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 p < 0.05. The cohort included 180 tumor samples from 170 chRCC patients. Most patients were adults (n = 167, 98.2%) and White (n = 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.

Thymic carcinoma (TC) is a rare and aggressive malignancy with poor prognosis, and its genomic landscape remains incompletely defined. Identifying the somatic alterations that shape TC biology is essential for improving diagnostic precision, developing targeted therapies, and informing early detection strategies. We performed a retrospective genomic analysis of 141 TC tumor specimens from 134 patients using de-identified data from the American Association for Cancer Research (AACR) Project GENIE^® database. Somatic mutations and copy number alterations (CNAs) were characterized, and statistical analyses were conducted to evaluate associations with patient demographics (sex, race) and tumor site (primary vs. metastatic). The cohort was predominantly male (56.7%) and White (56.7%). The most frequently altered genes were TP53 (27.7%), CYLD (17.6%), and CDKN2A (12.1%). Recurrent homozygous deletions at chromosome 9p21.3 involving CDKN2A and CDKN2B were common. Sex-stratified analysis revealed several significant male-specific alterations. Although the Pacific Islander subgroup was small (n = 2), preliminary analysis suggested enrichment of alterations in key cancer-associated genes, including TP53, BRCA1, and STAT5B, underscoring the need for diverse representation in TC genomics. Notably, MTOR mutations were significantly enriched in a subset of local recurrences and lymph node metastases (n = 3; q = 0.013), suggesting a potential role in disease progression. This large-scale genomic analysis reinforces the central involvement of TP53, cell-cycle control, and chromatin-modifying pathways in TC. The identification of sex-associated and race-associated mutational patterns, together with the enrichment of MTOR alterations in recurrent and metastatic disease, highlights biologically plausible mechanisms of progression and potential therapeutic vulnerabilities. These findings support the value of comprehensive genomic profiling in TC and emphasize the need for prospective, multi-omic studies to validate these observations and guide the development of more personalized treatment strategies.

Background: Bladder adenocarcinoma (BA) is a rare malignancy, accounting for up to 2% of bladder cancers. Its molecular drivers remain poorly defined, limiting therapeutic options and prognostic assessment. This study characterizes the genomic landscape of BA using a large, multi-institutional sequencing database to identify recurrent alterations and potential therapeutic targets. Methods: Clinical and genomic data for BA were extracted from the AACR Project GENIE® database (accessed July 2025). Samples underwent targeted next-generation sequencing (50–555 genes, >500× coverage). Analyses included somatic mutation frequency, copy number alterations (CNAs), tumor mutational burden (TMB), and stratification by sex, race, and tumor site (primary vs. metastatic). Statistical comparisons used chi-squared, Student’s t-test, or Mann–Whitney U with Benjamini–Hochberg correction. Results: A total of 206 tumor samples from 195 patients were an-alyzed. The cohort was predominantly male (61%) and White (43%). Common somatic point mutations included TP53 (65.0%), KRAS (35.4%), PIK3CA (17.0%), SMAD4 (16.5%), and ARID1A (11.2%). CNAs were frequently affected by CDKN2A (11.6%), CDKN2B (11.6%), and SMAD4 (7.0%). Sex-stratified analysis revealed male enrichment in ARFGAP3, PTEN, LATS2, TSC2, and PRKDC, while CD40, FOXQ1, and WEE1 were observed only in females. Race-based differences included FANCD2 and EGFR en-richment in Asian patients. Co-occurring somatic point mutations were identified between ARID1A–TERT, NSD1–KDM6A, and KRAS–SMAD4, while SMAD4 and KDM6A point mutations demonstrated mutual exclusivity. Discussion: Findings confirm TP53, KRAS, and PIK3CA as recurrently mutated drivers in BA and highlight FGFR3 as a novel re-currently mutated gene, as well as frequent copy number losses involving SMAD4, CDKN2A, and CDKN2B. Subgroup analyses highlight sex- and race-associated muta-tional differences, suggesting potential biologic underpinnings of demographic dispari-ties. Co-occurrence and exclusivity analyses reveal previously unreported interactions, underscoring pathway redundancy and cooperation in tumor progression. Conclusion: This study provides one of the most comprehensive genomic characterizations of BA to date, identifying recurrent drivers, subgroup-specific alterations, and mutational inter-actions. These insights highlight TP53, KRAS, and PIK3CA pathway disruption as central in BA biology and support the development of targeted therapeutics and prospective validation in independent cohorts.

Background: Seminoma is a malignant germ cell tumor that most commonly involves the testicles but may involve the mediastinum, the retroperitoneum, and other extra-gonadal sites as well. This study aims to investigate the somatic genomic landscape of seminoma. Methods: Data for a retrospective observational analysis of seminoma was acquired from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) with clinical and genomic data from 2017 and beyond. Using the R and R Studio software (R 4.5.0), analyses for common somatic mutations and copy number alterations were run with a statistical significance of p < 0.05. Results: The most mutated genes included KIT (22.6%), KRAS (17.1%), and MTOR (5.1%), with significant copy number alterations in CDKN1B (17.2%), KRAS (14.7%), CCND2 (10.3%), and H3F3C (9.8%). These suggest involvement within the KIT/RAS/MAPK and PI3K/AKT/mTOR (PAM) pathways for seminoma development. A novel finding within comparative evaluation of PMS1 and AMER1 mutations were found in Black individuals. Additionally, our findings were consistent with a lower testicular cancer rate among individuals with African ancestry than European ancestry. BRD4 mutations were found only in metastatic samples while KMT2C, STAG2, ALK, AXL, and EGFR were only found in primary samples, suggesting a possible association. Conclusions: This study provided a comprehensive molecular and genetic profiling of seminoma including key genetic alterations, affected pathways, and potential therapeutic strategies. Moreover, overlap between pathways and gene mutations provides the potential for alternative treatment options for seminoma via multiple pathways.