Rare loss of function variants in candidate genes and risk of colorectal cancer

Hum Genet. 2018 Oct;137(10):795-806. doi: 10.1007/s00439-018-1938-4. Epub 2018 Sep 28.


Although ~ 25% of colorectal cancer or polyp (CRC/P) cases show familial aggregation, current germline genetic testing identifies a causal genotype in the 16 major genes associated with high penetrance CRC/P in only 20% of these cases. As there are likely other genes underlying heritable CRC/P, we evaluated the association of variation at novel loci with CRC/P. We evaluated 158 a priori selected candidate genes by comparing the number of rare potentially disruptive variants (PDVs) found in 84 CRC/P cases without an identified CRC/P risk-associated variant and 2440 controls. We repeated this analysis using an additional 73 CRC/P cases. We also compared the frequency of PDVs in select genes among CRC/P cases with two publicly available data sets. We found a significant enrichment of PDVs in cases vs. controls: 20% of cases vs. 11.5% of controls with ≥ 1 PDV (OR = 1.9, p = 0.01) in the original set of cases. Among the second cohort of CRC/P cases, 18% had a PDV, significantly different from 11.5% (p = 0.02). Logistic regression, adjusting for ancestry and multiple testing, indicated association between CRC/P and PDVs in NTHL1 (p = 0.0001), BRCA2 (p = 0.01) and BRIP1 (p = 0.04). However, there was no significant difference in the frequency of PDVs at each of these genes between all 157 CRC/P cases and two publicly available data sets. These results suggest an increased presence of PDVs in CRC/P cases and support further investigation of the association of NTHL1, BRCA2 and BRIP1 variation with CRC/P.

Publication types

  • Clinical Trial
  • Multicenter Study

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • BRCA2 Protein / genetics*
  • Colorectal Neoplasms / genetics*
  • Deoxyribonuclease (Pyrimidine Dimer) / genetics*
  • Fanconi Anemia Complementation Group Proteins / genetics*
  • Female
  • Genetic Loci*
  • Genetic Variation*
  • Humans
  • Male
  • Middle Aged
  • RNA Helicases / genetics*
  • Risk Factors


  • BRCA2 Protein
  • BRCA2 protein, human
  • Fanconi Anemia Complementation Group Proteins
  • Deoxyribonuclease (Pyrimidine Dimer)
  • NTHL1 protein, human
  • BRIP1 protein, human
  • RNA Helicases

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