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

Authors

Elisabeth A. Rosenthal, University of Washington School of Medicine
Brian H. Shirts, University of Washington School of Medicine
Laura M. Amendola, University of Washington School of Medicine
Martha Horike-Pyne, University of Washington School of Medicine
Peggy D. Robertson, University of Washington, Seattle
Fuki M. Hisama, University of Washington School of Medicine
Robin L. Bennett, University of Washington School of Medicine
Michael O. Dorschner, University of Washington, Seattle
Deborah A. Nickerson, University of Washington, Seattle
Ian B. Stanaway, University of Washington School of Medicine
Rami Nassir, University of California, Davis
Kathy T. Vickers, Fred Hutchinson Cancer Research Center
Christopher Li, Fred Hutchinson Cancer Research Center
William M. Grady, Fred Hutchinson Cancer Research Center
Ulrike Peters, Fred Hutchinson Cancer Research Center
Gail P. Jarvik, University of Washington School of Medicine
Stacey B. Gabriel
David M. Altshuler
Gonçalo R. Abecasis
Hooman Allayee
Sharon Cresci
Mark J. Daly
Paul I.W. de Bakker
Mark A. DePristo
Ron Do
Peter Donnelly
Deborah N. Farlow
Tim Fennell
Kiran Garimella
Stanley L. Hazen
Youna Hu
Daniel M. Jordan

Document Type

Journal Article

Publication Date

10-1-2018

Journal

Human Genetics

Volume

137

Issue

10

DOI

10.1007/s00439-018-1938-4

Abstract

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. 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.

APA Citation

Rosenthal, E., Shirts, B., Amendola, L., Horike-Pyne, M., Robertson, P., Hisama, F., Bennett, R., Dorschner, M., Nickerson, D., Stanaway, I., Nassir, R., Vickers, K., Li, C., Grady, W., Peters, U., Jarvik, G., Gabriel, S., Altshuler, D., Abecasis, G., Allayee, H., Cresci, S., Daly, M., de Bakker, P., DePristo, M., Do, R., Donnelly, P., Farlow, D., Fennell, T., Garimella, K., Hazen, S., Hu, Y., & Jordan, D. (2018). Rare loss of function variants in candidate genes and risk of colorectal cancer. Human Genetics, 137 (10). http://dx.doi.org/10.1007/s00439-018-1938-4