Genomic Characterization of Radiotherapy-Associated Muscle Invasive Bladder Cancer after Prostate Cancer Treatment.

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    • Abstract:
      Patients with prior radiotherapy (RT) for prostate cancer (PCa) are at increased risk for an aggressive secondary bladder cancer (BCa). Genetic changes may contribute to this risk, but there are limited data on the altered genomic landscape of RT-associated BCa. Other RT-associated secondary cancers are known to have an increased rate of genomic insertions (INS), deletions (DEL), and structural variants (SVs). We characterized the genomes of the largest known cohort of RT-associated BCa to identify signatures that may be used in patient selection and risk stratification. We identified BCa patients with a history of RT for PCa (n=41), and a control (CTRL) cohort of BCa patients with no record of pelvic RT (n=41) but having standard of care Foundation Medicine sequencing (FMI). Clinical factors such as T-, N- and M- staging, smoking status, and time from RT to BCa (i.e., short latency (<10y) vs. long latency (>10y)). Tumor-only targeted FMI was performed on RT-associated BCa FFPE tissue. Mutation/SV calls and analysis was performed using a combination of Mutect2, MutSigCV2, Pindel, and Lumpy. We also identified known smoking and RT mutational signatures and quantified the relative contribution and association with overall survival (OS). Within CTRL and RT cohorts, race and smoking were not significantly different. While cT stage was similar between cohorts, the CTRL cohort was significantly biased toward higher cN and cM stages with no difference in OS (median OS: CTRL = 20m, RT = 23m). The median latency from RT to BCa was 8.5y (range: 2-28y). Patients with short latency tumors had a significantly shorter OS than long latency (p<0.01, HR=5.59 (1.81-17.3)) but not CTRL patients (p=0.17, HR=1.55 (0.82-2.94)). Long latency tumor patients had a significantly longer OS than CTRL patients (p<0.01, HR = 0.22 (0.07-0.63)). Relative to CTRL, we observed increased INS (p<0.001), SNVs (p<0.001), large DEL (p<0.001) and balanced INV (p<0.001) in the RT cohort; however, we observed a decrease in small DEL (p<0.001). We observed a significant enrichment of KDM6A mutations within RT samples (p<0.001). In the RT group, smoking signature predominant contribution and RT signature predominant contribution had significant associations with hazard of death relative to other signatures (p=0.036) and (p=0.026), respectively. Within CDKN2A DEL samples but not wild-type samples, short latency tumors had worse prognosis than CTRL (HR=7.11 (1.89-26.7), p=0.004). Patients with BCa within a short interval following pelvic RT have a worse OS. Genomic analysis showed RT-associated tumors have more genetic alterations, including KDM6A mutations, than tumors without prior RT, regardless of smoking status. Additionally, smoking and CDKN2A loss may synergistically contribute to field cancerization and create a permissive environment for RT to drive malignant transformation. To our knowledge, this is the first report of an RT-associated alteration in a specific gene in BCa. [ABSTRACT FROM AUTHOR]
    • Abstract:
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