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 Jr; 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

Eur Urol. 2022 May;81(5):458-462. doi: 10.1016/j.eururo.2021.12.023. Epub 2022 Jan 12.

Authors

Burcu F Darst¹, Raymond Hughley², Aaron Pfennig³, Ujani Hazra³, Caoqi Fan⁴, Peggy Wan², Xin Sheng², Lucy Xia², Caroline Andrews⁵, Fei Chen², Sonja I Berndt⁶, Zsofia Kote-Jarai⁷, Koveela Govindasami⁸, Jeannette T Bensen⁹, Sue A Ingles¹⁰, Benjamin A Rybicki¹¹, Barbara Nemesure¹², Esther M John¹³, Jay H Fowke¹⁴, Chad D Huff¹⁵, Sara S Strom¹⁵, William B Isaacs¹⁶, Jong Y Park¹⁷, Wei Zheng¹⁸, Elaine A Ostrander¹⁹, Patrick C Walsh¹⁶, John Carpten²⁰, Thomas A Sellers¹⁷, Kosj Yamoah²¹, Adam B Murphy²², Maureen Sanderson²³, Dana C Crawford²⁴, Susan M Gapstur²⁵, William S Bush²⁴, Melinda C Aldrich²⁶, Olivier Cussenot²⁷, Gyorgy Petrovics²⁸, Jennifer Cullen²⁹, Christine Neslund-Dudas¹¹, Rick A Kittles³⁰, Jianfeng Xu³¹, Mariana C Stern¹⁰, Anand P Chokkalingam³², Luc Multigner³³, Marie-Elise Parent³⁴, Florence Menegaux³⁵, Geraldine Cancel-Tassin²⁷, Adam S Kibel³⁶, Eric A Klein³⁷, Phyllis J Goodman³⁸, Janet L Stanford³⁹, Bettina F Drake⁴⁰, Jennifer J Hu⁴¹, Peter E Clark⁴², Pascal Blanchet⁴³, Graham Casey⁴⁴, Anselm J M Hennis⁴⁵, Alexander Lubwama⁴⁶, Ian M Thompson Jr⁴⁷, Robin J Leach⁴⁸, Susan M Gundell², Loreall Pooler², James L Mohler⁴⁹, Elizabeth T H Fontham⁵⁰, Gary J Smith⁵¹, Jack A Taylor⁵², Laurent Brureau⁴³, William J Blot¹⁸, Richard Biritwum⁵³, Evelyn Tay⁵³, Ann Truelove⁵⁴, Shelley Niwa⁵⁴, Yao Tettey⁵⁵, Rohit Varma⁵⁶, Roberta McKean-Cowdin¹⁰, Mina Torres⁵⁶, Mohamed Jalloh⁵⁷, Serigne Magueye Gueye⁵⁷, Lamine Niang⁵⁷, Olufemi Ogunbiyi⁵⁸, Michael Oladimeji Idowu⁵⁹, Olufemi Popoola⁵⁸, Akindele O Adebiyi⁵⁸, Oseremen I Aisuodionoe-Shadrach⁶⁰, Maxwell Nwegbu⁶⁰, Ben Adusei⁶¹, Sunny Mante⁶¹, Afua Darkwa-Abrahams⁵³, Edward D Yeboah⁵⁵, James E Mensah⁵³, Andrew Anthony Adjei⁵³, Halimatou Diop⁶², Michael B Cook⁶, Stephen J Chanock⁶, Stephen Watya⁶³, Rosalind A Eeles⁸, Charleston W K Chiang⁴, Joseph Lachance³, Timothy R Rebbeck⁵, David V Conti¹⁰, Christopher A Haiman⁶⁴

Affiliations

¹ Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA. Electronic address: bdarst@usc.edu.
² Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³ School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA.
⁴ Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA.
⁵ Harvard TH Chan School of Public Health and Division of Population Sciences, Dana Farber Cancer Institute, Boston, MA, USA.
⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health, Bethesda, MD, USA.
⁷ The Institute of Cancer Research, Sutton, London, UK.
⁸ The Institute of Cancer Research, Sutton, London, UK; Royal Marsden NHS Foundation Trust, London, UK.
⁹ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁰ Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
¹¹ Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA.
¹² Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, NY, USA.
¹³ Department of Epidemiology & Population Health and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹⁴ Division of Epidemiology, Department of Preventive Medicine, The University of Tennessee Health Science Center, TN, USA.
¹⁵ Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
¹⁶ James Buchanan Brady Urological Institute, Johns Hopkins Hospital and Medical Institution, Baltimore, MD, USA.
¹⁷ Department of Cancer Epidemiology, Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
¹⁸ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
¹⁹ Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
²⁰ Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
²¹ Department of Radiation Oncology and Cancer Epidemiology, Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
²² Department of Urology, Northwestern University, Chicago, IL, USA.
²³ Department of Family and Community Medicine, Meharry Medical College, Nashville, TN, USA.
²⁴ Cleveland Institute for Computational Biology, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
²⁵ Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.
²⁶ Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁷ CeRePP & Sorbonne Universite, GRC n° 5, AP-HP, Tenon Hospital, Paris, France.
²⁸ Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
²⁹ Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
³⁰ Department of Population Sciences, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
³¹ Program for Personalized Cancer Care and Department of Surgery, NorthShore University HealthSystem, Evanston, IL, USA.
³² School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
³³ Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) -UMR_S 1085, Rennes, France.
³⁴ Centre Armand-Frappier Santé Biotechnologie, Institut national de la recherche scientifique, University of Quebec, Laval, Quebec, Canada.
³⁵ Université Paris-Saclay, Université Paris-Sud, CESP (Center for Research in Epidemiology and Population Health), Inserm, Team Cancer-Environment, Villejuif, France.
³⁶ Division of Urology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, MA, USA; Washington University, St. Louis, MO, USA.
³⁷ Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, OH, USA.
³⁸ SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
³⁹ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
⁴⁰ Department of Surgery, Division of Public Health Sciences, Washington University School of Medicine, St. Louis, MO, USA.
⁴¹ Sylvester Comprehensive Cancer Center and Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, USA.
⁴² Atrium Health/Levine Cancer Institute, Charlotte, NC, USA.
⁴³ CHU de Guadeloupe, Univ Antilles, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) -UMR_S 1085, Rennes, France.
⁴⁴ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
⁴⁵ Department of Preventive Medicine, Stony Brook University, Stony Brook, NY, USA; George Alleyne Chronic Disease Research Centre and Faculty of Medical Sciences, The University of the West Indies, Bridgetown, Barbados.
⁴⁶ School of Public Health, Makerere University College of Health Sciences, Kampala, Uganda.
⁴⁷ CHRISTUS Santa Rosa Health System and The University of Texas Health Science Center, San Antonio, TX, USA.
⁴⁸ Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
⁴⁹ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA.
⁵⁰ School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
⁵¹ Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA.
⁵² Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA; Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
⁵³ Korle Bu Teaching Hospital, Accra, Ghana.
⁵⁴ Westat, Rockville, MD, USA.
⁵⁵ Korle Bu Teaching Hospital, Accra, Ghana; University of Ghana Medical School, Accra, Ghana.
⁵⁶ Southern California Eye Institute, CHA Hollywood Presbyterian Medical Center, Los Angeles, CA, USA.
⁵⁷ Hôpital Général Idrissa Pouye, Dakar, Senegal.
⁵⁸ College of Medicine, University of Ibadan and University College Hospital, Ibadan, Nigeria.
⁵⁹ College of Medicine, University of Ibadan, Ibadan, Nigeria.
⁶⁰ College of Health Sciences, University of Abuja, University of Abuja Teaching Hospital and Cancer Science Center, Abuja, Nigeria.
⁶¹ 37 Military Hospital, Accra, Ghana.
⁶² Laboratoires Bacteriologie et Virologie, Hôpital Aristide Le Dantec, Dakar, Senegal.
⁶³ School of Public Health, Makerere University College of Health Sciences, Kampala, Uganda; Uro Care, Kampala, Uganda.
⁶⁴ Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA. Electronic address: haiman@usc.edu.

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.

MeSH terms

Case-Control Studies
Early Detection of Cancer*
Genetic Predisposition to Disease
Germ Cells / pathology
Germ-Line Mutation
Homeodomain Proteins / genetics
Humans
Male
Prostate-Specific Antigen / genetics
Prostatic Neoplasms* / genetics
Prostatic Neoplasms* / pathology

Substances

HOXB13 protein, human
Homeodomain Proteins
Prostate-Specific Antigen

Abstract

MeSH terms

Substances

Grants and funding