Profiling of early-onset bladder cancer identifies key genomic alterations and potential targets

Younger patients with bladder cancer typically have fewer environmental exposures or risk factors, suggesting molecular pathways implicated in early-onset disease differ from older patients. Dissecting the genomic profile of early-onset tumors may define targeted treatments for these young patients. We compared the frequency of somatic mutations in early-onset bladder cancer, defined as diagnosis before the age of 55 years old which encompasses about 1 in 10 diagnoses, in two cohorts: the Mass General Brigham Young Cystectomy Cohort (MGB-YCC, n=134 patients) and the Memorial Sloan-Kettering-IMPACT bladder cancer cohort (MSK-IMPACT, n=1271). Both MGB-YCC and MSK-IMPACT cohorts were predominantly male with younger patients less likely to smoke or have muscle-invasive disease. Genomic characterization in MGB-YCC demonstrated KMT2D mutations almost exclusively among the youngest patients (83% <45-years-old, p=0.008). MSK-IMPACT revealed a significant increase of FGFR3 mutations in younger patients (37% vs 23%, p<0.001). Altogether, our results find key somatic mutations likely drive early-onset bladder cancers, some of which may be targetable; this suggests potential benefit from genomic tumor profiling to guide personalized treatment.