TY - JOUR
T1 - 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
AU - Karyadi, Danielle M.
AU - Geybels, Milan S.
AU - Karlins, Eric
AU - Decker, Brennan
AU - McIntosh, Laura
AU - Hutchinson, Amy
AU - Kolb, Suzanne
AU - McDonnell, Shannon K.
AU - Hicks, Belynda
AU - Middha, Sumit
AU - FitzGerald, Liesel M.
AU - DeRycke, Melissa S.
AU - Yeager, Meredith
AU - Schaid, Daniel J.
AU - Chanock, Stephen J.
AU - Thibodeau, Stephen N.
AU - Berndt, Sonja I.
AU - Stanford, Janet L.
AU - Ostrander, Elaine A.
N1 - Funding Information:
This work was supported by the Intramural Program of the National Human Genome Research Institute (D.M. Karyadi, E. Karlins, B. Decker, E.A. Ostrander) and National Cancer Institute (E. Karlins, A. Hutchinson, B. Hicks, M. Yeager, S.J. Chanock, S.I. Berndt), by grants from the National Cancer Institute, NIH (R01 CA056678, R01 CA092579, and R01 CA080122 to J.L. Stanford; U01 CA89600 to S.N. Thibodeau) with additional support from the Fred Hutchinson Cancer Research Center and the Prostate Cancer Foundation and by a Dutch Cancer Society Fellowship (BUIT 2014-6645 to M. Geybels). The Center for Inherited Disease Research, which provided sequencing services for 19 families, is funded through a contact from NIH to The Johns Hopkins University (contract number HHSN268200782096C). Sequencing of the 56 families at Mayo Clinic was supported by a grant from the National Cancer Institute, NIH (U01 CA89600).
PY - 2017
Y1 - 2017
N2 - Prostate cancer (PCa) susceptibility is defined by a continuum from rare, highpenetrance 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.
AB - Prostate cancer (PCa) susceptibility is defined by a continuum from rare, highpenetrance 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.
KW - Cancer susceptibility
KW - Case-control association
KW - High-risk families
KW - Prostate cancer
KW - Whole exome sequencing
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U2 - 10.18632/oncotarget.13646
DO - 10.18632/oncotarget.13646
M3 - Article
C2 - 27902461
AN - SCOPUS:85009473775
SN - 1949-2553
VL - 8
SP - 1495
EP - 1507
JO - Oncotarget
JF - Oncotarget
IS - 1
ER -