Dataset Information

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.

SUBMITTER: Darst BF

PROVIDER: S-EPMC9018520 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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

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

European urology 20220112 5

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 ra ...[more]

PMID: 35031163

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Project description:BackgroundAlthough men of African ancestry (AA) have the highest mortality rate from prostate cancer (PCa), relatively little is known about the germline variants that are associated with PCa risk in AA men. The goal of this study is to systematically evaluate rare, recurrent nonsynonymous variants across the exome for their association with PCa in AA men.MethodsWhole exome sequencing (WES) of germline DNA in two AA PCa patient cohorts of Johns Hopkins Hospital (N = 960) and Wayne State University (N = 747) was performed. All nonsynonymous variants present in both case cohorts, with a carrier rate between 0.5% and 1%, were identified. Their carrier rates were compared with rates from 8128 African/African American (AFR) control subjects from The Genome Aggregation Database (gnomAD) using Fisher's exact test. Significant variants, defined as false discovery rate (FDR) adjusted p-value ≤ 0.05, were further evaluated in AA PCa cases (N = 132) and controls (N = 1184) from the UK Biobank (UKB).ResultsTwo variants reached a pre-specified statistical significance level. The first was p.R14Q in GPRC5C (found in 0.47% of PCa cases and 0.01% of population controls); odds ratio (OR) for PCa was 37.46 (95% confidence interval CI 4.68-299.72), pexact = 7.01E-06, FDR-adjusted p-value = 0.05. The second was p.R511Q in IGF1R (found in 0.53% of PCa cases and 0.01% of population controls); OR for PCa was 21.54 (95%CI 4.65-99.76), pexact = 5.51E-06, FDR-adjusted p-value = 0.05. The mean percentage of African ancestry was similar between variant carriers and noncarriers of each variant, p > 0.05. In the UKB AA men, GPRC5C R14Q was 0.76% and 0.08% in cases and controls, respectively, OR for PCa was 9.00 (95%CI 0.56-145.23), pexact = 0.19. However, IGF1R R511Q was not found in cases or controls.ConclusionsThis WES study identified two rare, recurrent nonsynonymous PCa risk-associated variants in AA. Confirmation in additional large populations of AA PCa cases and controls is required.

Dataset Information

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

Publications

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

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