Evaluating Germline Testing Panels in Southern African Males With Advanced Prostate Cancer

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Kazzem Gheybi Ancestry & Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, The University of Sydney, Camperdown, NSW, Australia

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Jue Jiang Ancestry & Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, The University of Sydney, Camperdown, NSW, Australia

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Shingai B.A. Mutambirwa Department of Urology, Sefako Mekgatho Health Sciences University, Dr. George Mukhari Academic Hospital, Medunsa, South Africa

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Pamela X.Y. Soh Ancestry & Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, The University of Sydney, Camperdown, NSW, Australia

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Zsofia Kote-Jarai Oncogenetics Team, The Institute of Cancer Research, Surrey, United Kingdom

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Weerachai Jaratlerdsiri Ancestry & Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, The University of Sydney, Camperdown, NSW, Australia

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Rosalind A. Eeles Oncogenetics Team, The Institute of Cancer Research, Surrey, United Kingdom

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M.S. Riana Bornman School of Health Systems and Public Health, University of Pretoria, Pretoria, South Africa

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Vanessa M. Hayes Ancestry & Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, The University of Sydney, Camperdown, NSW, Australia
School of Health Systems and Public Health, University of Pretoria, Pretoria, South Africa

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Background: Germline testing for prostate cancer is on the increase, with clinical implications for risk assessment, treatment, and management. Regardless of family history, NCCN recommends germline testing for patients with metastatic, regional, very-high-risk localized, and high-risk localized prostate cancer. Although African ancestry is a significant risk factor for aggressive prostate cancer, due to a lack of available data no testing criteria have been established for ethnic minorities. Patients and Methods: Through deep sequencing, we interrogated the 20 most common germline testing panel genes in 113 Black South African males presenting with largely advanced prostate cancer. Bioinformatic tools were then used to identify the pathogenicity of the variants. Results: After we identified 39 predicted deleterious variants (16 genes), further computational annotation classified 17 variants as potentially oncogenic (12 genes; 17.7% of patients). Rare pathogenic variants included CHEK2 Arg95Ter, BRCA2 Trp31Arg, ATM Arg3047Ter (2 patients), and TP53 Arg282Trp. Notable oncogenic variants of unknown pathogenicity included novel BRCA2 Leu3038Ile in a patient with early-onset disease, whereas patients with FANCA Arg504Cys and RAD51C Arg260Gln reported a family history of prostate cancer. Overall, rare pathogenic and early-onset or familial-associated oncogenic variants were identified in 6.9% (5/72) and 9.2% (8/87) of patients presenting with a Gleason score ≥8 or ≥4 + 3 prostate cancer, respectively. Conclusions: In this first-of-its-kind study of southern African males, we provide support of African inclusion for advanced, early-onset, and familial prostate cancer genetic testing, indicating clinical value for 30% of current gene panels. Recognizing current panel limitations highlights an urgent need to establish testing guidelines for men of African ancestry. We provide a rationale for considering lowering the pathologic diagnostic inclusion criteria and call for further genome-wide interrogation to ensure the best possible African-relevant prostate cancer gene panel.

Submitted August 7, 2022; final revision received October 25, 2022; accepted for publication November 7, 2022

Author contributions: Study concept and design: Hayes. Data curation: Jiang, Mutambirwa, Soh, Jaratlerdsiri, Bornman, Hayes. Funding acquisition: Hayes. Investigation: Gheybi, Soh, Kote-Jarai, Jaratlerdsiri, Eeles, Bornman, Hayes. Statistical analysis: Gheybi. Supervision: Hayes. Visualization: Gheybi, Hayes. Writing—original draft: Gheybi, Hayes. Writing—review and editing: All authors.

Disclosures: Dr. Hayes has disclosed receiving grant/research support from the Petre Foundation and the University of Sydney Foundation, Australia. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: Research reported in this publication was supported by the National Health and Medical Research Council of Australia (APP1165762 and APP2010551; V.M. Hayes), and was partially supported by the U.S. Congressionally Directed Medical Research Program Prostate Cancer Research Program Ideas, TARGET Africa (PC200390l; V.M. Hayes, W. Jaratlerdsiri, S.B.A. Mutambirwa, R.A. Eeles, R. Bornman) and Health Equity Research and Outcomes Improvement Consortium, HEROIC Prostate Cancer Precision Health Africa1K (PC210168; V.M. Hayes, R. Bornman).

Correspondence: Vanessa M. Hayes, PhD, Ancestry & Health Genomics Laboratory, Charles Perkins Centre, The University of Sydney, John Hopkins Drive, Camperdown, NSW 2006, Australia. Email: vanessa.hayes@sydney.edu.au

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