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Purpose: This study investigates a real-world multicenter cohort of patients with urinary tract cancer (UTC), with primary disease sites including the bladder, urethra, and upper tract, who enrolled for research molecular testing of their germline and tumor. The purpose of this study was to evaluate factors that could affect the likelihood of identifying a clinically actionable germline pathogenic variant (PV)., Methods: Patients with UTC were identified from 10 cancer institutes of the Oncology Research Information Exchange Network consortium. The data set comprised abstracted clinical data with germline and tumor genomic data, and comparative analyses were conducted., Results: Clinically actionable germline PVs in cancer predisposition genes were identified in 16 (4.5%) of 354 patients. A higher proportion of patients with the urethra and the upper tract as the primary sites of disease had PVs with a prevalence of 11% (5/45), compared with only 3.6% (11/308) in those with the bladder as the primary site of disease ( P = .04). There were no significant differences in markers of genomic instability (such as tumor mutational burden, microsatellite instability [MSI], and loss of heterozygosity, copy number, and chromosomal instability) between those with PVs and those without ( P > .05). Of the PVs identified, 10 (62%) were in homologous recombination repair (HRR) genes, three (19%) in mismatch repair (MMR) genes, and three (19%) in genes associated with other pathways., Conclusion: Tissue-based assessment of genomic instability, such as MSI, does not reliably indicate germline PV. A comprehensive clinical germline testing approach that includes HRR genes in addition to MMR genes is likely to yield PVs in approximately one of 10 patients with nonbladder primary disease sites such as the upper tract and the urethra.

Purpose: Establishing accurate age-related penetrance figures for the broad range of cancer types that occur in individuals harboring a pathogenic germline variant in the TP53 gene is essential to determine the most effective clinical management strategies. These figures also permit optimal use of cosegregation data for classification of TP53 variants of unknown significance. Penetrance estimation can easily be affected by bias from ascertainment criteria, an issue not commonly addressed by previous studies., Materials and Methods: We performed a maximum likelihood penetrance estimation using full pedigree data from a multicenter study of 146 TP53 -positive families, incorporating adjustment for the effect of ascertainment and population-specific background cancer risks. The analysis included pedigrees from Australia, Spain, and United States, with phenotypic information for 4,028 individuals., Results: Core Li-Fraumeni syndrome (LFS) cancers (breast cancer, adrenocortical carcinoma, brain cancer, osteosarcoma, and soft tissue sarcoma) had the highest hazard ratios of all cancers analyzed in this study. The analysis also detected a significantly increased lifetime risk for a range of cancers not previously formally associated with TP53 pathogenic variant status, including colorectal, gastric, lung, pancreatic, and ovarian cancers. The cumulative risk of any cancer type by age 50 years was 92.4% (95% CI, 82.2 to 98.3) for females and 59.7% (95% CI, 39.9 to 81.3) for males. Females had a 63.3% (95% CI, 35.6 to 90.1) cumulative risk of developing breast cancer by age 50 years., Conclusion: The results from maximum likelihood analysis confirm the known high lifetime risk for the core LFS-associated cancer types providing new risk estimates and indicate significantly increased lifetime risks for several additional cancer types. Accurate cancer risk estimates will help refine clinical recommendations for TP53 pathogenic variant carriers and improve TP53 variant classification.

Purpose: Germline mutations in DNA repair (DR) genes and susceptibility genes CDKN2A and HOXB13 have previously been associated with prostate cancer (PC) incidence and/or progression. However, the role and prevalence of this class of mutations in metastatic PC (mPC) are not fully understood., Patients and Methods: To evaluate the frequency of pathogenic/likely pathogenic germline variants (PVs/LPVs) in men with mPC, this study sequenced 38 DR genes, CDKN2A , and HOXB13 in a predominantly white cohort of 317 patients with mPC. A PC registry at the University of Utah was used for patient sample acquisition and retrospective clinical data collection. Deep target sequencing allowed for germline and copy number variant analyses. Validated PVs/LPVs were integrated with clinical and demographic data for statistical correlation analyses., Results: All pathogenic variants were found in men self-reported as white, with a carrier frequency of 8.5% (DR genes, 7.3%; CDKN2A / HOXB13 , 1.2%). Consistent with previous reports, mutations were most frequently identified in the breast cancer susceptibility gene BRCA2 . It was also found that 50% of identified PVs/LPVs were categorized as founder mutations with European origins. Correlation analyses did not support a trend toward more advanced or earlier-onset disease in comparisons between carriers and noncarriers of deleterious DR or HOXB13 G84E mutations., Conclusion: These findings demonstrate a lower prevalence of germline PVs/LPVs in an unselected, predominantly white mPC cohort than previously reported, which may have implications for the design of clinical trials testing targeted therapies. Larger studies in broad and diverse populations are needed to more accurately define the prevalence of germline mutations in men with mPC., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Wendy KohlmannEmployment: BioFire Diagnostics (I)Benjamin L. MaughanConsulting or Advisory Role: Janssen Oncology, Exelixis, Tempus, Peleton, Bristol-Myers Squibb, Astellas Medivation, Bayer Research Funding: Clovis Oncology (Inst), Bristol-Myers Squibb (Inst), Bavarian Nordic (Inst) Travel, Accommodations, Expenses: ExelixisBing-Jian FengResearch Funding: Pfizer (Inst), Regeneron (Inst) Patents, Royalties, Other Intellectual Property: Inventor of PERCH software, which has been nonexclusively licensed to Ambry Genetics for clinical genetic testing service and research.Neeraj AgarwalConsulting or Advisory Role: Pfizer, Astellas Medivation, Bristol-Myers Squibb, AstraZeneca, Nektar, Eli Lilly, Bayer, Foundation One, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Janssen Oncology, Merck, Novartis Research Funding: Bayer (Inst), Bristol-Myers Squibb (Inst), GlaxoSmithKline (Inst), Takeda Pharmaceutical (Inst), Novartis (Inst), Pfizer (Inst), BN ImmunoTherapeutics (Inst), Exelixis (Inst), TRACON Pharma (Inst), Rexahn Pharmaceuticals (Inst), Amgen (Inst), AstraZeneca (Inst), Active Biotech (Inst), Bavarian Nordic (Inst), Calithera Biosciences (Inst), Celldex (Inst), Eisai (Inst), Genentech (Inst), Immunomedics (Inst), Janssen (Inst), Merck (Inst), Newlink Genetics (Inst), Prometheus (Inst), Sanofi (Inst)Kathleen A. CooneyPatents, Royalties, Other Intellectual Property: Patent awarded for discovery of HOXB13 as prostate cancer susceptibility gene (Inst). Travel, Accommodations, Expenses: Boston Scientific (I) No other potential conflicts of interest were reported., (© 2020 by American Society of Clinical Oncology.)