DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility

Barbara Pardini, Alda Corrado, Elisa Paolicchi, Giovanni Cugliari, Sonja I. Berndt, Stephane Bezieau, Stephanie A. Bien, Hermann Brenner, Bette J. Caan, Peter T. Campbell, Graham Casey, Andrew T. Chan, Jenny Chang-Claude, Michelle Cotterchio, Manish Gala, Steven J. Gallinger, Robert W. Haile, Tabitha A. Harrison, Richard B. Hayes, Michael HoffmeisterJohn L. Hopper, Li Hsu, Jeroen Huyghe, Mark A. Jenkins, Loic Le Marchand, Yi Lin, Noralane M. Lindor, Hongmei Nan, Polly A. Newcomb, Shuji Ogino, John D. Potter, Robert E. Schoen, Martha L. Slattery, Emily White, Ludmila Vodickova, Veronika Vymetalkova, Pavel Vodicka, Federica Gemignani, Ulrike Peters, Alessio Naccarati, Stefano Landi

Research output: Contribution to journalArticle

Abstract

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10−6) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10−6). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10−6. Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.

Original languageEnglish (US)
JournalInternational Journal of Cancer
DOIs
StateAccepted/In press - Jan 1 2019

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Keywords

  • cancer susceptibility
  • colon cancer
  • DNA repair
  • genome-wide association studies
  • rectal cancer
  • single nucleotide polymorphisms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Pardini, B., Corrado, A., Paolicchi, E., Cugliari, G., Berndt, S. I., Bezieau, S., Bien, S. A., Brenner, H., Caan, B. J., Campbell, P. T., Casey, G., Chan, A. T., Chang-Claude, J., Cotterchio, M., Gala, M., Gallinger, S. J., Haile, R. W., Harrison, T. A., Hayes, R. B., ... Landi, S. (Accepted/In press). DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility. International Journal of Cancer. https://doi.org/10.1002/ijc.32516