(UroToday.com) The estimated hereditary component of urinary bladder cancer (UBC) is estimated to be up to 30%. Still, familial clustering is limited and high penetrant germline gene variants are predominantly found in cancer syndromes that present with a broader cancer spectrum.
As an alternative approach to studying the underlying genetics of UBC, they performed whole genome sequencing on individuals with an extremely early age of UBC onset (range 12-31 years; n=126). For 54 of the individuals, they were able to include parents for sequencing which allowed us to investigate inheritance patterns and focus on de novo mutations. Rare variants (population frequency 15) to enrich for damaging variants and variants were classified using PathoMAN.
They identified recurrent germline missense variants in known cancer predisposition genes associated with bladder cancer (RB1, TSC1, TSC2, BAP1, and AGL), and in bladder cancer driver genes (KMT2C, ZFHX3, ERCC1, and EP300) that were predicted to be pathogenic by multiple prediction tools. In addition, (likely) pathogenic mutations were identified in multiple genes not yet associated with bladder cancer predisposition. An example is a stop gain in the centrosomal protein gene CEP152 in two patients. One of the two patients had two uncles with bladder cancer, of which one could be tested and confirmed to carry this variant as well. Furthermore, in a third patient, they identified a de novo mutation in CEP192. Subsequent pathway analysis revealed the presence of damaging variants in centrosome maturation genes in 13.5% of the patients, suggesting that this pathway may play a role in early age at onset of bladder cancer.
In conclusion, a trio-design including extremely early age at onset patients may yield new information on susceptibility genes and pathogenic pathways for bladder cancer.
Presented by: Sita Vermeulen, PhD, Radboud University Medical Center, Nijmegen, The Netherlands
Written by: Stephen B. Williams, MD, MBA, MS @SWilliams_MD on Twitter during the International Bladder Cancer Network Annual Meeting, September 28-October 1, 2022, Barcelona, Spain