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

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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.
Funding Information
  • Association Anne de Bretagne Genetique
  • California Department of Public Health (HHSN261201000035C)
  • Fondazione Umberto Veronesi
  • Grantová Agentura České Republiky (17‐16857S)
  • Ministerstvo Zdravotnictví Ceské Republiky (AZV 15‐27580, AZV 17‐30920)
  • National Cancer Institute (HHSN2612013000121, K07 CA190673, N01‐CN‐67009, N01‐PC‐35142, P01 CA087969, P30 CA015704, P50 CA127003, R01 CA042182, R01 CA059045, R01 CA137178, R01 CA151993, R01 CA48998, R35 CA197735, U01 CA074778, U01 CA137088, U01 CA164930, U01 HG 004438, U01/U24 CA074783, U01/U24 CA074794, U01/U24 CA074799, U01/U24 CA074800, U01/U24 CA074806, U01/U24 CA097735, U19 CA148107, UM1 CA186107, Z01 CP 010200)
  • National Heart, Lung, and Blood Institute (HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN268201100046C, HHSN271201100004C)
  • National Institutes of Health (K05 CA154337, P01 CA033619, P01 CA055075, R01 CA063464, R01 CA076366, R01 CA143247, R01 CA60987, R37 CA54281, U01 CA074783, U01 CA122839, U01 CA167551, U01 CA167552, U01 HG004446, UM1 CA167552)
  • Conseil Régional des Pays de la Loire

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