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Stenling, Roger
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Glimelius, B., Melin, B., Enblad, G., Alafuzoff, I., Beskow, A., Ahlström, H., . . . Sjöblom, T. (2018). U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden. Acta Oncologica, 57(2), 187-194
Open this publication in new window or tab >>U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden
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2018 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 2, p. 187-194Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Taylor & Francis, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-144850 (URN)10.1080/0284186X.2017.1337926 (DOI)000423473200003 ()28631533 (PubMedID)
Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-06-09Bibliographically approved
Rutegård, M., Palmqvist, R., Stenling, R., Lindberg, J. & Rutegård, J. (2017). Efficiency of Colorectal Cancer Surveillance in Patients With Ulcerative Colitis: 38 Years' Experience in a Patient Cohort From a Defined Population Area. Scandinavian Journal of Surgery, 106(2), 133-138
Open this publication in new window or tab >>Efficiency of Colorectal Cancer Surveillance in Patients With Ulcerative Colitis: 38 Years' Experience in a Patient Cohort From a Defined Population Area
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2017 (English)In: Scandinavian Journal of Surgery, ISSN 1457-4969, E-ISSN 1799-7267, Vol. 106, no 2, p. 133-138Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Sage Publications, 2017
Keywords
Cancer risk, colonoscopy, dysplasia, inflammatory bowel disease, neoplasm, ulcerative colitis
National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-134977 (URN)10.1177/1457496916659224 (DOI)000401558200005 ()27431978 (PubMedID)
Available from: 2017-05-15 Created: 2017-05-15 Last updated: 2018-06-09Bibliographically approved
Ling, A., Löfgren-Burström, A., Larsson, P., Li, X., Wikberg, M. L., Öberg, Å., . . . Palmqvist, R. (2017). TAP1 down-regulation elicits immune escape and poor prognosis in colorectal cancer. Oncoimmunology, 6(11), Article ID e1356143.
Open this publication in new window or tab >>TAP1 down-regulation elicits immune escape and poor prognosis in colorectal cancer
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2017 (English)In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 6, no 11, article id e1356143Article in journal (Refereed) Published
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.

Keywords
TAP1, antigen presentation, colorectal cancer, immune escape, prognosis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-142377 (URN)10.1080/2162402X.2017.1356143 (DOI)000414522400004 ()29147604 (PubMedID)
Funder
Swedish Cancer Society, CAN 2014/858Västerbotten County Council, VLL-463871
Available from: 2017-11-29 Created: 2017-11-29 Last updated: 2018-11-13Bibliographically approved
Svenson, U., Öberg, Å., Stenling, R., Palmqvist, R. & Roos, G. (2016). Telomere length in peripheral leukocytes is associated with immune cell tumor infiltration and prognosis in colorectal cancer patients. Tumor Biology, 37(8), 10877-10882
Open this publication in new window or tab >>Telomere length in peripheral leukocytes is associated with immune cell tumor infiltration and prognosis in colorectal cancer patients
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2016 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 37, no 8, p. 10877-10882Article in journal (Refereed) Published
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.

Keywords
Telomere length, Peripheral leukocytes, Colorectal carcinoma, Immune cell infiltration
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-126330 (URN)10.1007/s13277-016-4987-0 (DOI)000382672900088 ()26883253 (PubMedID)
Available from: 2016-10-27 Created: 2016-10-03 Last updated: 2019-05-09Bibliographically approved
Lundberg, I. V., Löfgren Burström, A., Edin, S., Eklöf, V., Öberg, Å., Stenling, R., . . . Wikberg, M. L. (2014). SOX2 expression is regulated by BRAF and contributes to poor patient prognosis in colorectal cancer. PLoS ONE, 9(7), Article ID e101957.
Open this publication in new window or tab >>SOX2 expression is regulated by BRAF and contributes to poor patient prognosis in colorectal cancer
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, article id e101957Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Public library of science, 2014
Keywords
island methylator phenotype, transcription factor sox2, dna copy number, gene-expression, microsatellite instability, v600e mutation, lung-cancer, stem-cells, carcinoma, growth
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-91747 (URN)10.1371/journal.pone.0101957 (DOI)000338763800054 ()
Available from: 2014-08-20 Created: 2014-08-15 Last updated: 2018-06-07Bibliographically approved
Wikberg, M. L., Edin, S., Lundberg, I. V., Van Guelpen, B., Dahlin, A. M., Rutegård, J., . . . Palmqvist, R. (2013). High intratumoral expression of fibroblast activation protein (FAP) in colon cancer is associated with poorer patient prognosis.. Tumor Biology, 34(2), 1013-1020
Open this publication in new window or tab >>High intratumoral expression of fibroblast activation protein (FAP) in colon cancer is associated with poorer patient prognosis.
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2013 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 34, no 2, p. 1013-1020Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Springer Netherlands, 2013
Keywords
Colorectal cancer, Fibroblast, Prognosis, Microsatellite instability, CIMP
National Category
Cancer and Oncology Surgery
Identifiers
urn:nbn:se:umu:diva-67856 (URN)10.1007/s13277-012-0638-2 (DOI)000316364500048 ()23328994 (PubMedID)
Available from: 2013-04-04 Created: 2013-04-04 Last updated: 2018-06-08Bibliographically approved
Duell, E. J., Lujan-Barroso, L., Llivina, C., Muñoz, X., Jenab, M., Boutron-Ruault, M.-C., . . . González, C. A. (2013). Vitamin C transporter gene (SLC23A1 and SLC23A2) polymorphisms, plasma vitamin C levels, and gastric cancer risk in the EPIC cohort. Genes & Nutrition, 8(6), 549-560
Open this publication in new window or tab >>Vitamin C transporter gene (SLC23A1 and SLC23A2) polymorphisms, plasma vitamin C levels, and gastric cancer risk in the EPIC cohort
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2013 (English)In: Genes & Nutrition, ISSN 1555-8932, E-ISSN 1865-3499, Vol. 8, no 6, p. 549-560Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2013
Keywords
Gastric cancer, Vitamin C, Antioxidants, Genetic susceptibility, SLC23A1, SLC23A2
National Category
Nutrition and Dietetics Medical Genetics
Identifiers
urn:nbn:se:umu:diva-82390 (URN)10.1007/s12263-013-0346-6 (DOI)000326103200003 ()23737080 (PubMedID)
Available from: 2013-10-31 Created: 2013-10-31 Last updated: 2018-06-08Bibliographically approved
Zamora-Ros, R., Agudo, A., Lujan-Barroso, L., Romieu, I., Ferrari, P., Knaze, V., . . . Gonzalez, C. A. (2012). Dietary flavonoid and lignan intake and gastric adenocarcinoma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. American Journal of Clinical Nutrition, 96(6), 1398-1408
Open this publication in new window or tab >>Dietary flavonoid and lignan intake and gastric adenocarcinoma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study
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2012 (English)In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 96, no 6, p. 1398-1408Article in journal (Refereed) Published
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.

National Category
Nutrition and Dietetics
Identifiers
urn:nbn:se:umu:diva-63013 (URN)10.3945/ajcn.112.037358 (DOI)000311533300018 ()
Available from: 2013-01-02 Created: 2012-12-27 Last updated: 2018-06-08Bibliographically approved
Jakszyn, P., Agudo, A., Lujan-Barroso, L., Bueno-de-Mesquita, H. B., Jenab, M., Navarro, C., . . . Gonzalez, C. A. (2012). Dietary intake of heme iron and risk of gastric cancer in the European prospective investigation into cancer and nutrition study. International Journal of Cancer, 130(11), 2654-2663
Open this publication in new window or tab >>Dietary intake of heme iron and risk of gastric cancer in the European prospective investigation into cancer and nutrition study
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2012 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 130, no 11, p. 2654-2663Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2012
Keywords
diet, heme iron, gastric cancer, EPIC, prospective study
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-54306 (URN)10.1002/ijc.26263 (DOI)000302013200019 ()
Available from: 2012-04-24 Created: 2012-04-24 Last updated: 2018-06-08Bibliographically approved
Serafini, M., Jakszyn, P., Lujan-Barroso, L., Agudo, A., Bueno-de-Mesquita, H. B., van Duijnhoven, F. J. B., . . . Gonzalez, C. A. (2012). Dietary total antioxidant capacity and gastric cancer risk in the European prospective investigation into cancer and nutrition study. International Journal of Cancer, 131(4), E544-E554
Open this publication in new window or tab >>Dietary total antioxidant capacity and gastric cancer risk in the European prospective investigation into cancer and nutrition study
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2012 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 131, no 4, p. E544-E554Article in journal (Refereed) Published
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.

Keywords
stomach cancer, diet, antioxidant capacity, longitudinal studies
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-57422 (URN)10.1002/ijc.27347 (DOI)000305451300022 ()
Available from: 2012-07-23 Created: 2012-07-23 Last updated: 2018-06-08Bibliographically approved
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