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

Publication ,  Journal Article
Rosenthal, EA; Shirts, BH; Amendola, LM; Horike-Pyne, M; Robertson, PD; Hisama, FM; Bennett, RL; Dorschner, MO; Nickerson, DA; Stanaway, IB ...
Published in: Hum Genet
October 2018

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.

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Published In

Hum Genet

DOI

EISSN

1432-1203

Publication Date

October 2018

Volume

137

Issue

10

Start / End Page

795 / 806

Location

Germany

Related Subject Headings

  • Risk Factors
  • RNA Helicases
  • Middle Aged
  • Male
  • Humans
  • Genetics & Heredity
  • Genetic Variation
  • Genetic Loci
  • Female
  • Fanconi Anemia Complementation Group Proteins
 

Citation

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MLA
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Rosenthal, E. A., Shirts, B. H., Amendola, L. M., Horike-Pyne, M., Robertson, P. D., Hisama, F. M., … NHLBI GO Exome Sequencing Project, . (2018). Rare loss of function variants in candidate genes and risk of colorectal cancer. Hum Genet, 137(10), 795–806. https://doi.org/10.1007/s00439-018-1938-4
Rosenthal, Elisabeth A., Brian H. Shirts, Laura M. Amendola, Martha Horike-Pyne, Peggy D. Robertson, Fuki M. Hisama, Robin L. Bennett, et al. “Rare loss of function variants in candidate genes and risk of colorectal cancer.Hum Genet 137, no. 10 (October 2018): 795–806. https://doi.org/10.1007/s00439-018-1938-4.
Rosenthal EA, Shirts BH, Amendola LM, Horike-Pyne M, Robertson PD, Hisama FM, et al. Rare loss of function variants in candidate genes and risk of colorectal cancer. Hum Genet. 2018 Oct;137(10):795–806.
Rosenthal, Elisabeth A., et al. “Rare loss of function variants in candidate genes and risk of colorectal cancer.Hum Genet, vol. 137, no. 10, Oct. 2018, pp. 795–806. Pubmed, doi:10.1007/s00439-018-1938-4.
Rosenthal EA, Shirts BH, Amendola LM, Horike-Pyne M, Robertson PD, Hisama FM, Bennett RL, Dorschner MO, Nickerson DA, Stanaway IB, Nassir R, Vickers KT, Li C, Grady WM, Peters U, Jarvik GP, NHLBI GO Exome Sequencing Project. Rare loss of function variants in candidate genes and risk of colorectal cancer. Hum Genet. 2018 Oct;137(10):795–806.
Journal cover image

Published In

Hum Genet

DOI

EISSN

1432-1203

Publication Date

October 2018

Volume

137

Issue

10

Start / End Page

795 / 806

Location

Germany

Related Subject Headings

  • Risk Factors
  • RNA Helicases
  • Middle Aged
  • Male
  • Humans
  • Genetics & Heredity
  • Genetic Variation
  • Genetic Loci
  • Female
  • Fanconi Anemia Complementation Group Proteins