Prostate cancer risk variants of the HOXB genetic locus

Abstract The G84E germline mutation of HOXB13 predisposes to prostate cancer and is clinically tested for familial cancer care. We investigated the HOXB locus to define a potentially broader contribution to prostate cancer heritability. We sought HOXB locus germline variants altering prostate cancer...

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Autores principales:	William D. Dupont, Joan P. Breyer, Spenser H. Johnson, W. Dale Plummer, Jeffrey R. Smith
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5debdd290a10471e8699db5a1802f7b5
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spelling	oai:doaj.org-article:5debdd290a10471e8699db5a1802f7b52021-12-02T17:50:57ZProstate cancer risk variants of the HOXB genetic locus10.1038/s41598-021-89399-72045-2322https://doaj.org/article/5debdd290a10471e8699db5a1802f7b52021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89399-7https://doaj.org/toc/2045-2322Abstract The G84E germline mutation of HOXB13 predisposes to prostate cancer and is clinically tested for familial cancer care. We investigated the HOXB locus to define a potentially broader contribution to prostate cancer heritability. We sought HOXB locus germline variants altering prostate cancer risk in three European-ancestry case–control study populations (combined 7812 cases and 5047 controls): the International Consortium for Prostate Cancer Genetics Study; the Nashville Familial Prostate Cancer Study; and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Multiple rare genetic variants had concordant and strong risk effects in these study populations and exceeded genome-wide significance. Independent risk signals were best detected by sentinel variants rs559612720 within SKAP1 (OR = 8.1, P = 2E−9) and rs138213197 (G84E) within HOXB13 (OR = 5.6, P = 2E−11), separated by 567 kb. Half of carriers inherited both risk alleles, while others inherited either alone. Under mutual adjustment, the variants separately carried 3.6- and 3.1-fold risk, respectively, while joint inheritance carried 11.3-fold risk. These risks were further accentuated among men meeting criteria for hereditary prostate cancer, and further still for those with early-onset or aggressive disease. Among hereditary prostate cancer cases diagnosed under age 60 and with aggressive disease, joint inheritance carried a risk of OR = 27.7 relative to controls, P = 2E−8. The HOXB sentinel variant pair more fully captured genetic risk for prostate cancer within the study populations than either variant alone.William D. DupontJoan P. BreyerSpenser H. JohnsonW. Dale PlummerJeffrey R. SmithNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q William D. Dupont Joan P. Breyer Spenser H. Johnson W. Dale Plummer Jeffrey R. Smith Prostate cancer risk variants of the HOXB genetic locus
description	Abstract The G84E germline mutation of HOXB13 predisposes to prostate cancer and is clinically tested for familial cancer care. We investigated the HOXB locus to define a potentially broader contribution to prostate cancer heritability. We sought HOXB locus germline variants altering prostate cancer risk in three European-ancestry case–control study populations (combined 7812 cases and 5047 controls): the International Consortium for Prostate Cancer Genetics Study; the Nashville Familial Prostate Cancer Study; and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Multiple rare genetic variants had concordant and strong risk effects in these study populations and exceeded genome-wide significance. Independent risk signals were best detected by sentinel variants rs559612720 within SKAP1 (OR = 8.1, P = 2E−9) and rs138213197 (G84E) within HOXB13 (OR = 5.6, P = 2E−11), separated by 567 kb. Half of carriers inherited both risk alleles, while others inherited either alone. Under mutual adjustment, the variants separately carried 3.6- and 3.1-fold risk, respectively, while joint inheritance carried 11.3-fold risk. These risks were further accentuated among men meeting criteria for hereditary prostate cancer, and further still for those with early-onset or aggressive disease. Among hereditary prostate cancer cases diagnosed under age 60 and with aggressive disease, joint inheritance carried a risk of OR = 27.7 relative to controls, P = 2E−8. The HOXB sentinel variant pair more fully captured genetic risk for prostate cancer within the study populations than either variant alone.
format	article
author	William D. Dupont Joan P. Breyer Spenser H. Johnson W. Dale Plummer Jeffrey R. Smith
author_facet	William D. Dupont Joan P. Breyer Spenser H. Johnson W. Dale Plummer Jeffrey R. Smith
author_sort	William D. Dupont
title	Prostate cancer risk variants of the HOXB genetic locus
title_short	Prostate cancer risk variants of the HOXB genetic locus
title_full	Prostate cancer risk variants of the HOXB genetic locus
title_fullStr	Prostate cancer risk variants of the HOXB genetic locus
title_full_unstemmed	Prostate cancer risk variants of the HOXB genetic locus
title_sort	prostate cancer risk variants of the hoxb genetic locus
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/5debdd290a10471e8699db5a1802f7b5
work_keys_str_mv	AT williamddupont prostatecancerriskvariantsofthehoxbgeneticlocus AT joanpbreyer prostatecancerriskvariantsofthehoxbgeneticlocus AT spenserhjohnson prostatecancerriskvariantsofthehoxbgeneticlocus AT wdaleplummer prostatecancerriskvariantsofthehoxbgeneticlocus AT jeffreyrsmith prostatecancerriskvariantsofthehoxbgeneticlocus
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Prostate cancer risk variants of the HOXB genetic locus

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