A Rare Germline HOXB13 Variant Contributes to Risk of Prostate Cancer in Men of African Ancestry
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, Jr., 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, and Haiman CA. A Rare Germline HOXB13 Variant Contributes to Risk of Prostate Cancer in Men of African Ancestry. Eur Urol 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.
ePub ahead of print