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

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

doi:10.1016/j.eururo.2021.12.023

Cited by 30 publications

(22 citation statements)

References 10 publications

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“…13,14,25,26 In a large PCa cases-control study of AA, X285K carrier rate was estimated at 0.35% in 10,477 cases and 0.14% in 9,688 controls, OR=2.42, p=2E-04. 14 The estimated PCa risk for these two nonsynonymous variants were likely over-estimated due to a combination of low frequency and relatively small sample size of cases and controls. When we included additional AFR controls from gnomAD WGS (4,359), the OR reduced to 11.59 (95%CI: 3.79-35.47) for p.R14Q of GPRC5C.…”

Section: Discussionmentioning

confidence: 99%

Association of rare, recurrent nonsynonymous variants in the germline of prostate cancer patients of African ancestry

et al. 2022

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Background: Although 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.Methods: Whole 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 presented in both case cohorts, with a carrier rate between 0.3% and 1%, were identi ed. Their carrier rates were compared with rates from 8,128 African/African American (AFR) control subjects fromThe Genome Aggregation Database (gnomAD) using Fisher's exact test. Signi cant variants, de ned as false discovery rate (FDR) adjusted p-value £0.05, were further evaluated in AA PCa cases (N=132) and controls (N=1,184) from the UK Biobank (UKB).Results: Two variants reached a pre-speci ed statistical signi cance level. The rst 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%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 non-carriers 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.Conclusions: This WES study identi ed two rare, recurrent nonsynonymous PCa risk-associated variants in AA. Con rmation in additional large populations of AA PCa cases and controls is required.

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Section: Discussionmentioning

confidence: 99%

Association of rare, recurrent nonsynonymous variants in the germline of prostate cancer patients of African ancestry

et al. 2022

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“…13,14,25,26 In a large PCa cases-control study of AA, X285K carrier rate was estimated at 0.35% in 10,477 cases and 0.14% in 9,688 controls, OR = 2.42, p = 2E-04. 14 The estimated PCa risk for these two nonsynonymous variants were likely over-estimated due to a combination of low frequency and relatively small sample size of cases and controls. When we included additional AFR controls from gnomAD WGS (4,359), the OR reduced to 11.59 (95%CI: 3.79-35.47) for p.R14Q of GPRC5C.…”

Section: Discussionmentioning

confidence: 99%

“…However, these carrier rates were similar to the recently established pathogenic mutation of HOXB13 X285K in AA. 13,14,25,26 In a large PCa cases-control study of AA, X285K carrier rate was estimated at 0.35% in 10,477 cases and 0.14% in 9,688 controls, OR = 2.42, p = 2E-04. 14 The estimated PCa risk for these two nonsynonymous variants were likely over-estimated due to a combination of low frequency and relatively small sample size of cases and controls.…”

Section: Discussionmentioning

confidence: 99%

Association of rare, recurrent nonsynonymous variants in the germline of prostate cancer patients of African ancestry

Wei

Beebe‐Dimmer

et al. 2022

Preprint

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Background Although 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. Methods Whole 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 presented in both case cohorts, with a carrier rate between 0.3% and 1%, were identified. Their carrier rates were compared with rates from 8,128 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 = 1,184) from the UK Biobank (UKB). Results Two 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%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 non-carriers 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. Conclusions This 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.

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“…Three recent studies have highlighted important genetic risk variants that are only found in African populations [59][60][61]. These three studies are notable in several respects.…”

Section: Single Nucleotide Polymorphismsmentioning

confidence: 99%

“…The first study describes a relatively common but novel SNP of African origin (rs72725854) that carries a much higher effect size for PCa risk than is typically seen and is enriched in men with a PCa family history [59]. The other two studies describe a novel variant in the HOXB13 gene (X285K) that, unlike the vast majority of similar variants, is associated with increased risk for more aggressive disease in men of African descent [60,61]. These variants should provide important new tools for more effective identification of African men at elevated risk for all PCa, and importantly, in the latter case, for more aggressive disease.…”

Section: Single Nucleotide Polymorphismsmentioning

confidence: 99%

The role of genetic testing in prostate cancer screening, diagnosis, and treatment

Calle

Bhanji²,

Pavlovich³

et al. 2022

Current Opinion in Oncology

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Purpose of reviewThis review provides an overview of the current role of genetic testing in prostate cancer screening, diagnosis, and treatment. Recent findingsRecent studies have uncovered few but highly penetrant rare pathogenic mutations (RPMs), in genes, such as BRCA2, with strong prostate cancer risk and outcomes associations. Over 260 single nucleotide polymorphisms (SNPs) have also been identified, each associated with small incremental prostate cancer risk and when combined in a polygenic risk score (PRS), they provide strong prostate cancer risk prediction but do not seem to predict outcomes. Tumor tissue sequencing can also help identify actionable somatic mutations in many patients with advanced prostate cancer and inform on their risk of harboring a germline pathogenic mutation. SummaryRPM testing, PRS testing, and tumor sequencing all have current and/or potential future roles in personalized prostate cancer care. Keywords genetic testing, germline mutations, polygenic risk score, prostate cancer MEASURES OF INHERITED PROSTATE CANCER RISK Family history and genetic ancestryRecording family history, self-reported race and ethnicity are some of the earliest forms of 'genetic' testing, and along with age remain some of the

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

Cited by 30 publications

References 10 publications

Association of rare, recurrent nonsynonymous variants in the germline of prostate cancer patients of African ancestry

Association of rare, recurrent nonsynonymous variants in the germline of prostate cancer patients of African ancestry

Association of rare, recurrent nonsynonymous variants in the germline of prostate cancer patients of African ancestry

The role of genetic testing in prostate cancer screening, diagnosis, and treatment

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