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Whole exome sequencing in 75 high-risk families with validation and replication in independent case-control studies identifies TANGO2, OR5H14, and CHAD as new prostate cancer susceptibility genes

Citation

Karyadi, DM and Geybels, MS and Karlins, E and Decker, B and McIntosh, L and Hutchinson, A and Kolb, S and McDonnell, SK and Hicks, B and Middha, S and FitzGerald, LM and DeRycke, MS and Yeager, M and Schaid, DJ and Chanock, SJ and Thibodeau, SN and Berndt, SI and Stanford, JL and Ostrander, EA, Whole exome sequencing in 75 high-risk families with validation and replication in independent case-control studies identifies TANGO2, OR5H14, and CHAD as new prostate cancer susceptibility genes, OncoTarget, 8, (1) pp. 1495-1507. ISSN 1949-2553 (2017) [Refereed Article]


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Copyright 2017 The Authors. Licensed under Creative Commons Attribution 3.0 Unported (CC BY 3.0) https://creativecommons.org/licenses/by/3.0/

DOI: doi:10.18632/oncotarget.13646

Abstract

Prostate cancer (PCa) susceptibility is defined by a continuum from rare, high-penetrance to common, low-penetrance alleles. Research to date has concentrated on identification of variants at the ends of that continuum. Taking an alternate approach, we focused on the important but elusive class of low-frequency, moderately penetrant variants by performing disease model-based variant filtering of whole exome sequence data from 75 hereditary PCa families. Analysis of 341 candidate risk variants identified nine variants significantly associated with increased PCa risk in a population-based, case-control study of 2,495 men. In an independent nested case-control study of 7,121 men, there was risk association evidence for TANGO2 p.Ser17Ter and the established HOXB13 p.Gly84Glu variant. Meta-analysis combining the case-control studies identified two additional variants suggestively associated with risk, OR5H14 p.Met59Val and CHAD p.Ala342Asp. The TANGO2 and HOXB13 variants co-occurred in cases more often than expected by chance and never in controls. Finally, TANGO2 p.Ser17Ter was associated with aggressive disease in both case-control studies separately. Our analyses identified three new PCa susceptibility alleles in the TANGO2, OR5H14 and CHAD genes that not only segregate in multiple high-risk families but are also of importance in altering disease risk for men from the general population. This is the first successful study to utilize sequencing in high-risk families for the express purpose of identifying low-frequency, moderately penetrant PCa risk mutations.

Item Details

Item Type:Refereed Article
Keywords:cancer susceptibility, case-control association, high-risk families, prostate cancer, whole exome sequencing
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Epigenetics (incl. Genome Methylation and Epigenomics)
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Cancer and Related Disorders
Author:FitzGerald, LM (Dr Liesel Fitzgerald)
ID Code:112977
Year Published:2017 (online first 2016)
Deposited By:Menzies Institute for Medical Research
Deposited On:2016-12-06
Last Modified:2017-04-13
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