MP15-19 DETERMINING THE GENETIC CAUSES OF BLADDER CANCER IN A FAMILY WITH A HERITABLE PATTERN OF BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology I (MP15)1 May 2024MP15-19 DETERMINING THE GENETIC CAUSES OF BLADDER CANCER IN A FAMILY WITH A HERITABLE PATTERN OF BLADDER CANCER Aditya Sathe, David P. Murray, Charles Peyton, Anindya Dutta, Andre Leier, Cristina Magi-Galluzzi, and James Ferguson Aditya SatheAditya Sathe , David P. MurrayDavid P. Murray , Charles PeytonCharles Peyton , Anindya DuttaAnindya Dutta , Andre LeierAndre Leier , Cristina Magi-GalluzziCristina Magi-Galluzzi , and James FergusonJames Ferguson View All Author Informationhttps://doi.org/10.1097/01.JU.0001009500.87761.bf.19AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: This study examines a distinct familial incidence of bladder cancer manifesting in four out of five siblings and spanning three generations including their father, paternal aunt and paternal great uncle, challenging prevailing perceptions that bladder cancer is caused primarily by environmental carcinogens and sporadic somatic mutations. Certain genetic conditions like Lynch syndrome, characterized by defects in DNA mismatch repair and microsatellite instability, have been implicated in bladder cancer, though with only a∼5% increased risk. This investigation sought to uncover potential heritable mutations responsible for this family's susceptibility to bladder cancer. METHODS: The concerned family members underwent comprehensive genetic counseling, followed by germline testing using the CancerNext-Expanded® panel from Ambry Genetics. This panel encompasses 77 genes highly linked with hereditary cancer. Selected tumor samples were also analyzed for microsatellite instability (MSI) through PCR of seven MSI loci. RESULTS: 3 out of 4 affected siblings underwent germline testing and were found to be carriers (heterozygous) for the FANCC pL554P mutation. FANCC is part of a multi-protein complex which drives DNA damage repair, and is somatically mutated in 2% of muscle invasive bladder cancers. The unaffected sibling is also a carrier but an unaffected cousin was wild-type for FANCC. No other mutations were found in the panel, including those highly attributable to bladder cancer such as the Lynch-related genes. None of the tumor samples analyzed were found to have any foci of microsatellite instability. CONCLUSIONS: Carriers of an FANCC pL554P mutation may be at higher risk for development of bladder cancer. However, as FANCC carrier registries have not demonstrated increased cancer incidence compared with the general population, we hypothesize that this family harbors a novel germline mutation leading to their bladder cancer propensity. Future studies are underway to perform whole-genome sequencing of germline and tumor DNA to identify additional heritable mutations that may predict bladder cancer risk. Candidate mutations, including FANCC pL55P, will be screened for biological relevance and will be experimentally evaluated in bladder cancer cell lines with gene expression analyses. Source of Funding: N/A © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e237 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Aditya Sathe More articles by this author David P. Murray More articles by this author Charles Peyton More articles by this author Anindya Dutta More articles by this author Andre Leier More articles by this author Cristina Magi-Galluzzi More articles by this author James Ferguson More articles by this author Expand All Advertisement PDF downloadLoading ...