Epidemiological Trends and Germline Variant Analysis of Young-Onset Bladder Cancer

The incidence of bladder cancer (BCa) is rising worldwide. Recent reports suggest a disproportionate increase among younger individuals, raising questions about epidemiologic and genetic contributors to early-onset disease. We aimed to characterize incidence and prevalence trends across younger and older populations and to evaluate germline genetic factors associated with young-onset bladder cancer (YOBC).

Using the TriNetX research network, we analyzed BCa incidence and prevalence trends from 2011 to 2023, stratified by age and sex. Germline variant data from the UK Biobank (UKBB) were analyzed to identify genetic associations in YOBC using a genome-wide regression approach.

TriNetX identified 299,272 patients with BCa. Among individuals aged ≥50 years, incidence increased steadily, with male predominance. In contrast, the <50 cohort showed a more rapid rise in incidence, with a higher proportion of female cases. By 2022, females accounted for 38.9% of incident cases in the <50 cohort compared with 18.9% in the ≥50 cohort, exceeding Surveillance, Epidemiology, and End Results (SEER) expectations. In the UKBB, 4571 BCa cases were identified, including 369 (8.1%) YOBC cases, in which 3 genome-wide significant, ultra-rare variants were detected.

BCa burden is increasing across age groups, with a disproportionate rise among younger women. Although rare germline variants in HERC2, CNTN4, CACNA2D3, CHRNB4, RBFOX3, SRGAP1, and SERPINB13 were identified, their rarity suggests they do not fully explain observed epidemiologic trends. These findings support further replication, functional studies, and investigation of sex-specific environmental factors, with implications for earlier evaluation of hematuria in young women.