SESAUA 2024: Determining the Genetic Causes of Bladder Cancer in a Family with Heritable Pattern of Bladder Cancer

( The 2024 Southeastern Section of the AUA (SESAUA) annual meeting featured a bladder cancer session and a presentation by Dr. Aditya Sathe discussing the genetic causes of bladder cancer in a family with heritable pattern of bladder cancer.

Bladder cancer is the 9th most common cancer worldwide with a yearly incidence of approximately 430,000 cases. The etiology of bladder cancer association with environmental factors is well characterized, but studies demonstrating inherited forms of bladder cancer are still limited. Although predominantly attributed to non-heritable causes, certain genetic conditions like Lynch syndrome, characterized by defects in DNA mismatch repair genes and microsatellite instability, have been implicated in bladder cancer, though with an increased risk of only ~5%. 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. This investigation sought to uncover potential heritable mutations responsible for this family’s strong susceptibility to bladder cancer.

A single family spanning three generations with a known diagnosis of bladder cancer across multiple members was selected for the investigation. 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 linked with hereditary cancer, inclusive of mismatch repair genes:
77 genes linked with hereditary cancer
Selected tumor samples were also analyzed for microsatellite instability through PCR of seven MSI loci.

Dr. Sathe and colleagues noted that 3 out of 4 affected siblings underwent germline testing and each was found to be a carrier (heterozygous) for FANCC pL554P mutation:table of family members undergoing genetic testing FANCC bladder cancer branch pathway
FANCC is part of a multi-protein complex which drives DNA repair of inter-strand crosslinks and is somatically mutated in 2% of muscle invasive bladder cancer. This mechanism is distinct from the mismatch repair pathway (MutS, MutL, MutH), which is aberrant in Lynch syndrome, an independent risk factor for bladder cancer:ICL damage and FANCC illustration
No other mutation was found to be present in the panel, and none of the tumor samples analyzed were found to have foci of microsatellite instability. 

Dr. Sathe concluded his presentation discussing the genetic causes of bladder cancer in a family with a heritable pattern of bladder cancer with the following conclusions:

  • This is the strongest familial pattern of bladder cancer described to date
  • FANCC pL554P heterozygosity may be contributing to this family’s bladder cancer risk, but Dr. Sathe and colleagues hypothesize that other novel germline mutations are driving 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 genes, including FANCC, will be screened for biological relevance and will be experimentally evaluated in bladder cancer cell lines with gene expression and signaling pathway analyses

Presented by: Aditya Sathe, MD, University of Alabama - Birmingham, Birmingham, AL

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 Southeastern Section of the American Urological Association (SESAUA) Annual Meeting, Austin, TX, Wed, Mar 20 – Sat, Mar 23, 2024.