Poor prognosis among radiation associated bladder cancer is defined by clinicogenomic features.

Radiation therapy (RT) for prostate cancer has been associated with an increased risk for the development of bladder cancer. We aimed to integrate clinical and genomic data to better understand the development of RT-associated bladder cancer. A retrospective analysis was performed to identify control (CTRL; n= 41) and RT-associated (n=41) bladder cancer patients. RT and CTRL specific features were then identified through integration and analysis of the genomic sequencing data and clinical variables. RT-associated bladder tumors were significantly enriched for alterations in KDM6A and ATM, while CTRL tumors were enriched for CDKN2A mutation. Globally, there was an increased number of variants within RT tumors, albeit at a lower variant allele frequency. Mutational signature analysis revealed three predominate motif patterns, with similarity to SBS2/13 (APOBEC3A), SBS5 (ERCC2/Smoking) and SBS6/15 (MMR). Poor prognostic factors in the RT cohort include, a short tumor latency, smoking status, the presence of the smoking and XRT mutational signatures, and CDKN2A copy number loss. Based on the clinical and genomic findings, we suggest, at least two potential pathways leading to RT-associated bladder cancer; the first, occurs in the setting of field cancerization, related to smoking or pre-existing genetic alterations and leads to the development of more aggressive bladder tumors, and the second, in which RT initiates the oncogenic process in otherwise healthy urothelium, leading to a longer latency and less aggressive disease.

Genomic profiling and comparative analysis of male versus female metastatic breast cancer across subtypes.

BACKGROUND: Male breast cancer (MaBC) has limited data on genomic alterations. We aimed to comprehensively describe and compare MaBC's genomics with female breast cancer's (FBC) across subtypes. METHODS: Using genomic data from Foundation Medicine, we categorized 253 MaBC into estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative (n = 210), ER-positive/HER2-positive (n = 22) and triple-negative (n = 20). One ER-negative/HER2-positive case was excluded due to n-of-1. The genomics of the final MaBC cohort (n = 252) were compared to a FBC cohort (n = 2708) stratified by molecular subtype, with adjusted p-values. In the overall MaBC and FBC cohorts, we compared mutational prevalence in cancer susceptibility genes (CSG) (ATM/BRCA1/BRCA2/CHEK2/PALB2). RESULTS: Comparing ER-positive/HER2-negative cases, MaBc had increased alterations in GATA3 (26.2% vs. 15.9%, p = 0.005), BRCA2 (13.8% vs. 5.3%, p < 0.001), MDM2 (13.3% vs. 6.14%, p = 0.004) and CDK4 (7.1% vs. 1.8%, p < 0.001); and decreased frequency of TP53 (11.0% vs. 42.6%, p < 0.001) and ESR1 mutations (5.7% vs. 14.6%, p < 0.001). Comparing ER-positive/HER2-positive cases, MaBC had increased short variants in ERBB2 (22.7% vs. 0.6%, p = 0.002), GATA3 (36.3% vs. 6.2%, p = 0.004), and MDM2 (36.3% vs. 4.9%, p = 0.002); decreased frequency of TP53 alterations was seen in MaBC versus FBC (9.1% vs. 61.7%, p < 0.001). Within triple-negative cases, MaBC had decreased alterations in TP53 compared to FBC (25.0% vs. 84.4%, p < 0.001). MaBC had higher frequency of CSG variants than FBC (22.6% vs. 14.6%, p < 0.05), with increased BRCA mutations in MaBC (14.6% vs. 9.1%, p < 0.05). CONCLUSIONS: Although MaBC and FBC share some common alterations, our study revealed several important differences relevant to tumor biology and implications for targeted therapies.