Molecular Drivers of Chromophobe Renal Cell Carcinoma Revealed Through Genomic Analysis Using AACR Project GENIE

Chromophobe renal cell carcinoma (chRCC) is a distinct subtype of non-clear cell renal cell carcinoma (ncRCC), arising from intercalated cells of the distal nephron collecting ducts. No standard treatments are specifically approved for chRCC, which is further hindered by lack of a universally accepted grading system. This study sought to find molecular drivers that may aid in the diagnosis or development of treatments for chRCC. A retrospective analysis of chRCC was conducted using data from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) repository, accessed through cBioPortal (version 17.0-public) on 21 July 2025. The study examined recurrent somatic mutations and assessed co-occurrence with Benjamini-Hochberg False Discovery Rate (FDR) correction. Additional analyses evaluated mutation by sex and race, with significance set at <i>p</i> < 0.05. The cohort included 180 tumor samples from 170 chRCC patients. Most patients were adults (<i>n</i> = 167, 98.2%) and White (<i>n</i> = 115, 67.6%). Recurrent alterations occurred in genes part of the p53, PI3K/mTOR, Hippo, and NOTCH signaling pathway. Exploratory demographic analyses identified isolated single-patient mutations in select genes across sex and race; however, these rare events are not interpretable as population-level differences. This study provides a comprehensive genomic profile of chRCC across multiple demographic categories.