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PWE-002 The association of low penetrance variants in dna repair genes with colorectal cancer: a systematic review and meta-analysis
  1. N Aggarwal,
  2. ND Donald,
  3. S Malik,
  4. SS Selvendran,
  5. M McPhail,
  6. KJ Monahan


Introduction Approximately 35% of colorectal cancer (CRC) risk is attributable to heritable factors, with known hereditary syndromes accounting for 6% of the total. The remainder may be largely due to lower penetrance genetic risk factors in genes including those, which control DNA replication and repair. Complex evolutionary conserved DNA repair pathways include Base Excision Repair (BER), Nucleotide Excision Repair (NER), Mismatch Repair (MMR), Direct Reversal Repair (DRR) and Double-Strand Break (DSB) repair. These pathways are critical in carcinogenesis. Repair and replication gene mutations occur in over 58% of cancer cell lines and germline mutations in these DNA repair genes are associated with known high penetrance CRC syndromes including Lynch syndrome and many polyposis syndromes. However, the association of low penetrance polymorphisms of DNA repair genes with CRC risk is unclear.

Method A systematic literature review of PubMed and HuGENet databases was conducted. Studies were included/excluded based on pre-specified criteria. Per-allele, pooled odds ratio calculations disclosed the risk attributed to each individual variant. Heterogeneity was investigated by subgroup analyses for ethnicity and tumour location; funnel plots and Egger’s test assessed any publication bias.

Results Sixty-one polymorphisms in 26 different DNA repair genes were identified. Meta-analyses for 22 of these polymorphisms in 17 genes, with 1706 to 9682 CRC cases per polymorphism, revealed 6 polymorphisms were significantly associated with CRC risk within BER (APE1, PARP1), NER (ERCC5, XPC), DSB (RAD18), and DRR (MGMT), but none within the MMR pathway. Subgroup analyses revealed significant association of OGG1 rs1052133 with rectal cancer risk. Egger’s test revealed publication bias was not a source of heterogeneity.

Conclusion Low penetrance polymorphisms in highly conserved DNA repair genes alter susceptibility to CRC. Knowledge of which DNA repair gene polymorphisms are associated with CRC risk may allow a better understanding of global risk and facilitate personalised CRC risk assessment.

Disclosure of Interest None Declared


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