqvist, Richard
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zhang, Anju
    Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Hospital and Institute, Stockholm, Sweden.
    Xu, Dawei
    Department of Medicine, Cancer Center Karolinska, Karolinska Hospital and Institute, Stockholm, Sweden.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Norrback, Karl-Fredrik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gruber, Astrid
    Department of Medicine, Cancer Center Karolinska, Karolinska Hospital and Institute, Stockholm, Sweden.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    hTERT gene copy number is not associated with hTERT RNA expression or telomerase activity in colorectal cancer2005In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 116, no 3, p. 395-400Article in journal (Refereed)
    Abstract [en]

    In a majority of malignant human tumors telomerase activity can be detected, suggesting an immortal phenotype. Expression of the reverse transcriptase subunit, hTERT, in the human telomerase complex is required for telomerase activity. The regulation of hTERT, from gene level to a fully functional protein, is still a poorly understood process. Increased copy number of the hTERT gene has been demonstrated in a significant portion of established cell lines and tumors of different origin but its relevance for telomerase activity levels is unclear. In the present study, we examined the hTERT gene copy number using fluorescence in situ hybridization (FISH) in samples from 64 colorectal carcinomas and an increased copy number (≥ 3 hTERT gene copies/nucleus) was observed in 31 cases (48%). No statistical association existed between hTERT gene copy number and hTERT RNA expression or telomerase activity. However, a significant relationship was found between an increase in hTERT gene copy number and p53 protein accumulation (p = 0.002) and aneuploidy (p = 0.036). Only 4 tumors showed microsatellite instability, 3 of which had a normal hTERT gene copy number. The data indicated that the increased copy number of the hTERT gene in colorectal carcinoma was a result of genomic instability with no obvious consequence for telomerase activity levels.

  • 36.
    Rutegård, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lindberg, Jan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Efficiency of Colorectal Cancer Surveillance in Patients With Ulcerative Colitis: 38 Years' Experience in a Patient Cohort From a Defined Population Area2017In: Scandinavian Journal of Surgery, ISSN 1457-4969, E-ISSN 1799-7267, Vol. 106, no 2, p. 133-138Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Ulcerative colitis increases the risk of developing colorectal cancer. Colonoscopic surveillance is recommended although there are no randomized trials evaluating the efficacy of such a strategy. This study is an update of earlier studies from an ongoing colonoscopic surveillance program.

    MATERIAL AND METHODS: All patients with ulcerative colitis were invited to the surveillance program that started in 1977 at Örnsköldsvik Hospital, located in the northern part of Sweden. Five principal endoscopists performed the colonoscopies and harvested mucosal sampling for histopathological evaluation. Some 323 patients from the defined catchment area were studied from 1977 to 2014. At the end of the study period, 130 patients, including those operated on, had had total colitis for more than 10 years.

    RESULTS: In total, 1481 colonoscopies were performed on 323 patients during the study period without any major complications. In all, 10 cases of colorectal cancer were diagnosed in 9 patients, of whom 1 died from colorectal cancer. The cumulative incidence of colorectal cancer was 1.4% at 10 years, 2.0% at 20 years, 3.0% at 30 years, and 9.4% at 40 years of disease duration, respectively. The standardized colorectal cancer incidence ratio was 3.01 (95% confidence interval: 1.42-5.91). Major surgery was performed on 65 patients; for 20 of these, the indication for surgery was dysplasia or colorectal cancer. Panproctocolectomy was performed in 43 patients.

    CONCLUSION: This study supports that colonoscopic surveillance is a safe and effective long-term measure to detect dysplasia and progression to cancer. The low numbers of colorectal cancer-related deaths in our study suggest that early detection of neoplasia and adequate surgical intervention within a surveillance program may reduce colorectal cancer mortality in ulcerative colitis patients.

  • 37. Sala, Núria
    et al.
    Muñoz, Xavier
    Travier, Noemie
    Agudo, Antonio
    Duell, Eric J
    Moreno, Víctor
    Overvad, Kim
    Tjonneland, Anne
    Boutron-Ruault, Marie Christine
    Clavel-Chapelon, Françoise
    Canzian, Federico
    Kaaks, Rudolf
    Boeing, Heiner
    Meidtner, Karina
    Trichopoulos, Antonia
    Tsiotas, Konstantine
    Zylis, Dimosthenis
    Vineis, Paolo
    Panico, Salvatore
    Palli, Domenico
    Krogh, Vittorio
    Tumino, Rosario
    Lund, Eiliv
    Bueno-de-Mesquita, H Bas
    Numans, Mattjis E
    Peeters, Petra H M
    Quirós, J Ramon
    Sánchez, María-José
    Navarro, Camen
    Ardanaz, Eva
    Dorronsoro, Miren
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Manjer, Jonas
    Allen, Naomi E
    Travis, Ruth C
    Khaw, Kay-Tee
    Jenab, Mazda
    Offerhaus, G Johan A
    Riboli, Elio
    González, Carlos A
    Prostate stem-cell antigen gene is associated with diffuse and intestinal gastric cancer in Caucasians: Results from the EPIC-EURGAST study.2012In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 130, no 10, p. 2417-2427Article in journal (Refereed)
    Abstract [en]

    A genome-wide study performed in a Japanese population identified a strong association between SNP rs2294008 (Met1Thr) in the Prostate Stem Cell Antigen gene (PSCA) and diffuse-type gastric cancer (GC). This association was validated in different Asian populations, and, very recently, a study has been published in Caucasians. In this study, we analyzed the association between PSCA variation and GC risk in Caucasians from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Six tagSNPs covering the PSCA gene region were genotyped in 411 incident gastric adenocarcinoma cases and 1530 matched controls from a nested case-control study in the EPIC cohort. Associations were analyzed by unconditional logistic regression, adjusting for age, sex and country. The T allele of rs2294008 in PSCA was found to be a highly significant risk factor for GC (per allele OR = 1.42, 95% CI: 1.23-1.66, p-value = 6.5 × 10(-6) ), particularly of the noncardia-type (per allele OR = 1.47, 95% CI: 1.19-1.81, p-value = 3 × 10(-4) ). At contrast with previous studies, no significant differences were observed between the diffuse (per allele OR = 1.54, 95% CI: 1.20-1.96, p-value = 5 × 10(-4) ) and the intestinal (per allele OR = 1.52, 95% CI: 1.20-1.93, p-value = 5 × 10(-4) ) GC histological subtypes. Although rs12155758 and rs9297976 were also found associated with GC, this association appeared to be due to linkage disequilibrium with rs2294008. Haplotype analysis did not provide additional information. These results confirm the association between variation in the promoter region of PSCA and GC risk in Caucasians and also indicate that the rs2294008 variant is a similar risk factor for both the diffuse and intestinal-types of GC.

  • 38. Serafini, Mauro
    et al.
    Jakszyn, Paula
    Lujan-Barroso, Leila
    Agudo, Antonio
    Bueno-de-Mesquita, H. Bas
    van Duijnhoven, Franzel J. B.
    Jenab, Mazda
    Navarro, Carmen
    Palli, Domenico
    Boeing, Heiner
    Wallstrom, Peter
    Regner, Sara
    Numans, Mattijs E.
    Carneiro, Fatima
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Francoise
    Morois, Sophie
    Grioni, Sara
    Panico, Salvatore
    Tumino, Rosario
    Sacerdote, Carlotta
    Ramon Quiros, Jose
    Molina-Montes, Esther
    Huerta Castano, Jose M.
    Barricarte, Aurelio
    Amiano, Pilar
    Khaw, Kay-Tee
    Wareham, Nicholas
    Allen, Naomi E.
    Key, Timothy J.
    Jeurnink, Suzanne M.
    Peeters, Petra H. M.
    Bamia, Christina
    Valanou, Elisabeth
    Trichopoulou, Antonia
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Bergmann, Manuela M.
    Lindkvist, Bjorn
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Dahm, Christina C.
    Overvad, Kim
    Jensen, Majken
    Olsen, Anja
    Tjonneland, Anne
    Lund, Eiliv
    Rinaldi, Sabina
    Michaud, Dominique
    Mouw, Traci
    Riboli, Elio
    Gonzalez, Carlos A.
    Dietary total antioxidant capacity and gastric cancer risk in the European prospective investigation into cancer and nutrition study2012In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 131, no 4, p. E544-E554Article in journal (Refereed)
    Abstract [en]

    A high intake of dietary antioxidant compounds has been hypothesized to be an appropriate strategy to reduce gastric cancer (GC) development. We investigated the effect of dietary total antioxidant capacity (TAC) in relation to GC in the European Prospective Investigation into Cancer (EPIC) study including 23 centers in 10 European countries. A total of 521,457 subjects (153,447 men) aged mostly 3570 years old, were recruited largely between 1992 and 1998. Ferric reducing antioxidant potential (FRAP) and total radical-trapping antioxidant parameter (TRAP), measuring reducing and chain-breaking antioxidant capacity were used to measure dietary TAC from plant foods. Dietary antioxidant intake is associated with a reduction in the risk of GC for both FRAP (adjusted HR 0.66; 95%CI (0.460.95) and TRAP (adjusted HR 0.61; 95%CI (0.430.87) (highest vs. lowest quintile). The association was observed for both cardia and noncardia cancers. A clear effect was observed in smokers with a significant reduction in GC risk for the fifth quintile of intake for both assays (highest vs. lowest quintile: adjusted HR 0.41; 95%CI (0.220.76) p for trend <0.001 for FRAP; adjusted HR 0.52; 95%CI (0.280.97) p for trend <0.001 for TRAP) but not in nonsmokers. In former smokers, the association with FRAP intake was statistically significant (highest vs. lowest quintile: adjusted HR 0.4; 95%CI (0.210.75) p < 0.05); no association was observed for TRAP. Dietary antioxidant capacity intake from different sources of plant foods is associated with a reduction in the risk of GC.

  • 39.
    Steffen, Annika
    et al.
    Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
    Schulze, Matthias B
    Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
    Pischon, Tobias
    Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
    Dietrich, Thomas
    Department of Oral Surgery, The School of Dentistry, University of Birmingham, Birmingham, United Kingdom.
    Molina, Esther
    Andalusian School of Public Health, Granada, Spain.
    Chirlaque, Maria-Dolores
    CIBER de Epidemiología y Salud Pública, Madrid, Spain.
    Barricarte, Aurelio
    CIBER de Epidemiología y Salud Pública, Madrid, Spain.
    Amiano, Pilar
    CIBER de Epidemiología y Salud Pública, Madrid, Spain.
    Quirós, J Ramón
    CIBER de Epidemiología y Salud Pública, Madrid, Spain.
    Tumino, Rosario
    Cancer Registry and Histopathology Unit, “Civile-M.P.Arezzo” Hospital, Ragusa, Italy.
    Mattiello, Amalia
    Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy.
    Palli, Domenico
    Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute, Florence, Italy.
    Vineis, Paolo
    Department of Epidemiology and Public Health, Imperial College, London, United Kingdom.
    Agnoli, Claudia
    Department of Preventive and Predictive Medicine, Nutritional Epidemiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
    Misirli, Gesthimani
    Department of Hygiene and Epidemiology, University of Athens Medical School, Athens, Greece.
    Boffetta, Paolo
    Lifestyle, Environment and Cancer Group, IARC, Lyon, France.
    Kaaks, Rudolf
    Division of Clinical Epidemiology, German Cancer Research Center, Heidelberg, Germany.
    Rohrmann, Sabine
    Division of Clinical Epidemiology, German Cancer Research Center, Heidelberg, Germany.
    Bueno-de-Mesquita, H Bas
    National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
    Peeters, Petra H M
    Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
    May, Anne M
    National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
    Spencer, Elizabeth A
    Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom.
    Allen, Naomi E
    Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom.
    Bingham, Sheila
    Department of Public Health and Primary Care, MRC Centre for Nutritional Epidemiology in Cancer Prevention and Survival, Cambridge, United Kingdom.
    Tjønneland, Anne
    Danish Cancer Society, Institute of Cancer Epidemiology, Copenhagen, Denmark.
    Halkjaer, Jytte
    Danish Cancer Society, Institute of Cancer Epidemiology, Copenhagen, Denmark.
    Overvad, Kim
    Department of Clinical Epidemiology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark.
    Stegger, Jakob
    Department of Cardiology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark.
    Manjer, Jonas
    Department of Surgery, Malmö University Hospital, Malmö, Sweden.
    Lindkvist, Björn
    Department of Internal Medicine, Division of Gastroenterology and Hepatology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Hallmanns, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lund, Eiliv
    The Institute of Community Medicine, University of Tromsø, Tromsø, Norway.
    Riboli, Elio
    Department of Epidemiology and Public Health, Imperial College, London, United Kingdom.
    Gonzalez, Carlos A
    Department of Epidemiology, Catalan Institute of Oncology, IDIBELL, Barcelona, Spain .
    Boeing, Heiner
    Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
    Anthropometry and esophageal cancer risk in the European prospective investigation into cancer and nutrition2009In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 18, no 7, p. 2079-2089Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Increasing evidence suggests that general obesity [measured by body mass index (BMI)] is positively associated with risk of esophageal adenocarcinoma (EAC). In contrast, previous studies have shown inverse relations with esophageal squamous cell carcinoma (ESCC). However, it is still unclear whether body fat distribution, particularly abdominal obesity, is associated with each type of esophageal cancer. METHODS: We applied multivariable adjusted Cox proportional hazards regression to investigate the association between anthropometric measures and risk of EAC and ESCC among 346,554 men and women participating in the European Prospective Investigation into Cancer and Nutrition. All statistical tests were two sided. RESULTS: During 8.9 years of follow-up, we documented 88 incident cases of EAC and 110 cases of ESCC. BMI, waist circumference, and waist-to-hip ratio (WHR) were positively associated with EAC risk [highest versus lowest quintile; relative risk (RR), 2.60; 95% confidence interval (95% CI), 1.23-5.51; P(trend) < 0.01; RR, 3.07; 95% CI, 1.35-6.98; P(trend) < 0.003; and RR, 2.12; 95% CI, 0.98-4.57; P(trend) < 0.004]. In contrast, BMI and waist circumference were inversely related to ESCC risk, whereas WHR showed no association with ESCC. In stratified analyses, BMI and waist circumference were significantly inversely related to ESCC only among smokers but not among nonsmokers. However, when controlled for BMI, we found positive associations for waist circumference and WHR with ESCC, and these associations were observed among smokers and nonsmokers. CONCLUSION: General and abdominal obesity were associated with higher EAC risk. Further, our study suggests that particularly an abdominal body fat distribution might also be a risk factor for ESCC.

  • 40.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    The enterocyte in small intestinal adaption: an experimental and clinicopathological study with special reference to the ultrastructure of the brush border1984Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The small intestine mucosa is known to be able to adapt itself to several kinds of both physiological and pathological conditions. The adaptive patterns of the structure of the enterocytes, particularly their apical surface (brush border), were studied in three models: (1) in rats, subjected to antrectomy or antral exclusion, combined with gastroduodenostomy and gastrojejunostomy; (2) in rats with alloxan dia­betes; (3) in children with coeliac disease; a) in its active phase; b) after long-term treatment with gluten-free diets; c) after long-term challenge with dietary gluten following treatment; d) after short-term elimination of dietary gluten. Gut mucosa from fasting or fed, normal or sham-operated rats, fasting cats, and short-statured children with no signs of gastrointestinal disease served as controls. - The specimens were prepared for light microscopy (LM), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Quantitation of structural variables was achieved by means of LM and TEM morphometrical procedures.

    Differentiation of the rat enterocytes from the base to the crest of the villi was structurally reflected by doubling of their apical cell area, an increase in cell height, and a decrease of both nuclear and mitochondrial volume densities. In mature normal rat enterocytes, high-power SEM showed regularly arranged, nude microvilli in thir apical surfaces, whereas in cat and man the apical surfaces were covered by a thick glycocalyx. - Fasting for 24 hours decreased the total length of the rat small intestine and the height of the enterocytes. Antrectomy and antral exclusion with gastrojejunostomy produced an increase of the apical surfaces of the enterocytes of the seif-emptying duodenal blind loop, whereas no changes occurred after antrectomy with gastroduodeno­stomy. In the jejunum, the apical surface area was reduced both after antrectomy and antral exclusion. In the diabetic rats a slight decrease of the apical surface area, together with an elongation of both the vil­li and the crypts, was observed in the jejunum, whereas no structural changes occurred in the duodenal mucosa.

    Both in active coeliac disease and after long-term challenge with dietary gluten, SEM analyses showed uniformly destructed villi. The api­cal surfaces of the enterocytes were frequently convex and irregular in size and delineation (the surface of the normal enterocytes was polygo­nal and flat). Ultrastructurally, the apical surfaces were severely damaged with a distortion of the glycocalyx and with marked irregularity of the microvilli. - After gluten elimination, the surface ultrastructu­re of the enterocytes in the coeliac gut mucosa generally showed a rapid, clear-cut restoration despite a remaining severe atrophy of the villi. Successful dietary treatment (after about one year of gluten-free diet) restored the small intestine mucosa to normal as assessed both by LM and low-power SEM. In contrast, high-power SEM often disclosed per­sisting lesions of the enterocytes. Another provocation with gluten for up to 9 days in clinically healed coeliac mucosa did not significantly alter the surface ultrastructure of the enterocytes.

  • 41.
    Stenling, Roger
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Lindberg, Jan
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Altered expression of CK7 and CK20 in preneoplastic and neoplastic lesions in ulcerative colitis.2007In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 115, no 11, p. 1219-1226Article in journal (Other academic)
  • 42.
    Svenson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Telomere length in peripheral leukocytes is associated with immune cell tumor infiltration and prognosis in colorectal cancer patients2016In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 37, no 8, p. 10877-10882Article in journal (Refereed)
    Abstract [en]

    Telomeres are protective structures at the end of chromosomes, essential for chromosomal integrity. A large number of studies have investigated leukocyte telomere length as a possible risk marker for various cancers, colorectal cancer (CRC) included. In contrast, studies investigating leukocyte telomere length in relation to CRC survival are lacking. We previously reported that relative telomere length (RTL) of leukocytes collected at diagnosis predicted survival in patients with breast and kidney cancer. We suggested that these findings might reflect various immunological mechanisms, affected by the presence of a tumor. In the present study, leukocyte RTL was examined in relation to immune cell tumor infiltration and prognosis in 130 patients with CRC diagnosis. RTL was measured with a well-established qPCR method. We found that patients with the highest degree of lymphocyte tumor infiltration had shorter leukocyte RTL. Consistent with our previous findings, short RTL was a favorable prognostic marker in univariate survival analysis. In the current study, RTL did not remain as an independent predictor in multivariate survival analysis, when including metastatic status in the model. However, a non-significant trend towards a similar telomere-associated survival pattern was observed in patients with limited disease. In contrast, for patients who died of other causes than CRC, short RTL was associated with significantly shorter survival time. To our knowledge, this is the first study to investigate an association between leukocyte RTL, immune cell tumor infiltration, and cancer-specific survival in CRC patients. Larger studies are warranted to verify these findings.

  • 43. Uddhammar, Agneta
    et al.
    Eriksson, Anna-Lena
    Nyström, Lennarth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Increased mortality due to cardiovascular disease in patients with giant cell arteritis in Northern Sweden2002In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 29, no 4, p. 737-742Article in journal (Refereed)
    Abstract [en]

    Objective. To study the cause of death pattern in patients with giant cell arteritis (GCA) or polymyalgia rheumatica (PMR). and to analyze the effect of the disease, or its therapy, on the risk of a cardiovascular event (CVE).

    Methods. Patients with biopsy proven GCA or with PMR, whose condition was diagnosed between 1973 and 1979, were followed until December 31, 1995. The standardized mortality ratio (SMR) was estimated using data for the population of V sterbotten, Northern Sweden, as reference value. Information for sex, age at diagnosis, erythrocyte sedimentation rate (ESR) at diagnosis, corticosteroid therapy, comorbidity from diagnosis, and date and cause of death was collected.

    Results. A total of 136 patients with GCA and 35 with PMR were identified. At the time of followup 114 patients with GCA and 25 with PMR were deceased. The overall mortality was significantly increased in the female patients, SMR = 133 (95% Cl 110-162). Death due to cardiovascular disease (CVD) was significantly increased in both women and men, SMR = 149 (95% CI 118-189) and 158 (95% Cl 112-224), respectively, and mainly due to ischemic heart disease. An excess mortality was found in women with the hi-hest ESR, the highest prescribed dose of prednisolone at diagnosis, or a daily prednisolone dose of 10 mg or more one year after diagnosis. In multiple Cox regression analysis, male sex and hypertension significantly increased the risk of a CVE.

    Conclusion. Death due to CVD was increased in patients with GCA. Increased mortality was related to either the corticosteroid therapy itself or insufficient control of inflammation.

  • 44.
    Van Guelpen, Bethany
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Riboli, E
    Winkvist, A
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Low folate levels may protect against colorectal cancer2006In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 55, no 10, p. 1461-1466Article in journal (Other academic)
    Abstract [en]

    BACKGROUND AND AIMS: Dietary folate is believed to protect against colorectal cancer (CRC). However, few studies have addressed the role of circulating levels of folate. The aim of this study was to relate prediagnostic plasma folate and homocysteine concentrations and the methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C polymorphisms to the risk of developing CRC.

    SUBJECTS: Subjects were 226 cases and 437 matched referents from the population based Northern Sweden Health and Disease Cohort.

    RESULTS: We observed a bell-shaped association between plasma folate concentrations and CRC risk; multivariate odds ratio for middle versus lowest quintile 2.00 (95% confidence interval (CI) 1.13-3.56). In subjects with follow up times greater than the median of 4.2 years however, plasma folate concentrations were strongly positively related to CRC risk; multivariate odds ratio for highest versus lowest quintile 3.87 (95% CI 1.52-9.87; p trend = 0.007). Homocysteine was not associated with CRC risk. Multivariate odds ratios for the MTHFR polymorphisms were, for 677 TT versus CC, 0.41 (95% CI 0.19-0.85; p trend = 0.062), and for 1298 CC versus AA, 1.62 (95% CI 0.94-2.81; p trend = 0.028). Interaction analysis suggested that the result for 1298A>C may have been largely due to linkage disequilibrium with 677C>T. The reduced CRC risk in 677 TT homozygotes was independent of plasma folate status.

    CONCLUSIONS: Our findings suggest a decreased CRC risk in subjects with low folate status. This possibility of a detrimental component to the role of folate in carcinogenesis could have implications in the ongoing debate in Europe concerning mandatory folate fortification of foods.

  • 45. Vollset, Stein Emil
    et al.
    Igland, Jannicke
    Jenab, Mazda
    Fredriksen, Ase
    Meyer, Klaus
    Eussen, Simone
    Gjessing, Håkon K
    Ueland, Per Magne
    Pera, Guillem
    Sala, Núria
    Agudo, Antonio
    Capella, Gabriel
    Del Giudice, Giuseppe
    Palli, Domenico
    Boeing, Heiner
    Weikert, Cornelia
    Bueno-de-Mesquita, H Bas
    Carneiro, Fátima
    Pala, Valeria
    Vineis, Paolo
    Tumino, Rosario
    Panico, Salvatore
    Berglund, Göran
    Manjer, Jonas
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Martínez, Carmen
    Dorronsoro, Miren
    Barricarte, Aurelio
    Navarro, Carmen
    Quirós, José R
    Allen, Naomi
    Key, Timothy J
    Bingham, Sheila
    Linseisen, Jakob
    Kaaks, Rudolf
    Overvad, Kim
    Tjønneland, Anne
    Büchner, Frederike L
    Peeters, Petra H M
    Numans, Mattijs E
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Trichopoulou, Antonia
    Lund, Eiliv
    Slimani, Nadia
    Ferrari, Pietro
    Riboli, Elio
    González, Carlos A
    The association of gastric cancer risk with plasma folate, cobalamin, and methylenetetrahydrofolate reductase polymorphisms in the European prospective investigation into cancer and nutrition.2007In: Cancer Epidemiology Biomarkers & Prevention, ISSN 1055-9965, Vol. 16, no 11, p. 2416-24Article in journal (Refereed)
  • 46.
    Wikberg, Maria L.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundberg, Ida V.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High intratumoral expression of fibroblast activation protein (FAP) in colon cancer is associated with poorer patient prognosis.2013In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 34, no 2, p. 1013-1020Article in journal (Refereed)
    Abstract [en]

    -An active stroma is important for cancer cell invasion and metastasis. We investigated the expression of fibroblast activation protein (FAP) in relation to patient prognosis in colorectal cancer. Colorectal cancer specimens from 449 patients were immunohistochemically stained with a FAP antibody and evaluated in the tumor center and tumor front using a semiquantitative four-level scale. FAP was expressed by fibroblasts in 85-90 % of the tumors examined. High versus no/low expression in the tumor center was associated with poor prognosis (multivariate hazard ratio, HR = 1.72; 95 % CI 1.07-2.77, p = 0.025). FAP expression in the tumor front, though more frequent than in the tumor center, was not associated with prognosis. FAP expression in the tumor center was more common in specimens with positive microsatellite instability (MSI) screening status and in patients with high CpG island methylator phenotype (CIMP) status. However, inclusion of MSI screening status and CIMP status in the multivariate analysis strengthened the risk estimates for high FAP expression in the tumor center (HR = 1.89; 95 % CI 1.13-3.14; p = 0.014), emphasizing the role of FAP as an independent prognostic factor. Stromal FAP expression is common in colorectal cancer, and we conclude that high FAP expression in the tumor center, but not the tumor front, is an independent negative prognostic factor.

  • 47. Zamora-Ros, Raul
    et al.
    Agudo, Antonio
    Lujan-Barroso, Leila
    Romieu, Isabelle
    Ferrari, Pietro
    Knaze, Viktoria
    Bueno-de-Mesquita, H. Bas
    Leenders, Max
    Travis, Ruth C.
    Navarro, Carmen
    Sanchez-Cantalejo, Emilio
    Slimani, Nadia
    Scalbert, Augustin
    Fedirko, Veronika
    Hjartaker, Anette
    Engeset, Dagrun
    Skeie, Guri
    Boeing, Heiner
    Foerster, Jana
    Li, Kuanrong
    Teuchet, Birgit
    Agnoli, Claudia
    Tumino, Rosario
    Mattiello, Amalia
    Saieva, Calogero
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Luisa Redondo, Maria
    Wallstrom, Peter
    Ericson, Ulrika
    Khaw, Kay-Tee
    Mulligan, Angela A.
    Trichopoulou, Antonia
    Dilis, Vardis
    Katsoulis, Michael
    Peeters, Petra H. M.
    Igali, Lazslo
    Tjonneland, Anne
    Halkjaer, Jytte
    Touillaud, Marina
    Perquier, Florence
    Fagherazzi, Guy
    Amiano, Pilar
    Ardanaz, Eva
    Bredsdorff, Lea
    Overvad, Kim
    Ricceri, Fulvio
    Riboli, Elio
    Gonzalez, Carlos A.
    Dietary flavonoid and lignan intake and gastric adenocarcinoma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study2012In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 96, no 6, p. 1398-1408Article in journal (Refereed)
    Abstract [en]

    Background: Several experimental studies have suggested potential anticarcinogenic effects of flavonoids, although epidemiologic evidence for the impact of dietary flavonoids on risk of gastric cancer (GC) is limited. Objective: We investigated the association between intake of dietary flavonoids and lignans and incident GC. Design: The study followed 477,312 subjects (29.8% men) aged 35-70 y from 10 European countries who participated in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Validated dietary questionnaires and lifestyle information were collected at baseline. A food-composition database on flavonoids and lignans was compiled by using data from USDA and Phenol-Explorer databases. Results: During an average follow-up of 11 y, 683 incident GC cases (57.8% men) were mostly validated by a panel of pathologists and used in this analysis. We observed a significant inverse association between total flavonoid intake and GC risk in women (HR: 0.81; 95% CI: 0.70, 0.94; for the continuous variable after log2 transformation) but not in men (HR: 0.97; 95% CI: 0.85, 1.09). in women, significant inverse associations with GC risk were also observed for intakes of some flavonoid subgroups (anthocyanidins, flavonols, flavones, and flavanols), particularly with intestinal type tumors for total flavonoid and flavanol intakes (P-heterogeneity < 0.1). After stratification by smoking status and sex, there was no significant heterogeneity in these associations between ever- and never-smokers. Conclusion: Total dietary flavonoid intake is associated with a significant reduction in the risk of GC in women. Am J Clin Nutr 2012;96:1398-408.

  • 48.
    Öberg, Åke
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Höyhtyä, Matti
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lindmark, Gudrun
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Limited value of preoperative serum analyses of matrix metalloproteinases (MMP-2, MMP-9) and tissue inhibitors of matrix metalloproteinases (TIMP-1, TIMP-2) in colorectal cancer2000In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 20, no 2B, p. 1085-1091Article in journal (Refereed)
    Abstract [en]

    PURPOSE: We studied whether preoperative serum levels of free MMP-2, the MMP-2/TIMP-2 complex, and total amounts of MMP-9, TIMP-1 and TIMP-2 correlated to the tumor stage and prognosis in colorectal cancer.

    METHODS: Samples from 158 patients operated on for colorectal cancer (100 colon, 58 rectum) and samples from 80 healthy blood donors were analyzed using an ELISA technique. One hundred and thirty-three patients were resected for cure, (31, 61, and 41 in Dukes' stages A, B, and C, respectively). At follow-up in January 1998, 44 patients had died from their cancer after a median time 14 months (range 2-55). Fifteen patients died without tumor relapse. Ninety-nine patients were alive after, a median time of 46 months (range 17-68).

    RESULTS: Wide, overlapping ranges were observed for all factors both in the patients and in the control group. The patients as compared to the control group had significantly higher levels of free MMP-2 and total amounts of MMP-9, TIMP-1 and TIMP-2, whereas the level of the MMP-2/TIMP-2 complex was significantly lower. TIMP-1 was significantly higher in Dukes' D compared to Dukes' A-C cases; the other factors did not correlate to tumor stage. Elevated TIMP-2 levels (median cut-off limit), only, correlated to worse prognosis when analysed in all patients (p < 0.05). None of the factors (median cut-off limit) correlated to survival in Dukes' A-C patients; analyses based on the upper quartile cut-off limit demonstrated that elevated MMP-2 levels correlated to shorter survival time (p < 0.05).

    CONCLUSION: Serum analyses of free MMP-2 the MMP-2/TIMP-2 complex and total amounts of MMP-9, TIMP-1 and TIMP-2 are of limited value for tumor staging and prognosis in colorectal cancer.

  • 49.
    Öberg, Åke
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Samii, S
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lindmark, Gudrun
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Different occurrence of CD8+, CD45R0+, and CD68+ immune cells in regional lymph node metastases from colorectal cancer as potential prognostic predictors2002In: International Journal of Colorectal Disease, ISSN 0179-1958, E-ISSN 1432-1262, Vol. 17, no 1, p. 25-29Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: To study whether there are differences in the immunohistochemical staining of CD8, CD45R0, and CD68 of immune cells in regional lymph node metastases from colorectal cancer that are of potential interest in prognostic prediction.

    MATERIALS AND METHODS: Analysis of archival specimens from 93 patients operated on for colorectal cancer (based on monoclonal antibodies, the ABC technique, and semiquantitative classification).

    RESULTS: There was a significant difference in survival time between patients with respect to the number of positive immune cells. The cancer-specific 5-year survival rate was 77% for patients with high numbers of CD8+ cells, compared to 33% for those with lower numbers. The corresponding figures for patients with CD45R0+ cells were 66% vs. 33%, and for patients with CD68+ cells 60% vs. 38%. Significant differences remained among the 74 patients without adjuvant radio/chemotherapy regarding CD8 and CD45R0 but not CD68.

    CONCLUSION: The presence of CD8+, CD45R0+, and CD68+ immune cells in regional lymph node metastases may serve as predictors of patients survival in colorectal cancer Dukes' stage C.

  • 50.
    Öberg, Åke
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lindmark, Gudrun
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Are lymph node micrometastases of any clinical significance in Dukes' stages A and B colorectal cancer?1998In: Diseases of the Colon & Rectum, ISSN 0012-3706, E-ISSN 1530-0358, Vol. 41, no 10, p. 1244-1249Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The aim was to investigate the significance of lymph node micrometastases in Dukes Stages A and B colorectal cancer.

    METHODS: Archival specimens were examined from 147 patients (96 colon, 51 rectum; 44 Stage A, 103 Stage B) who had surgery between 1987 and 1994. One lymph node section from each node (colon, 1-11; median, 4; rectum, 1-15; median, 3) was examined with use of an anticytokeratin antibody.

    RESULTS: Forty-seven (32 percent) patients had micrometastases. At follow-up in June 1996, 23 patients had died of cancer or with known tumor relapse, after a median time of 28 (range, 5-67) months; 8 of 47 (17 percent) patients had micrometastases, 15 of 100 (15 percent) did not. No statistically significant differences were observed according to micrometastases when the results were analyzed with respect to Dukes stage or survival time. The median survival time of living patients with micrometastases was 48 (range, 18-97) months, and for patients without micrometastases, 48 (range, 19-111) months. Six of 96 living patients had a tumor relapse; three of these displayed micrometastases.

    CONCLUSION: Lymph node micrometastases are not a useful prognostic marker in Dukes Stages A and B and do not imply different strategies for additional therapy or follow-up.

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