UNLABELLED: Early recognition of hereditary urological cancers may influence diagnostic and therapeutic decision-making, and potentially alter the fate of patients and family members. Here, we introduce readers to the current knowledge on germline genetic testing and clinical practice in prostate, bladder, renal, and testicular carcinoma. Considering all urological cancer patients, routine inquiries about familial cancer history should become a standard practice in clinical settings. If suspicion arises, patients can opt for two avenues: referral to genetic counseling or undergoing genetic tests after consultation with the treating urologist. PATIENT SUMMARY: Tumors of the urogenital tract (prostate, kidney, bladder, and testes) can sometimes be related to genetic mutations that are present in all the cells of the body. Such mutations can be inherited and run in families. Therefore, it is relevant to obtain information on the incidence of all cancers in the family history. The information obtained may initiate genetic testing, leading to the identification of mutations that are related to cancer in the current or next generation. In addition, these mutations may offer alternative treatment options for patients.

Biomedical Center Faculty of Medicine Charles University Pilsen Czech Republic

Department of Urology Comprehensive Cancer Center Innsbruck Medical University of Innsbruck Innsbruck Austria

Department of Urology Erasmus MC Cancer Institute University Medical Centre Rotterdam The Netherlands

Department of Urology Radboud University Medical Centre Nijmegen The Netherlands

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Division of Experimental Urology Department of Urology Medical University of Innsbruck Innsbruck Austria

Research Program in Systems Oncology and ICAN Digital Precision Cancer Medicine Flagship Department of Urology Helsinki University Hospital Helsinki Finland

Survivorship Program Dana Farber Cancer Institute Harvard Medical School Boston MA USA

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Gupta S., Provenzale D., Llor X., et al. NCCN guidelines insights: genetic/familial high-risk assessment: colorectal, version 2.2019. J Natl Compr Canc Netw. 2019;17:1032–1041. PubMed

Daly M.B., Pal T., Berry M.P., et al. Genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2021;19:77–102. PubMed

Giri V.N., Knudsen K.E., Kelly W.K., et al. Implementation of germline testing for prostate cancer: Philadelphia Prostate Cancer Consensus Conference 2019. J Clin Oncol. 2020;38:2798–2811. PubMed PMC

Aslanian H.R., Lee J.H., Canto M.I. AGA clinical practice update on pancreas cancer screening in high-risk individuals: expert review. Gastroenterology. 2020;159:358–362. PubMed

Pilarski R. How have multigene panels changed the clinical practice of genetic counseling and testing. J Natl Compr Canc Netw. 2021;19:103–108. PubMed

Mottet N., van den Bergh R.C.N., Briers E., et al. EAU-EANM-ESTRO-ESUR-SIOG guidelines on prostate cancer—2020 update. Part 1: screening, diagnosis, and local treatment with curative intent. Eur Urol. 2021;79:243–262. PubMed

Brandt A., Bermejo J.L., Sundquist J., Hemminki K. Age of onset in familial breast cancer as background data for medical surveillance. Br J Cancer. 2010;102:42–47. PubMed PMC

Roudgari H., Hemminki K., Brandt A., Sundquist J., Fallah M. Prostate cancer risk assessment model: a scoring model based on the Swedish Family-Cancer Database. J Med Genet. 2012;49:345–352. PubMed

Grill S., Fallah M., Leach R.J., et al. Incorporation of detailed family history from the Swedish Family Cancer Database into the PCPT risk calculator. J Urol. 2015;193:460–465. PubMed PMC

Frank C., Sundquist J., Yu H., Hemminki A., Hemminki K. Concordant and discordant familial cancer: familial risks, proportions and population impact. Int J Cancer. 2017;140:1510–1516. PubMed

Weires M., Bermejo J.L., Sundquist J., Hemminki K. Clustering of concordant and discordant cancer types in Swedish couples is rare. Eur J Cancer. 2011;47:98–106. PubMed

Frank C., Fallah M., Sundquist J., Hemminki A., Hemminki K. Population landscape of familial cancer. Sci Rep. 2015;5:12891. PubMed PMC

Hemminki K., Li X. Familial risks of cancer as a guide to gene identification and mode of inheritance. Int J Cancer. 2004;110:291–294. PubMed

Kiemeney L.A., Broeders M.J., Pelger M., et al. Screening for prostate cancer in Dutch hereditary prostate cancer families. Int J Cancer. 2008;122:871–876. PubMed

Hemminki K., Ji J., Brandt A., Mousavi S.M., Sundquist J. The Swedish Family-Cancer Database 2009: prospects for histology-specific and immigrant studies. Int J Cancer. 2010;126:2259–2267. PubMed

Hemminki K., Sundquist K., Sundquist J., Försti A., Hemminki A., Li X. Familial risks and proportions describing population landscape of familial cancer. Cancers (Basel) 2021;13:4385. PubMed PMC

Rahman N. Realizing the promise of cancer predisposition genes. Nature. 2014;505:302–308. PubMed PMC

Dorling L., Carvalho S., Allen J., González-Neira A., Luccarini C., Wahlström C., et al. Breast cancer risk genes—association analysis in more than 113,000 women. N Engl J Med. 2021;384:428–439. PubMed PMC

Hemminki K., Li X., Försti A., Eng C. Are population level familial risks and germline genetics meeting each other? Hered Cancer Clin Pract. 2023;21:3. PubMed PMC

Sud A., Horton R.H., Hingorani A.D., et al. Realistic expectations are key to realising the benefits of polygenic scores. BMJ. 2023;380 PubMed PMC

Pritchard C.C., Mateo J., Walsh M.F., et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375:443–453. PubMed PMC

Castro E., Romero-Laorden N., Del Pozo A., et al. PROREPAIR-B: A prospective cohort study of the impact of germline DNA repair mutations on the outcomes of patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2019;37:490–503. PubMed

Boyle J.L., Hahn A.W., Kapron A.L., et al. Pathogenic germline DNA repair gene and HOXB13 mutations in men with metastatic prostate cancer. JCO Precis Oncol. 2020;4 PO.19.00284. PubMed PMC

Robinson D., Van Allen E.M., Wu Y.M., et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;162:454. PubMed

Page E.C., Bancroft E.K., Brook M.N., et al. Interim results from the IMPACT study: evidence for prostate-specific antigen screening in BRCA2 mutation carriers. Eur Urol. 2019;76:831–842. PubMed PMC

Carter H.B., Helfand B., Mamawala M., et al. Germline mutations in ATM and BRCA1/2 are associated with grade reclassification in men on active surveillance for prostate cancer. Eur Urol. 2019;75:743–749. PubMed PMC

Castro E., Goh C., Leongamornlert D., et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68:186–193. PubMed

Brady L., Newcomb L.F., Zhu K., et al. Germline mutations in penetrant cancer predisposition genes are rare in men with prostate cancer selecting active surveillance. Cancer Med. 2022;11:4332–4340. PubMed PMC

Mehra N., Kloots I., Vlaming M., et al. Genetic aspects and molecular testing in prostate cancer: a report from a Dutch multidisciplinary consensus meeting. Eur Urol Open Sci. 2023;49:23–31. PubMed PMC

Lincoln S.E., Nussbaum R.L., Kurian A.W., et al. Yield and utility of germline testing following tumor sequencing in patients with cancer. JAMA Netw Open. 2020;3 PubMed PMC

de Bono J., Mateo J., Fizazi K., et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382:2091–2102. PubMed

Ahadova A., Gallon R., Gebert J., et al. Three molecular pathways model colorectal carcinogenesis in Lynch syndrome. Int J Cancer. 2018;143:139–150. PubMed

Cerrato C., Pandolfo S.D., Autorino R., et al. Gender-specific counselling of patients with upper tract urothelial carcinoma and Lynch syndrome. World J Urol. 2023;41:1741–1749. PubMed

Smyrk T.C., Watson P., Kaul K., Lynch H.T. Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma. Cancer. 2001;91:2417–2422. PubMed

Shia J. Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part I. the utility of immunohistochemistry. J Mol Diagn. 2008;10:293–300. PubMed PMC

Dominguez-Valentin M., Sampson J.R., Seppala T.T., et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med. 2020;22:15–25. PubMed PMC

Pradere B., Lotan Y., Roupret M. Lynch syndrome in upper tract urothelial carcinoma: significance, screening, and surveillance. Curr Opin Urol. 2017;27:48–55. PubMed

Audenet F., Colin P., Yates D.R., et al. A proportion of hereditary upper urinary tract urothelial carcinomas are misclassified as sporadic according to a multi-institutional database analysis: proposal of patient-specific risk identification tool. BJU Int. 2012;110(11 Pt B):E583–E589. PubMed

Gayhart M.G., Johnson N., Paul A., et al. Universal mismatch repair protein screening in upper tract urothelial carcinoma. Am J Clin Pathol. 2020;154:792–801. PubMed

Schneider B., Glass A., Jagdmann S., et al. Loss of mismatch-repair protein expression and microsatellite instability in upper tract urothelial carcinoma and clinicopathologic implications. Clin Genitourin Cancer. 2020;18:e563–e572. PubMed

Ju J.Y., Mills A.M., Mahadevan M.S., et al. Universal Lynch syndrome screening should be performed in all upper tract urothelial carcinomas. Am J Surg Pathol. 2018;42:1549–1555. PubMed

Roupret M., Seisen T., Birtle A.J., et al. European Association of Urology guidelines on upper urinary tract urothelial carcinoma: 2023 update. Eur Urol. 2023;84:49–64. PubMed

American Association for Cancer Research. PD-1 inhibitor bests chemo for colorectal cancer. Cancer Discov 2020;10:OF2. PubMed

Koutros S., Decker K.L., Baris D., et al. Bladder cancer risk associated with family history of cancer. Int J Cancer. 2021;148:2915–2923. PubMed PMC

Pemov A., Wegman-Ostrosky T., et al. Identification of genetic risk factors for familial urinary bladder cancer: an exome sequencing study. JCO Precis. Oncol. 2021;5 PO .21.00115. PubMed PMC

Carlo M.I., Hakimi A.A., Stewart G.D., et al. Familial kidney cancer: implications of new syndromes and molecular insights. Eur Urol. 2019;76:754–764. PubMed PMC

Shuch B., Vourganti S., Ricketts C.J., et al. Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. J Clin Oncol. 2014;32:431–437. PubMed PMC

Chahoud J., McGettigan M., Parikh N., et al. Evaluation, diagnosis and surveillance of renal masses in the setting of VHL disease. World J Urol. 2021;39:2409–2415. PubMed PMC

Truong H., Sheikh R., Kotecha R., et al. Germline variants identified in patients with early-onset renal cell carcinoma referred for germline genetic testing. Eur Urol Oncol. 2021;4:993–1000. PubMed PMC

Park J.S., Kim J., Elghiaty A., Ham W.S. Recent global trends in testicular cancer incidence and mortality. Medicine (Baltimore) 2018;97 PubMed PMC

Akre O., Pettersson A., Richiardi L. Risk of contralateral testicular cancer among men with unilaterally undescended testis: a meta analysis. Int J Cancer. 2009;124:687–689. PubMed

Ferguson L., Agoulnik A.I. Testicular cancer and cryptorchidism. Front Endocrinol (Lausanne) 2013;4:32. PubMed PMC

Zhang L., Hemminki O., Chen T., et al. Familial clustering, second primary cancers and causes of death in penile, vulvar and vaginal cancers. Sci Rep. 2019;9:11804. PubMed PMC

Litchfield K., Thomsen H., Mitchell J.S., et al. Quantifying the heritability of testicular germ cell tumour using both population-based and genomic approaches. Sci Rep. 2015;5:13889. PubMed PMC

AlDubayan S.H., Pyle L.C., Gamulin M., et al. Association of inherited pathogenic variants in checkpoint kinase 2 (CHEK2) with susceptibility to testicular germ cell tumors. JAMA Oncol. 2019;5:514–522. PubMed PMC

Pluta J., Pyle L.C., Nead K.T., et al. Identification of 22 susceptibility loci associated with testicular germ cell tumors. Nat Commun. 2021;12:4487. PubMed PMC

Hussain S.K., Sundquist J., Hemminki K. Familial clustering of cancer at human papillomavirus-associated sites according to the Swedish Family-Cancer Database. Int J Cancer. 2008;122:1873–1878. PubMed

Gudmundsson J., Sulem P., Gudbjartsson D.F., et al. A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer. Nat Genet. 2012;44:1326–1329. PubMed PMC

Wei J.T., Barocas D., Carlsson S., et al. Early detection of prostate cancer: AUA/SUO guideline part I: prostate cancer screening. J Urol. 2023;210:46–53. PubMed PMC