A Rare Germline HOXB13 Variant Contributes to Risk of Prostate Cancer in Men of African Ancestry

Burcu F. Darst; Raymond Hughley; Aaron Pfennig; Ujani Hazra; Caoqi Fan; Peggy Wan; Xin Sheng; Lucy Xia; Caroline Andrews; Fei Chen; Sonja I. Berndt; Zsofia Kote-Jarai; Koveela Govindasami; Jeannette T. Bensen; Sue A. Ingles; Benjamin A. Rybicki; Barbara Nemesure; Esther M. John; Jay H. Fowke; Chad D. Huff; Sara S. Strom; William B. Isaacs; Jong Y. Park; Wei Zheng; Elaine A. Ostrander; Patrick C. Walsh; John Carpten; Thomas A. Sellers; Kosj Yamoah; Adam B. Murphy; Maureen Sanderson; Dana C. Crawford; Susan M. Gapstur; William S. Bush; Melinda C. Aldrich; Olivier Cussenot; Gyorgy Petrovics; Jennifer Cullen; Christine Neslund-Dudas; Rick A. Kittles; Jianfeng Xu; Mariana C. Stern; Anand P. Chokkalingam; Luc Multigner; Marie Elise Parent; Florence Menegaux; Geraldine Cancel-Tassin; Adam S. Kibel; Eric A. Klein; Phyllis J. Goodman; Janet L. Stanford; Bettina F. Drake; Jennifer J. Hu; Peter E. Clark; Pascal Blanchet; Graham Casey; Anselm J.M. Hennis; Alexander Lubwama; Ian M. Thompson; Robin J. Leach; Susan M. Gundell; Loreall Pooler; James L. Mohler; Elizabeth T.H. Fontham; Gary J. Smith; Jack A. Taylor; Laurent Brureau; William J. Blot; Richard Biritwum; Evelyn Tay; Ann Truelove; Shelley Niwa; Yao Tettey; Rohit Varma; Roberta McKean-Cowdin; Mina Torres; Mohamed Jalloh; Serigne Magueye Gueye; Lamine Niang; Olufemi Ogunbiyi; Michael Oladimeji Idowu; Olufemi Popoola; Akindele O. Adebiyi; Oseremen I. Aisuodionoe-Shadrach; Maxwell Nwegbu; Ben Adusei; Sunny Mante; Afua Darkwa-Abrahams; Edward D. Yeboah; James E. Mensah; Andrew Anthony Adjei; Halimatou Diop; Michael B. Cook; Stephen J. Chanock; Stephen Watya; Rosalind A. Eeles; Charleston W.K. Chiang; Joseph Lachance; Timothy R. Rebbeck; David V. Conti; Christopher A. Haiman

doi:10.1016/j.eururo.2021.12.023

A Rare Germline HOXB13 Variant Contributes to Risk of Prostate Cancer in Men of African Ancestry

Burcu F. Darst^*, Raymond Hughley, Aaron Pfennig, Ujani Hazra, Caoqi Fan, Peggy Wan, Xin Sheng, Lucy Xia, Caroline Andrews, Fei Chen, Sonja I. Berndt, Zsofia Kote-Jarai, Koveela Govindasami, Jeannette T. Bensen, Sue A. Ingles, Benjamin A. Rybicki, Barbara Nemesure, Esther M. John, Jay H. Fowke, Chad D. HuffSara S. Strom, William B. Isaacs, Jong Y. Park, Wei Zheng, Elaine A. Ostrander, Patrick C. Walsh, John Carpten, Thomas A. Sellers, Kosj Yamoah, Adam B. Murphy, Maureen Sanderson, Dana C. Crawford, Susan M. Gapstur, William S. Bush, Melinda C. Aldrich, Olivier Cussenot, Gyorgy Petrovics, Jennifer Cullen, Christine Neslund-Dudas, Rick A. Kittles, Jianfeng Xu, Mariana C. Stern, Anand P. Chokkalingam, Luc Multigner, Marie Elise Parent, Florence Menegaux, Geraldine Cancel-Tassin, Adam S. Kibel, Eric A. Klein, Phyllis J. Goodman, Janet L. Stanford, Bettina F. Drake, Jennifer J. Hu, Peter E. Clark, Pascal Blanchet, Graham Casey, Anselm J.M. Hennis, Alexander Lubwama, Ian M. Thompson, Robin J. Leach, Susan M. Gundell, Loreall Pooler, James L. Mohler, Elizabeth T.H. Fontham, Gary J. Smith, Jack A. Taylor, Laurent Brureau, William J. Blot, Richard Biritwum, Evelyn Tay, Ann Truelove, Shelley Niwa, Yao Tettey, Rohit Varma, Roberta McKean-Cowdin, Mina Torres, Mohamed Jalloh, Serigne Magueye Gueye, Lamine Niang, Olufemi Ogunbiyi, Michael Oladimeji Idowu, Olufemi Popoola, Akindele O. Adebiyi, Oseremen I. Aisuodionoe-Shadrach, Maxwell Nwegbu, Ben Adusei, Sunny Mante, Afua Darkwa-Abrahams, Edward D. Yeboah, James E. Mensah, Andrew Anthony Adjei, Halimatou Diop, Michael B. Cook, Stephen J. Chanock, Stephen Watya, Rosalind A. Eeles, Charleston W.K. Chiang, Joseph Lachance, Timothy R. Rebbeck, David V. Conti, Christopher A. Haiman

^*Corresponding author for this work

Urology

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

A rare African ancestry–specific germline deletion variant in HOXB13 (X285K, rs77179853) was recently reported in Martinican men with early-onset prostate cancer. Given the role of HOXB13 germline variation in prostate cancer, we investigated the association between HOXB13 X285K and prostate cancer risk in a large sample of 22 361 African ancestry men, including 11 688 prostate cancer cases. The risk allele was present only in men of West African ancestry, with an allele frequency in men that ranged from 0.40% in Ghana and 0.31% in Nigeria to 0% in Uganda and South Africa, with a range of frequencies in men with admixed African ancestry from North America and Europe (0–0.26%). HOXB13 X285K was associated with 2.4-fold increased odds of prostate cancer (95% confidence interval [CI] = 1.5-3.9, p = 2 × 10⁻⁴), with greater risk observed for more aggressive and advanced disease (Gleason ≥8: odds ratio [OR] = 4.7, 95% CI = 2.3–9.5, p = 2 × 10⁻⁵; stage T3/T4: OR = 4.5, 95% CI = 2.0–10.0, p = 2 × 10⁻⁴; metastatic disease: OR = 5.1, 95% CI = 1.9–13.7, p = 0.001). We estimated that the allele arose in West Africa 1500–4600 yr ago. Further analysis is needed to understand how the HOXB13 X285K variant impacts the HOXB13 protein and function in the prostate. Understanding who carries this mutation may inform prostate cancer screening in men of West African ancestry. Patient summary: A rare African ancestry–specific germline deletion in HOXB13, found only in men of West African ancestry, was reported to be associated with an increased risk of overall and advanced prostate cancer. Understanding who carries this mutation may help inform screening for prostate cancer in men of West African ancestry.

Original language	English (US)
Pages (from-to)	458-462
Number of pages	5
Journal	European urology
Volume	81
Issue number	5
DOIs	https://doi.org/10.1016/j.eururo.2021.12.023
State	Published - May 2022

Funding

Funding/Support and role of the sponsor: This work was supported by the National Cancer Institute at the National Institutes of Health, grants U19 CA148537, U19 CA214253, R01 CA165862, and K99CA246063. Dr. Burcu F. Darst was supported in part by an award from the Achievement Rewards for College Scientists Foundation Los Angeles Founder Chapter.

Keywords

African ancestry
Allelic age
Genetics
HOXB13
Health disparities
Prostate cancer
Rare genetic variants

ASJC Scopus subject areas

Urology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.eururo.2021.12.023

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Darst, B. F., Hughley, R., Pfennig, A., Hazra, U., Fan, C., Wan, P., Sheng, X., Xia, L., Andrews, C., Chen, F., Berndt, S. I., Kote-Jarai, Z., Govindasami, K., Bensen, J. T., Ingles, S. A., Rybicki, B. A., Nemesure, B., John, E. M., Fowke, J. H., ... Haiman, C. A. (2022). A Rare Germline HOXB13 Variant Contributes to Risk of Prostate Cancer in Men of African Ancestry. European urology, 81(5), 458-462. https://doi.org/10.1016/j.eururo.2021.12.023

@article{c796e8c821194fa89ad38b51a6518a34,

title = "A Rare Germline HOXB13 Variant Contributes to Risk of Prostate Cancer in Men of African Ancestry",

abstract = "A rare African ancestry–specific germline deletion variant in HOXB13 (X285K, rs77179853) was recently reported in Martinican men with early-onset prostate cancer. Given the role of HOXB13 germline variation in prostate cancer, we investigated the association between HOXB13 X285K and prostate cancer risk in a large sample of 22 361 African ancestry men, including 11 688 prostate cancer cases. The risk allele was present only in men of West African ancestry, with an allele frequency in men that ranged from 0.40% in Ghana and 0.31% in Nigeria to 0% in Uganda and South Africa, with a range of frequencies in men with admixed African ancestry from North America and Europe (0–0.26%). HOXB13 X285K was associated with 2.4-fold increased odds of prostate cancer (95% confidence interval [CI] = 1.5-3.9, p = 2 × 10−4), with greater risk observed for more aggressive and advanced disease (Gleason ≥8: odds ratio [OR] = 4.7, 95% CI = 2.3–9.5, p = 2 × 10−5; stage T3/T4: OR = 4.5, 95% CI = 2.0–10.0, p = 2 × 10−4; metastatic disease: OR = 5.1, 95% CI = 1.9–13.7, p = 0.001). We estimated that the allele arose in West Africa 1500–4600 yr ago. Further analysis is needed to understand how the HOXB13 X285K variant impacts the HOXB13 protein and function in the prostate. Understanding who carries this mutation may inform prostate cancer screening in men of West African ancestry. Patient summary: A rare African ancestry–specific germline deletion in HOXB13, found only in men of West African ancestry, was reported to be associated with an increased risk of overall and advanced prostate cancer. Understanding who carries this mutation may help inform screening for prostate cancer in men of West African ancestry.",

keywords = "African ancestry, Allelic age, Genetics, HOXB13, Health disparities, Prostate cancer, Rare genetic variants",

author = "Darst, {Burcu F.} and Raymond Hughley and Aaron Pfennig and Ujani Hazra and Caoqi Fan and Peggy Wan and Xin Sheng and Lucy Xia and Caroline Andrews and Fei Chen and Berndt, {Sonja I.} and Zsofia Kote-Jarai and Koveela Govindasami and Bensen, {Jeannette T.} and Ingles, {Sue A.} and Rybicki, {Benjamin A.} and Barbara Nemesure and John, {Esther M.} and Fowke, {Jay H.} and Huff, {Chad D.} and Strom, {Sara S.} and Isaacs, {William B.} and Park, {Jong Y.} and Wei Zheng and Ostrander, {Elaine A.} and Walsh, {Patrick C.} and John Carpten and Sellers, {Thomas A.} and Kosj Yamoah and Murphy, {Adam B.} and Maureen Sanderson and Crawford, {Dana C.} and Gapstur, {Susan M.} and Bush, {William S.} and Aldrich, {Melinda C.} and Olivier Cussenot and Gyorgy Petrovics and Jennifer Cullen and Christine Neslund-Dudas and Kittles, {Rick A.} and Jianfeng Xu and Stern, {Mariana C.} and Chokkalingam, {Anand P.} and Luc Multigner and Parent, {Marie Elise} and Florence Menegaux and Geraldine Cancel-Tassin and Kibel, {Adam S.} and Klein, {Eric A.} and Goodman, {Phyllis J.} and Stanford, {Janet L.} and Drake, {Bettina F.} and Hu, {Jennifer J.} and Clark, {Peter E.} and Pascal Blanchet and Graham Casey and Hennis, {Anselm J.M.} and Alexander Lubwama and Thompson, {Ian M.} and Leach, {Robin J.} and Gundell, {Susan M.} and Loreall Pooler and Mohler, {James L.} and Fontham, {Elizabeth T.H.} and Smith, {Gary J.} and Taylor, {Jack A.} and Laurent Brureau and Blot, {William J.} and Richard Biritwum and Evelyn Tay and Ann Truelove and Shelley Niwa and Yao Tettey and Rohit Varma and Roberta McKean-Cowdin and Mina Torres and Mohamed Jalloh and {Magueye Gueye}, Serigne and Lamine Niang and Olufemi Ogunbiyi and {Oladimeji Idowu}, Michael and Olufemi Popoola and Adebiyi, {Akindele O.} and Aisuodionoe-Shadrach, {Oseremen I.} and Maxwell Nwegbu and Ben Adusei and Sunny Mante and Afua Darkwa-Abrahams and Yeboah, {Edward D.} and Mensah, {James E.} and {Anthony Adjei}, Andrew and Halimatou Diop and Cook, {Michael B.} and Chanock, {Stephen J.} and Stephen Watya and Eeles, {Rosalind A.} and Chiang, {Charleston W.K.} and Joseph Lachance and Rebbeck, {Timothy R.} and Conti, {David V.} and Haiman, {Christopher A.}",

note = "Publisher Copyright: {\textcopyright} 2022",

year = "2022",

month = may,

doi = "10.1016/j.eururo.2021.12.023",

language = "English (US)",

volume = "81",

pages = "458--462",

journal = "European urology",

issn = "0302-2838",

publisher = "Elsevier",

number = "5",

}

Darst, BF, Hughley, R, Pfennig, A, Hazra, U, Fan, C, Wan, P, Sheng, X, Xia, L, Andrews, C, Chen, F, Berndt, SI, Kote-Jarai, Z, Govindasami, K, Bensen, JT, Ingles, SA, Rybicki, BA, Nemesure, B, John, EM, Fowke, JH, Huff, CD, Strom, SS, Isaacs, WB, Park, JY, Zheng, W, Ostrander, EA, Walsh, PC, Carpten, J, Sellers, TA, Yamoah, K, Murphy, AB, Sanderson, M, Crawford, DC, Gapstur, SM, Bush, WS, Aldrich, MC, Cussenot, O, Petrovics, G, Cullen, J, Neslund-Dudas, C, Kittles, RA, Xu, J, Stern, MC, Chokkalingam, AP, Multigner, L, Parent, ME, Menegaux, F, Cancel-Tassin, G, Kibel, AS, Klein, EA, Goodman, PJ, Stanford, JL, Drake, BF, Hu, JJ, Clark, PE, Blanchet, P, Casey, G, Hennis, AJM, Lubwama, A, Thompson, IM, Leach, RJ, Gundell, SM, Pooler, L, Mohler, JL, Fontham, ETH, Smith, GJ, Taylor, JA, Brureau, L, Blot, WJ, Biritwum, R, Tay, E, Truelove, A, Niwa, S, Tettey, Y, Varma, R, McKean-Cowdin, R, Torres, M, Jalloh, M, Magueye Gueye, S, Niang, L, Ogunbiyi, O, Oladimeji Idowu, M, Popoola, O, Adebiyi, AO, Aisuodionoe-Shadrach, OI, Nwegbu, M, Adusei, B, Mante, S, Darkwa-Abrahams, A, Yeboah, ED, Mensah, JE, Anthony Adjei, A, Diop, H, Cook, MB, Chanock, SJ, Watya, S, Eeles, RA, Chiang, CWK, Lachance, J, Rebbeck, TR, Conti, DV & Haiman, CA 2022, 'A Rare Germline HOXB13 Variant Contributes to Risk of Prostate Cancer in Men of African Ancestry', European urology, vol. 81, no. 5, pp. 458-462. https://doi.org/10.1016/j.eururo.2021.12.023

TY - JOUR

T1 - A Rare Germline HOXB13 Variant Contributes to Risk of Prostate Cancer in Men of African Ancestry

AU - Darst, Burcu F.

AU - Hughley, Raymond

AU - Pfennig, Aaron

AU - Hazra, Ujani

AU - Fan, Caoqi

AU - Wan, Peggy

AU - Sheng, Xin

AU - Xia, Lucy

AU - Andrews, Caroline

AU - Chen, Fei

AU - Berndt, Sonja I.

AU - Kote-Jarai, Zsofia

AU - Govindasami, Koveela

AU - Bensen, Jeannette T.

AU - Ingles, Sue A.

AU - Rybicki, Benjamin A.

AU - Nemesure, Barbara

AU - John, Esther M.

AU - Fowke, Jay H.

AU - Huff, Chad D.

AU - Strom, Sara S.

AU - Isaacs, William B.

AU - Park, Jong Y.

AU - Zheng, Wei

AU - Ostrander, Elaine A.

AU - Walsh, Patrick C.

AU - Carpten, John

AU - Sellers, Thomas A.

AU - Yamoah, Kosj

AU - Murphy, Adam B.

AU - Sanderson, Maureen

AU - Crawford, Dana C.

AU - Gapstur, Susan M.

AU - Bush, William S.

AU - Aldrich, Melinda C.

AU - Cussenot, Olivier

AU - Petrovics, Gyorgy

AU - Cullen, Jennifer

AU - Neslund-Dudas, Christine

AU - Kittles, Rick A.

AU - Xu, Jianfeng

AU - Stern, Mariana C.

AU - Chokkalingam, Anand P.

AU - Multigner, Luc

AU - Parent, Marie Elise

AU - Menegaux, Florence

AU - Cancel-Tassin, Geraldine

AU - Kibel, Adam S.

AU - Klein, Eric A.

AU - Goodman, Phyllis J.

AU - Stanford, Janet L.

AU - Drake, Bettina F.

AU - Hu, Jennifer J.

AU - Clark, Peter E.

AU - Blanchet, Pascal

AU - Casey, Graham

AU - Hennis, Anselm J.M.

AU - Lubwama, Alexander

AU - Thompson, Ian M.

AU - Leach, Robin J.

AU - Gundell, Susan M.

AU - Pooler, Loreall

AU - Mohler, James L.

AU - Fontham, Elizabeth T.H.

AU - Smith, Gary J.

AU - Taylor, Jack A.

AU - Brureau, Laurent

AU - Blot, William J.

AU - Biritwum, Richard

AU - Tay, Evelyn

AU - Truelove, Ann

AU - Niwa, Shelley

AU - Tettey, Yao

AU - Varma, Rohit

AU - McKean-Cowdin, Roberta

AU - Torres, Mina

AU - Jalloh, Mohamed

AU - Magueye Gueye, Serigne

AU - Niang, Lamine

AU - Ogunbiyi, Olufemi

AU - Oladimeji Idowu, Michael

AU - Popoola, Olufemi

AU - Adebiyi, Akindele O.

AU - Aisuodionoe-Shadrach, Oseremen I.

AU - Nwegbu, Maxwell

AU - Adusei, Ben

AU - Mante, Sunny

AU - Darkwa-Abrahams, Afua

AU - Yeboah, Edward D.

AU - Mensah, James E.

AU - Anthony Adjei, Andrew

AU - Diop, Halimatou

AU - Cook, Michael B.

AU - Chanock, Stephen J.

AU - Watya, Stephen

AU - Eeles, Rosalind A.

AU - Chiang, Charleston W.K.

AU - Lachance, Joseph

AU - Rebbeck, Timothy R.

AU - Conti, David V.

AU - Haiman, Christopher A.

PY - 2022/5

Y1 - 2022/5

N2 - A rare African ancestry–specific germline deletion variant in HOXB13 (X285K, rs77179853) was recently reported in Martinican men with early-onset prostate cancer. Given the role of HOXB13 germline variation in prostate cancer, we investigated the association between HOXB13 X285K and prostate cancer risk in a large sample of 22 361 African ancestry men, including 11 688 prostate cancer cases. The risk allele was present only in men of West African ancestry, with an allele frequency in men that ranged from 0.40% in Ghana and 0.31% in Nigeria to 0% in Uganda and South Africa, with a range of frequencies in men with admixed African ancestry from North America and Europe (0–0.26%). HOXB13 X285K was associated with 2.4-fold increased odds of prostate cancer (95% confidence interval [CI] = 1.5-3.9, p = 2 × 10−4), with greater risk observed for more aggressive and advanced disease (Gleason ≥8: odds ratio [OR] = 4.7, 95% CI = 2.3–9.5, p = 2 × 10−5; stage T3/T4: OR = 4.5, 95% CI = 2.0–10.0, p = 2 × 10−4; metastatic disease: OR = 5.1, 95% CI = 1.9–13.7, p = 0.001). We estimated that the allele arose in West Africa 1500–4600 yr ago. Further analysis is needed to understand how the HOXB13 X285K variant impacts the HOXB13 protein and function in the prostate. Understanding who carries this mutation may inform prostate cancer screening in men of West African ancestry. Patient summary: A rare African ancestry–specific germline deletion in HOXB13, found only in men of West African ancestry, was reported to be associated with an increased risk of overall and advanced prostate cancer. Understanding who carries this mutation may help inform screening for prostate cancer in men of West African ancestry.

AB - A rare African ancestry–specific germline deletion variant in HOXB13 (X285K, rs77179853) was recently reported in Martinican men with early-onset prostate cancer. Given the role of HOXB13 germline variation in prostate cancer, we investigated the association between HOXB13 X285K and prostate cancer risk in a large sample of 22 361 African ancestry men, including 11 688 prostate cancer cases. The risk allele was present only in men of West African ancestry, with an allele frequency in men that ranged from 0.40% in Ghana and 0.31% in Nigeria to 0% in Uganda and South Africa, with a range of frequencies in men with admixed African ancestry from North America and Europe (0–0.26%). HOXB13 X285K was associated with 2.4-fold increased odds of prostate cancer (95% confidence interval [CI] = 1.5-3.9, p = 2 × 10−4), with greater risk observed for more aggressive and advanced disease (Gleason ≥8: odds ratio [OR] = 4.7, 95% CI = 2.3–9.5, p = 2 × 10−5; stage T3/T4: OR = 4.5, 95% CI = 2.0–10.0, p = 2 × 10−4; metastatic disease: OR = 5.1, 95% CI = 1.9–13.7, p = 0.001). We estimated that the allele arose in West Africa 1500–4600 yr ago. Further analysis is needed to understand how the HOXB13 X285K variant impacts the HOXB13 protein and function in the prostate. Understanding who carries this mutation may inform prostate cancer screening in men of West African ancestry. Patient summary: A rare African ancestry–specific germline deletion in HOXB13, found only in men of West African ancestry, was reported to be associated with an increased risk of overall and advanced prostate cancer. Understanding who carries this mutation may help inform screening for prostate cancer in men of West African ancestry.

KW - African ancestry

KW - Allelic age

KW - Genetics

KW - HOXB13

KW - Health disparities

KW - Prostate cancer

KW - Rare genetic variants

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U2 - 10.1016/j.eururo.2021.12.023

DO - 10.1016/j.eururo.2021.12.023

M3 - Article

C2 - 35031163

AN - SCOPUS:85122617547

SN - 0302-2838

VL - 81

SP - 458

EP - 462

JO - European urology

JF - European urology

IS - 5

ER -

A Rare Germline HOXB13 Variant Contributes to Risk of Prostate Cancer in Men of African Ancestry

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