The germline mutational landscape of genitourinary cancers and its indication for prognosis and risk

BMC Urol. 2022 Nov 30;22(1):196. doi: 10.1186/s12894-022-01141-1.


Background: Germline mutations represent a high risk of hereditary cancers in population. The landscape and characteristics of germline mutations in genitourinary cancer are largely unknown, and their correlation with patient prognosis has not been defined.

Methods: Variant data and relevant clinical data of 10,389 cancer patients in The Cancer Genome Atlas (TCGA) database was downloaded. The subset of data of 206 genitourinary cancer patients containing bladder urothelial carcinoma (BLCA), kidney chromophobe carcinoma (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP) and prostate adenocarcinoma (PRAD) cancer with germline mutation information was filtered for further analysis. Variants were classified into pathogenic, likely pathogenic and non-pathogenic categories based on American College of Medical Genetics and Genomics (ACMG) guidelines. Genome Aggregation Database (gnomAD) database was used to assist risk analysis.

Results: There were 48, 7, 44, 45 and 62 patients with germline mutations identified in BLCA, KICH, KIRC, KIRP and PRAD, respectively. Pathogenic germline mutations from 26 genes and likely pathogenic mutations from 33 genes were revealed. GJB2, MET, MUTYH and VHL mutations ranked top in kidney cancers, and ATM and CHEK2 mutations ranked top for bladder cancer, while ATM and BRCA1 mutations ranked top for prostate cancer. Frameshift, stop gained and missense mutations were the predominant mutation types. BLCA exhibited the highest ratio of stop gained mutations (22/48 = 45.8%). No difference in patient age was found among pathogenic, likely pathogenic and non-pathogenic groups for all cancer types. The number of male patients far overweight female patients whether PRAD was included (P = 0) or excluded (P < 0.001). Patients with pathogenic or likely pathogenic germline mutations exhibited significantly worse overall survival rate than the non-pathogenic group for all genitourinary cancers. More important, analyses assisted by gnomAD database revealed that pathogenic or likely pathogenic germline mutations significantly increased the risk for genitourinary cancer in population, with the odds ratio at 14.88 (95%CI 11.80-18.77) and 33.18 (95%CI 24.90-44.20), respectively.

Conclusions: The germline mutational status for genitourinary cancers has been comprehensively characterized. Pathogenic and likely pathogenic germline mutations increased the risk and indicated poor prognosis of genitourinary cancers.

Keywords: Bladder; Genitourinary cancer; Germline; Hereditary; Kidney; Mutation; Prognosis; Prostate.

MeSH terms

  • Carcinoma, Renal Cell* / genetics
  • Carcinoma, Transitional Cell*
  • Germ Cells
  • Germ-Line Mutation / genetics
  • Humans
  • Kidney Neoplasms* / genetics
  • Male
  • Prognosis
  • Prostatic Neoplasms* / genetics
  • Urinary Bladder Neoplasms* / genetics