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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Abstract
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 |
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Status: | Published |
Refereed: | Yes |
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 |
Publisher: | Springer |
ISSN: | 0340-6717 |
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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