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

// Danielle M. Karyadi 1 , Milan S. Geybels 2 , Eric Karlins 1, 3 , Brennan Decker 1 , Laura McIntosh 2 , Amy Hutchinson 3 , Suzanne Kolb 2 , Shannon K. McDonnell 4 , Belynda Hicks 3 , Sumit Middha 4 , Liesel M. FitzGerald 5 , Melissa S. DeRycke 6 , Meredith Yeager 3 , Daniel J. Schaid 4 , Stephen J. Chanock 3 , Stephen N. Thibodeau 6 , Sonja I. Berndt 3 , Janet L. Stanford 2, 7, * , Elaine A. Ostrander 1, * 1 National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA 2 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA 3 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 4 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA 5 Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia 6 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA 7 Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA * Co-senior authors. Correspondence to: Elaine A. Ostrander, email: eostrand@mail.nih.gov Keywords: whole exome sequencing, cancer susceptibility, high-risk families, case-control association, prostate cancer Received: September 20, 2016     Accepted: November 07, 2016      Published: November 26, 2016 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.