Abstract

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.

Source of Funding NCI K08CA282969-01A1 (FLC), BCAN Career Development Award (FLC), NCI 3P30CA006516-59W2 Early-Stage Surgeon-Scientist Program award (FLC).

Disclosures or conflicts none

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

Source of Funding: NCI K08CA282969-01A1, BCAN Career Development Award, NCI 3P30CA006516-59W2 Early-Stage Surgeon-Scientist Program award.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

IRB of Mass General Brigham gave ethical approval for this work (IRB 2021P002957).

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Data Availability

Data are archived in an institutional database, these are not publicly available. Aggregate data are provided in the manuscript and statistical analysis and code can be discussed upon request.

AbbreviationsFDAFood and Drug AdministrationMGB-YCCMass General Brigham Young Cystectomy CohortMSK-IMPACTMemorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer TargetsNCINational Cancer InstituteNSQIPNational Surgical Quality Improvement ProgramRCRadical Cystectomy