{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T10:01:21Z","timestamp":1785232881577,"version":"3.55.0"},"reference-count":39,"publisher":"Harborside Press, LLC","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> 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. <jats:bold>Patients and Methods:<\/jats:bold> 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. <jats:bold>Results:<\/jats:bold> 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 <jats:italic>CHEK2<\/jats:italic> Arg95Ter, <jats:italic>BRCA2<\/jats:italic> Trp31Arg, <jats:italic>ATM<\/jats:italic> Arg3047Ter (2 patients), and <jats:italic>TP53<\/jats:italic> Arg282Trp. Notable oncogenic variants of unknown pathogenicity included novel <jats:italic>BRCA2<\/jats:italic> Leu3038Ile in a patient with early-onset disease, whereas patients with <jats:italic>FANCA<\/jats:italic> Arg504Cys and <jats:italic>RAD51C<\/jats:italic> 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 \u22658 or \u22654\u2009+\u20093 prostate cancer, respectively. <jats:bold>Conclusions:<\/jats:bold> 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.<\/jats:p>","DOI":"10.6004\/jnccn.2022.7097","type":"journal-article","created":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T20:34:21Z","timestamp":1678480461000},"page":"289-296.e3","source":"Crossref","is-referenced-by-count":26,"title":["Evaluating Germline Testing Panels in Southern African Males With Advanced Prostate Cancer"],"prefix":"10.6004","volume":"21","author":[{"given":"Kazzem","family":"Gheybi","sequence":"first","affiliation":[{"name":"Ancestry & Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, The University of Sydney, Camperdown, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jue","family":"Jiang","sequence":"additional","affiliation":[{"name":"Ancestry & Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, The University of Sydney, Camperdown, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingai B.A.","family":"Mutambirwa","sequence":"additional","affiliation":[{"name":"Department of Urology, Sefako Mekgatho Health Sciences University, Dr. George Mukhari Academic Hospital, Medunsa, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela X.Y.","family":"Soh","sequence":"additional","affiliation":[{"name":"Ancestry & Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, The University of Sydney, Camperdown, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsofia","family":"Kote-Jarai","sequence":"additional","affiliation":[{"name":"Oncogenetics Team, The Institute of Cancer Research, Surrey, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weerachai","family":"Jaratlerdsiri","sequence":"additional","affiliation":[{"name":"Ancestry & Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, The University of Sydney, Camperdown, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalind A.","family":"Eeles","sequence":"additional","affiliation":[{"name":"Oncogenetics Team, The Institute of Cancer Research, Surrey, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.S. Riana","family":"Bornman","sequence":"additional","affiliation":[{"name":"School of Health Systems and Public Health, University of Pretoria, Pretoria, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa M.","family":"Hayes","sequence":"additional","affiliation":[{"name":"Ancestry & Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, The University of Sydney, Camperdown, NSW, Australia"},{"name":"School of Health Systems and Public Health, University of Pretoria, Pretoria, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4047","reference":[{"key":"B1","series-title":"Urology","first-page":"9","article-title":"Health care disparities in urologic oncology: a systematic review","volume":"136","author":"Das H","year":"2020","unstructured":"Das H, Rodriguez R. Health care disparities in urologic oncology: a systematic review. Urology 2020;136:9\u201318."},{"key":"B2","series-title":"Eur Urol","first-page":"134","article-title":"Combined effect of a polygenic risk score and rare genetic variants on prostate cancer risk","volume":"80","author":"Darst BF","year":"2021","unstructured":"Darst BF, Sheng X, Eeles RA,  Combined effect of a polygenic risk score and rare genetic variants on prostate cancer risk. Eur Urol 2021;80:134\u2013138."},{"key":"B3","series-title":"Br J Cancer","first-page":"1663","article-title":"Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease","volume":"110","author":"Leongamornlert D","year":"2014","unstructured":"Leongamornlert D, Saunders E, Dadaev T,  Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease. Br J Cancer 2014;110:1663\u20131672."},{"key":"B4","series-title":"J Natl Cancer Inst","first-page":"616","article-title":"Germline sequencing DNA repair genes in 5545 men with aggressive and nonaggressive prostate cancer","volume":"113","author":"Darst BF","year":"2021","unstructured":"Darst BF, Dadaev T, Saunders E,  Germline sequencing DNA repair genes in 5545 men with aggressive and nonaggressive prostate cancer. J Natl Cancer Inst 2021;113:616\u2013625."},{"key":"B5","series-title":"Am J Men Health","first-page":"1807","article-title":"Global trends and prostate cancer: a review of incidence, detection, and mortality as influenced by race, ethnicity, and geographic location","volume":"12","author":"Taitt HE","year":"2018","unstructured":"Taitt HE. Global trends and prostate cancer: a review of incidence, detection, and mortality as influenced by race, ethnicity, and geographic location. Am J Men Health 2018;12:1807\u20131823."},{"key":"B6","series-title":"CA Cancer J Clin","first-page":"209","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung H","year":"2021","unstructured":"Sung H, Ferlay J, Siegel RL,  Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209\u2013249."},{"key":"B7","series-title":"J Clin Oncol","first-page":"2798","article-title":"Implementation of germline testing for prostate cancer: Philadelphia Prostate Cancer Consensus Conference 2019","volume":"38","author":"Giri VN","year":"2020","unstructured":"Giri VN, Knudsen KE, Kelly WK,  Implementation of germline testing for prostate cancer: Philadelphia Prostate Cancer Consensus Conference 2019. J Clin Oncol 2020;38:2798\u20132811."},{"key":"B8","series-title":"JCO Precis Oncol","first-page":"32","article-title":"Pathogenic variants in cancer predisposition genes and prostate cancer risk in men of African ancestry","volume":"4","author":"Matejcic M","year":"2020","unstructured":"Matejcic M, Patel Y, Lilyquist J,  Pathogenic variants in cancer predisposition genes and prostate cancer risk in men of African ancestry. JCO Precis Oncol 2020;4:32\u201343."},{"key":"B9","series-title":"PLoS Genet","first-page":"e1003309","article-title":"Complex patterns of genomic admixture within southern Africa","volume":"9","author":"Petersen DC","year":"2013","unstructured":"Petersen DC, Libiger O, Tindall EA,  Complex patterns of genomic admixture within southern Africa. PLoS Genet 2013;9:e1003309."},{"key":"B10","series-title":"BMC Urol","first-page":"74","article-title":"Addressing the contribution of previously described genetic and epidemiological risk factors associated with increased prostate cancer risk and aggressive disease within men from South Africa","volume":"13","author":"Tindall EA","year":"2013","unstructured":"Tindall EA, Bornman MSR, van Zyl S,  Addressing the contribution of previously described genetic and epidemiological risk factors associated with increased prostate cancer risk and aggressive disease within men from South Africa. BMC Urol 2013;13:74."},{"key":"B11","series-title":"Nature","first-page":"552","article-title":"African-specific molecular taxonomy of prostate cancer","volume":"609","author":"Jaratlerdsiri W","year":"2022","unstructured":"Jaratlerdsiri W, Jiang J, Gong T,  African-specific molecular taxonomy of prostate cancer. Nature 2022;609:552\u2013559."},{"key":"B12","series-title":"Curr Protoc Bioinformatics","first-page":"11.10.1","article-title":"From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline","volume":"43","author":"Van der Auwera GA","year":"2018","unstructured":"Van der Auwera GA, Carneiro MO, Hartl C,  From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr Protoc Bioinformatics 2018;43:11.10.1\u201333."},{"key":"B13","series-title":"Bioinformatics","first-page":"1220","article-title":"Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications","volume":"32","author":"Chen X","year":"2016","unstructured":"Chen X, Schulz-Trieglaff O, Shaw R,  Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics 2016;32:1220\u20131222."},{"key":"B14","article-title":"NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer","author":"Schaeffer EM","unstructured":"Schaeffer EM, Srinivas S, An Y,  NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 4.2022. Accessed September 1, 2022. To view the most recent version, visit https:\/\/www.nccn.org"},{"key":"B15","series-title":"JAMA Oncol","first-page":"523","article-title":"Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines","volume":"5","author":"Nicolosi P","year":"2019","unstructured":"Nicolosi P, Ledet E, Yang S,  Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines. JAMA Oncol 2019;5:523\u2013528."},{"key":"B16","series-title":"Genet Med","first-page":"405","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards S","year":"2015","unstructured":"Richards S, Aziz N, Bale S,  Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405\u2013424."},{"key":"B17","series-title":"Am J Hum Genet","first-page":"267","article-title":"InterVar: clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines","volume":"100","author":"Li Q","year":"2017","unstructured":"Li Q, Wang K. InterVar: clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines. Am J Hum Genet 2017;100:267\u2013280."},{"key":"B18","series-title":"Genome Med","first-page":"25","article-title":"Cancer Genome Interpreter annotates the biological and clinical relevance of tumor alterations","volume":"10","author":"Tamborero D","year":"2018","unstructured":"Tamborero D, Rubio-Perez C, Deu-Pons J,  Cancer Genome Interpreter annotates the biological and clinical relevance of tumor alterations. Genome Med 2018;10:25."},{"key":"B19","series-title":"Nat Biotechnol","first-page":"24","article-title":"Integrative genomics viewer","volume":"29","author":"Robinson JT","year":"2011","unstructured":"Robinson JT, Thorvaldsd\u00f3ttir H, Winckler W,  Integrative genomics viewer. Nat Biotechnol 2011;29:24\u201326."},{"key":"B20","series-title":"Genome Res","first-page":"1881","article-title":"TITAN: inference of copy number architectures in clonal cell populations from tumor whole-genome sequence data","volume":"24","author":"Ha G","year":"2014","unstructured":"Ha G, Roth A, Khattra J,  TITAN: inference of copy number architectures in clonal cell populations from tumor whole-genome sequence data. Genome Res 2014;24:1881\u20131893."},{"key":"B21","series-title":"Eur Urol","first-page":"458","article-title":"A rare germline HOXB13 variant contributes to risk of prostate cancer in men of African ancestry","volume":"81","author":"Darst BF","year":"2022","unstructured":"Darst BF, Hughley R, Pfennig A,  A rare germline HOXB13 variant contributes to risk of prostate cancer in men of African ancestry. Eur Urol 2022;81:458\u2013462."},{"key":"B22","series-title":"Cancer Epidemiol Biomarkers Prev","first-page":"1366","article-title":"The HOXB13 G84E mutation is associated with an increased risk for prostate cancer and other malignancies","volume":"24","author":"Beebe-Dimmer JL","year":"2015","unstructured":"Beebe-Dimmer JL, Hathcock M, Yee C,  The HOXB13 G84E mutation is associated with an increased risk for prostate cancer and other malignancies. Cancer Epidemiol Biomarkers Prev 2015;24:1366\u20131372."},{"key":"B23","series-title":"Human Molecular Genetics","article-title":"Clonal hematopoiesis and risk of prostate cancer in large samples of European ancestry men","author":"Wang A","unstructured":"Wang A, Xu Y, Yu Y,  Clonal hematopoiesis and risk of prostate cancer in large samples of European ancestry men. Human Molecular Genetics. Published online August 26, 2022. doi:10.1093\/hmg\/ddac214"},{"key":"B24","series-title":"World J Clin Oncol","first-page":"428","article-title":"MUTYH: not just polyposis","volume":"11","author":"Curia MC","year":"2020","unstructured":"Curia MC, Catalano T, Aceto GM. MUTYH: not just polyposis. World J Clin Oncol 2020;11:428\u2013449."},{"key":"B25","series-title":"J Pathol","first-page":"214","article-title":"Monoallelic deleterious MUTYH germline variants as a driver for tumorigenesis","volume":"256","author":"Barreiro RAS","year":"2022","unstructured":"Barreiro RAS, Sabbaga J, Rossi BM,  Monoallelic deleterious MUTYH germline variants as a driver for tumorigenesis. J Pathol 2022;256:214\u2013222."},{"key":"B26","series-title":"Cell Rep","first-page":"1623","article-title":"ATM kinase is required for telomere elongation in mouse and human cells","volume":"13","author":"Lee SS","year":"2015","unstructured":"Lee SS, Bohrson C, Pike AM,  ATM kinase is required for telomere elongation in mouse and human cells. Cell Rep 2015;13:1623\u20131632."},{"key":"B27","series-title":"Genes (Basel)","first-page":"1034","article-title":"Understanding BRCA2 function as a tumor suppressor based on domain-specific activities in DNA damage responses","volume":"12","author":"Andreassen PR","year":"2021","unstructured":"Andreassen PR, Seo J, Wiek C,  Understanding BRCA2 function as a tumor suppressor based on domain-specific activities in DNA damage responses. Genes (Basel) 2021;12:1034."},{"key":"B28","series-title":"Hered Cancer Clin Pract","first-page":"19","article-title":"Prevalence of the CHEK2 R95* germline mutation","volume":"14","author":"Knappskog S","year":"2016","unstructured":"Knappskog S, Leirvaag B, Gansmo LB,  Prevalence of the CHEK2 R95* germline mutation. Hered Cancer Clin Pract 2016;14:19."},{"key":"B29","series-title":"J Immunol","first-page":"1228","article-title":"FATC domain deletion compromises ATM protein stability, blocks lymphocyte development, and promotes lymphomagenesis","volume":"206","author":"Milanovic M","year":"2021","unstructured":"Milanovic M, Shao Z, Estes VM,  FATC domain deletion compromises ATM protein stability, blocks lymphocyte development, and promotes lymphomagenesis. J Immunol 2021;206:1228\u20131239."},{"key":"B30","series-title":"N Engl J Med","first-page":"443","article-title":"Inherited DNA-repair gene mutations in men with metastatic prostate cancer","volume":"375","author":"Pritchard CC","year":"2016","unstructured":"Pritchard CC, Mateo J, Walsh MF,  Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med 2016;375:443\u2013453."},{"key":"B31","series-title":"Nat Commun","first-page":"1361","article-title":"Germline mutation landscape of DNA damage repair genes in African Americans with prostate cancer highlights potentially targetable RAD genes","volume":"13","author":"Kohaar I","year":"2022","unstructured":"Kohaar I, Zhang X, Tan SH,  Germline mutation landscape of DNA damage repair genes in African Americans with prostate cancer highlights potentially targetable RAD genes. Nat Commun 2022;13:1361."},{"key":"B32","series-title":"Br J Cancer","first-page":"1067","article-title":"BRCA1 and BRCA2 pathogenic variants and prostate cancer risk: systematic review and meta-analysis","volume":"126","author":"Nyberg T","year":"2022","unstructured":"Nyberg T, Tischkowitz M, Antoniou AC. BRCA1 and BRCA2 pathogenic variants and prostate cancer risk: systematic review and meta-analysis. Br J Cancer 2022;126:1067\u20131081."},{"key":"B33","series-title":"J Clin Oncol","first-page":"3735","article-title":"BRCA1 versus BRCA2 and PARP inhibitor sensitivity in prostate cancer: more different than alike?","volume":"38","author":"Markowski MC","year":"2020","unstructured":"Markowski MC, Antonarakis ES. BRCA1 versus BRCA2 and PARP inhibitor sensitivity in prostate cancer: more different than alike? J Clin Oncol 2020;38:3735\u20133739."},{"key":"B34","series-title":"Prostate","first-page":"321","article-title":"Rare germline mutations in African American men diagnosed with early-onset prostate cancer","volume":"78","author":"Beebe-Dimmer JL","year":"2018","unstructured":"Beebe-Dimmer JL, Zuhlke KA, Johnson AM,  Rare germline mutations in African American men diagnosed with early-onset prostate cancer. Prostate 2018;78:321\u2013326."},{"key":"B35","series-title":"Prostate","first-page":"433","article-title":"Comparison of germline mutations in African American and Caucasian men with metastatic prostate cancer","volume":"81","author":"Ledet EM","year":"2021","unstructured":"Ledet EM, Burgess EF, Sokolova AO,  Comparison of germline mutations in African American and Caucasian men with metastatic prostate cancer. Prostate 2021;81:433\u2013439."},{"key":"B36","series-title":"JCO Precis Oncol","first-page":"e2200234","article-title":"Germline variant spectrum among African American men undergoing prostate cancer germline testing: need for equity in genetic testing","volume":"6","author":"Giri VN","year":"2022","unstructured":"Giri VN, Hartman R, Pritzlaff M,  Germline variant spectrum among African American men undergoing prostate cancer germline testing: need for equity in genetic testing. JCO Precis Oncol 2022;6:e2200234."},{"key":"B37","series-title":"Prostate Cancer Prostatic Dis","first-page":"406","article-title":"Increased frequency of germline BRCA2 mutations associates with prostate cancer metastasis in a racially diverse patient population","volume":"22","author":"Petrovics G","year":"2019","unstructured":"Petrovics G, Price DK, Lou H,  Increased frequency of germline BRCA2 mutations associates with prostate cancer metastasis in a racially diverse patient population. Prostate Cancer Prostatic Dis 2019;22:406\u2013410."},{"key":"B38","series-title":"Eur Urol Oncol","first-page":"224","article-title":"Rare germline pathogenic mutations of DNA repair genes are most strongly associated with grade group 5 prostate cancer","volume":"3","author":"Wu Y","year":"2020","unstructured":"Wu Y, Yu H, Li S,  Rare germline pathogenic mutations of DNA repair genes are most strongly associated with grade group 5 prostate cancer. Eur Urol Oncol 2020;3:224\u2013230."},{"key":"B39","series-title":"J Clin Oncol","first-page":"414","article-title":"Role of genetic testing for inherited prostate cancer risk: Philadelphia Prostate Cancer Consensus Conference 2017","volume":"36","author":"Giri VN","year":"2018","unstructured":"Giri VN, Knudsen KE, Kelly WK,  Role of genetic testing for inherited prostate cancer risk: Philadelphia Prostate Cancer Consensus Conference 2017. J Clin Oncol 2018;36:414\u2013424."}],"container-title":["Journal of the National Comprehensive Cancer Network"],"original-title":[],"link":[{"URL":"https:\/\/jnccn.org\/view\/journals\/jnccn\/21\/3\/article-p289.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/jnccn.org\/downloadpdf\/journals\/jnccn\/21\/3\/article-p289.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/jnccn.org\/downloadpdf\/journals\/jnccn\/21\/3\/article-p289.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T20:37:23Z","timestamp":1678480643000},"score":1,"resource":{"primary":{"URL":"https:\/\/jnccn.org\/view\/journals\/jnccn\/21\/3\/article-p289.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3]]},"references-count":39,"journal-issue":{"issue":"3"},"URL":"https:\/\/doi.org\/10.6004\/jnccn.2022.7097","relation":{},"ISSN":["1540-1405","1540-1413"],"issn-type":[{"value":"1540-1405","type":"print"},{"value":"1540-1413","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3]]}}}