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  • American Association for Cancer Research (AACR)  (7)
  • Hoffmeister, Michael  (7)
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  • American Association for Cancer Research (AACR)  (7)
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  • 1
    Online Resource
    Online Resource
    Abstract 4585: Folate-mediated one-carbon metabolism polymorphisms associated with risk and survival of colorectal cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4585-4585
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4585-4585
    Abstract: Introduction Folate-mediated one-carbon metabolism (FOCM) is a key pathway necessary for nucleotide synthesis, DNA methylation, replication and repair. Genetic variants in FOCM genes, especially the MTHFR-C677T polymorphism, have been associated with colorectal neoplasia. Moreover, FOCM is an important target for chemotherapeutic drugs for the treatment of colorectal cancer (CRC), such as 5-fluorouracil (5-FU). We performed a comprehensive assessment of FOCM-related genetic variation in relation to CRC risk and survival in an unfortified population. Methods Associations of 457 tagging and candidate SNPs in 47 FOCM-related genes with CRC risk and survival were investigated within a German population-based case-control study (the DACHS- study). Using multivariate adjusted logistic (n = 1754 incident cases and 1781 matched controls) and Cox regression (5 years follow-up of CRC cases only; 585 deceased), we evaluated co-dominant, dominant, and log-additive modes of inheritance. SNPs were genotyped using the Illumina GoldenGate Assay. Correction for multiple testing was performed using false discovery rates (FDR). Results Individuals having both variant alleles of a candidate SNP in the ADH1C gene (rs1693482) had a significantly decreased risk of developing CRC (ORhet = 0.94 [95% CI = 0.81-1.10]; ORhzv = 0.74 [95% CI = 0.59-0.92] ; p-trend = 0.013). Before correction for multiple testing, 19 nominally significant genetic main effects on CRC risk were observed. None of the studied tagging SNPs was significantly associated with risk after multiple test correction. One polymorphism in the PON1 gene (rs3917538) was significantly associated with overall survival (HRhet = 1.22 [95% CI = 1.03-1.45]; HRhzv = 2.00 [95% CI = 1.48-2.71] ; p-trend = 0.01), after correction for multiple testing. Effect modification by 5-FU chemotherapy was observed between two polymorphisms (MTHFR-rs4846047 [Int-pFDR = 0.02] and TK1-rs1811086 [Int-pFDR = 0.02] ) for the endpoint overall survival. Cases with variant alleles of these SNPs had a reduced effect of 5-FU on overall survival. Conclusion Genetic variation in FOCM appears to be associated with CRC risk and survival. Furthermore, 5-FU might interact with FOCM polymorphisms. Further large investigations are required to replicate our findings. Citation Format: Akke Botma, Katharina Buck, Yesilda Balavarca, Dominique Scherer, Nina Habermann, Reka Toth, Lina Jansen, Michael Hoffmeister, Hermann Brenner, Elisabeth J. Kap, Petra Seibold, Axel Benner, Alexis Ulrich, Barbara Burwinkel, Jenny Chang-Claude, Cornelia M. Ulrich. Folate-mediated one-carbon metabolism polymorphisms associated with risk and survival of colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4585. doi:10.1158/1538-7445.AM2015-4585
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-4585
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 2
    Online Resource
    Online Resource
    Smoking, Lower Gastrointestinal Endoscopy, and Risk for Colorectal Cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 23, No. 3 ( 2014-03-01), p. 525-533
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 23, No. 3 ( 2014-03-01), p. 525-533
    Abstract: Background: Lower gastrointestinal endoscopy can decrease colorectal cancer risk strongly through detection and removal of adenomas. Thus, we aimed to investigate whether utilization of lower gastrointestinal endoscopy modifies the effect of lifetime smoking exposure on colorectal cancer risk in a population-based case–control study. Methods: In this study from Southern Germany including 2,916 patients with colorectal cancer and 3,044 controls, information about lifetime smoking and other risk factors was obtained from standardized interviews. Self-reported endoscopies were validated by medical records. Multivariate logistic regression was performed to investigate associations of smoking with colorectal cancer risk after stratification by utilization of lower gastrointestinal endoscopy in the preceding 10 years. Results: Median age of patients and controls was 69 and 70 years, respectively. Former regular smoking was associated with increased colorectal cancer risk in the group with no previous endoscopy [adjusted OR, 1.50; 95% confidence interval (CI), 1.28–1.75], whereas no association was found in the group with preceding endoscopy (OR, 1.05; CI, 0.83–1.33; P for interaction & lt;0.01). Lower gastrointestinal endoscopy did not modify the association of smoking and colorectal cancer risk among current smokers and among the more recent quitters. Conclusions: Our results suggest that the increased risk of colorectal cancer among former regular smokers is essentially overcome by detection and removal of adenomas at lower gastrointestinal endoscopy. However, risk of colorectal cancer was increased if smoking was continued into higher adult age. Impact: The strong protective effect of lower gastrointestinal endoscopy may be compromised by continued smoking. Smoking cessation may increase the efficacy of lower gastrointestinal endoscopy. Cancer Epidemiol Biomarkers Prev; 23(3); 525–33. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-13-0729-T
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 3
    Online Resource
    Online Resource
    Abstract 1891: Mutations in polymerase ϵ as key molecular alteration of the novel ultramutator phenotype do not define a clinically distinct entity of colorectal cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1891-1891
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1891-1891
    Abstract: Background: Recent molecular profiling studies reported a new class of ultramutated colorectal cancers (CRC), which are likely caused by exonuclease domain (END) mutations in DNA polymerase ϵ (POLE). However, data on the clinical implications of these biological findings as to whether these mutations in analogy to endometrial cancer define a unique CRC entity with distinct clinical outcome is entirely lacking. Methods: We performed Sanger sequencing of the POLE END in 431 well annotated microsatellite stable (MSS) CRCs of a population-based epidemiological case-control study (DACHS). Mutation data were correlated with major epidemiological, clinical, genetic and pathological parameters including overall and disease-specific survival. Results: In 373 out of 431 MSS CRC all exons of POLE END were analyzable. 47 mutations in the END of POLE were identifiable in 41 of these samples (11%). Besides already reported mutations affecting the codons 459, 411 and 286, we found many new mutations in exons 13 and 14 (corresponding to codons 411-491 of the END) as well as in exon 12 (corresponding to codons 268-301 of the END), which have not been reported yet. However, we found no associations of POLE END mutations with clinicopathological parameters, including sex, age, tumor location and tumor stage, CIMP, RAS and BRAF mutations. Survival analysis by cox regression revealed adjusted (for sex, age, tumor location and therapy) HRs of 1.38 and 1.44 for disease-specific and overall survival indicating slightly impaired survival of patients with mutations in POLE END, however, these differences were not statistically significant. This was also true for the subgroups of different exons, known/new, potentially damaging/non-damaging mutations and the type of mutation. Conclusions: In contrast to endometrial cancer, somatic POLE mutations do not appear to define a clinically strongly distinct disease entity in CRC. Citation Format: Albrecht Stenzinger, Endris Volker, Nicole Pfarr, Roland Penzel, Lina Jansen, Esther Herpel, Wilfried Roth, Hendrik Bläker, Jenny Chang-Claude, Hermann Brenner, Michael Hoffmeister, Wilko Weichert. Mutations in polymerase ϵ as key molecular alteration of the novel ultramutator phenotype do not define a clinically distinct entity of colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1891. doi:10.1158/1538-7445.AM2014-1891
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-1891
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 4
    Online Resource
    Online Resource
    Genetic Variants in the Regulatory T cell–Related Pathway and Colorectal Cancer Prognosis
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 29, No. 12 ( 2020-12-01), p. 2719-2728
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 29, No. 12 ( 2020-12-01), p. 2719-2728
    Abstract: High numbers of lymphocytes in tumor tissue, including T regulatory cells (Treg), have been associated with better colorectal cancer survival. Tregs, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and therefore variants in genes related to Treg differentiation and function could be associated with colorectal cancer prognosis. Methods: In a prospective German cohort of 3,593 colorectal cancer patients, we assessed the association of 771 single-nucleotide polymorphisms (SNP) in 58 Treg-related genes with overall and colorectal cancer–specific survival using Cox regression models. Effect modification by microsatellite instability (MSI) status was also investigated because tumors with MSI show greater lymphocytic infiltration and have been associated with better prognosis. Replication of significant results was attempted in 2,047 colorectal cancer patients of the International Survival Analysis in Colorectal Cancer Consortium (ISACC). Results: A significant association of the TGFBR3 SNP rs7524066 with more favorable colorectal cancer–specific survival [hazard ratio (HR) per minor allele: 0.83; 95% confidence interval (CI), 0.74–0.94; P value: 0.0033] was replicated in ISACC (HR: 0.82; 95% CI, 0.68–0.98; P value: 0.03). Suggestive evidence for association was found with two IL7 SNPs, rs16906568 and rs7845577. Thirteen SNPs with differential associations with overall survival according to MSI in the discovery analysis were not confirmed. Conclusions: Common genetic variation in the Treg pathway implicating genes such as TGFBR3 and IL7 was shown to be associated with prognosis of colorectal cancer patients. Impact: The implicated genes warrant further investigation.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-20-0714
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 5
    Online Resource
    Online Resource
    Validation of Genetic Markers Associated with Survival in Colorectal Cancer Patients Treated with Oxaliplatin-Based Chemotherapy
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 31, No. 2 ( 2022-02-01), p. 352-361
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 31, No. 2 ( 2022-02-01), p. 352-361
    Abstract: Associations between candidate genetic variants and treatment outcomes of oxaliplatin, a drug commonly used for colorectal cancer patients, have been reported but not robustly established. This study aimed to validate previously reported prognostic and predictive genetic markers for oxaliplatin treatment outcomes and evaluate additional putative functional variants. Methods: Fifty-three SNPs were selected based on previous reports (40 SNPs) or putative function in candidate genes (13 SNPs). We used data from 1,502 patients with stage II–IV colorectal cancer who received primary adjuvant chemotherapy, 37% of whom received oxaliplatin treatment. Multivariable Cox proportional hazards models for overall survival and progression-free survival were applied separately in stage II–III and stage IV patients. For predictive SNPs, differential outcomes according to the type of chemotherapy (oxaliplatin-based vs. others) were evaluated using an interaction term. For prognostic SNPs, the association was assessed solely in patients with oxaliplatin-based treatment. Results: Twelve SNPs were predictive and/or prognostic at P & lt; 0.05 with differential survival based on the type of treatment, in patients with stage II–III (GSTM5-rs11807, ERCC2-rs13181, ERCC2-rs1799793, ERCC5-rs2016073, XPC-rs2228000, P2RX7-rs208294, HMGB1-rs1360485) and in patients with stage IV (GSTM5-rs11807, MNAT1-rs3783819, MNAT1-rs4151330, CXCR1-rs2234671, VEGFA-rs833061, P2RX7-rs2234671). In addition, five novel putative functional SNPs were identified to be predictive (ATP8B3-rs7250872, P2RX7-rs2230911, RPA1-rs5030755, MGMT-rs12917, P2RX7-rs2227963). Conclusions: Some SNPs yielded prognostic and/or predictive associations significant at P & lt; 0.05, however, none of the associations remained significant after correction for multiple testing. Impact: We did not robustly confirm previously reported SNPs despite some suggestive findings but identified further potential predictive SNPs, which warrant further investigation in well-powered studies.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-21-0814
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 6
    Online Resource
    Online Resource
    Abstract 33: Thymidylate synthase polymorphisms and colorectal cancer risk and prognosis.
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 21, No. 11_Supplement ( 2012-11-01), p. 33-33
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 21, No. 11_Supplement ( 2012-11-01), p. 33-33
    Abstract: Background: Thymidylate synthase (TS) is a key enzyme in folate metabolism and crucial for DNA synthesis and repair. Moreover, TS is an important target for chemotherapeutic drugs, such as 5-fluorouracil (5-FU) - a universal chemotherapeutic drug used for the treatment of colorectal cancer (CRC). TS over-expression may result in resistance to chemotherapy and may thus be a promising biomarker for therapeutic success. Previous studies revealed that at least three polymorphisms in the 5'- and 3'-untranslated regions (UTR) of the TS gene are associated with altered gene expression of TS coupled with a poor response to 5-FU treatment in CRC patients. Methods: Eight tagSNPs in the TS gene as well as one insertion/deletion polymorphism located in the 3'-UTR of the gene were investigated for association with risk of CRC in 1,754 cases and 1,781 controls, and with overall survival (OS) and disease-specific survival (DSS) in 1,739 CRC cases of the German DACHS study. Patients were aged 30 years or older and diagnosed between 2003 and 2007. Associations were assessed using multiple logistic and Cox regression models. Results: After a median follow-up time of 4.1 years, of the 442 deceased patients, 324 died due to CRC. There was no association between any polymorphism and CRC risk. Individuals with the heterozygote (het), but not with the rare homozygote variant (hzv) genotype of the rs495139 polymorphism (intronic region) had a significantly increased risk for overall (HRhet=1.63, 95% confidence interval (CI)=1.29-1.74 and HRhzv=1.28, 95% CI=0.94-1.74) and disease-specific mortality (HRhet=1.65, 95% CI=1.25-2.18 and HRhzv=1.11, 95% CI=0.76-1.60). No other polymorphism was associated with OS or DSS. However, several polymorphisms were associated with CRC risk when analyses were stratified by non-steroidal anti-inflammatory drug (NSAID) use. Also, several polymorphisms were associated with OS when analyses were stratified by 5-FU treatment, tumor stage, sex, and cancer site. Conclusion: Genetic variation in the thymidylate synthase gene appears to be associated with CRC survival but not with CRC risk. Notably, effect modifications (which may be clinically relevant) were observed for several factors in the analysis of CRC risk and prognosis. Citation Format: Katharina Buck, Jolantha Beyerle, Dominique Scherer, Nina Habermann, Michael J. Paskow, Katrin Pfuetze, Swantje Richter, Petra Seibold, Lina Jansen, Katja Butterbach, Barbara Burwinkel, Michael Hoffmeister, Axel Benner, Jenny Chang-Claude, Hermann Brenner, Moritz Koch, Juergen Weitz, Cornelia M. Ulrich. Thymidylate synthase polymorphisms and colorectal cancer risk and prognosis. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 33.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.GWAS-33
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 7
    Online Resource
    Online Resource
    Physical Activity and Long-term Quality of Life among Colorectal Cancer Survivors—A Population-based Prospective Study
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Prevention Research Vol. 13, No. 7 ( 2020-07-01), p. 611-622
    Details
    In: Cancer Prevention Research, American Association for Cancer Research (AACR), Vol. 13, No. 7 ( 2020-07-01), p. 611-622
    Abstract: Evidence suggests that physical activity (PA) is positively associated with (health-related) quality of life (QOL) in colorectal cancer survivors. However, little is known regarding long-term effects of PA on QOL and if prediagnosis PA is associated with QOL in the years after diagnosis. Our study aimed to investigate the association of prediagnosis and postdiagnosis PA with long-term QOL in colorectal cancer survivors. This study is based on a population-based cohort from Germany of 1,781 newly diagnosed colorectal cancer survivors over a 5-year period. PA was assessed at diagnosis and at 5-year follow-up (5YFU). Quality of life was assessed by the European Organisation for Research and Treatment of Cancer C Quality of Life Questionnaire QLQ-C30 at 5YFU. Multivariable linear regression was used to explore associations between prediagnosis and postdiagnosis PA and QOL at 5YFU. No evidence of a positive association between higher levels of prediagnosis PA and better long-term QOL was found. Higher levels of prediagnosis work-related PA and vigorous PA were even associated with decreased QOL in domains such as cognitive [Beta(β) = −2.52, 95% confidence interval (CI) = −3.77, −1.27; β = −1.92, CI = −3.17, −0.67) and emotional functioning (β = −2.52, CI = −3.84, −1.19; β = −2.12, CI = −3.44, −0.80). In cross-sectional analyses, higher postdiagnosis PA was strongly associated with higher QOL. Survivors physically active at both prediagnosis and postdiagnosis as well as survivors who increased their PA between prediagnosis and postdiagnosis reported significantly higher long-term QOL compared with survivors who remained inactive at prediagnosis and postdiagnosis. In this study, higher prediagnosis PA does not appear to be associated with higher QOL among long-term colorectal cancer survivors but our results support the importance of ongoing PA throughout survivorship.
    Type of Medium: Online Resource
    ISSN: 1940-6207 , 1940-6215
    URL: Article
    DOI: 10.1158/1940-6207.CAPR-19-0377
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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