A Rare Germline HOXB13 Variant Contributes to Risk of Prostate Cancer in Men of African Ancestry
Authors: 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
Journal: European Urology (2022)

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.