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

Rosenthal, E. A. et al. (2018) Rare loss of function variants in candidate genes and risk of colorectal cancer. Human Genetics, 137(10), pp. 795-806. (doi: 10.1007/s00439-018-1938-4) (PMID:30267214) (PMCID:PMC6283057)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Padmanabhan, Professor Sandosh
Authors: Rosenthal, E. A., Shirts, B. H., Amendola, L. M., Horike-Pyne, M., Robertson, P. D., Hisama, F. M., Bennett, R. L., Dorschner, M. O., Nickerson, D. A., Stanaway, I. B., Nassir, R., Vickers, K. T., Li, C., Grady, W. M., Peters, U., Jarvik, G. P., and NHLBI GO Exome Sequencing Project,
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Human Genetics
ISSN (Online):1432-1203
Published Online:28 September 2018
Copyright Holders:Copyright © 2018 Springer-Verlag GmbH Germany, part of Springer Nature
First Published:First published in Human Genetics 137(10):795-806
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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