Genomic Features of Muscle-invasive Bladder Cancer Arising After Prostate Radiotherapy

Abstract

Background: Muscle-invasive bladder cancer (MIBC) is a rare but serious event following definitive radiation for prostate cancer. Radiation-associated MIBC (RA-MIBC) can be difficult to manage given the challenges of delivering definitive therapy to a previously irradiated pelvis. The genomic landscape of RA-MIBC and whether it is distinct from non-RA-MIBC are unknown.

Objective: To define mutational features of RA-MIBC and compare the genomic landscape of RA-MIBC with that of non-RA-MIBC.

Design, setting, and participants: We identified patients from our institution who received radiotherapy for prostate cancer and subsequently developed MIBC.

Outcome measurements and statistical analysis: We performed whole exome sequencing of bladder tumors from RA-MIBC patients. Tumor genetic alterations including mutations, copy number alterations, and mutational signatures were identified and were compared with genetic features of non-RA-MIBC. We used the Kaplan-Meier method to estimate recurrence-free (RFS) and overall (OS) survival.

Results and limitations: We identified 19 RA-MIBC patients with available tumor tissue (n = 22 tumors) and clinical data. The median age was 76 yr, and the median time from prostate cancer radiation to RA-MIBC was 12 yr. The median RFS was 14.5 mo and the median OS was 22.0 mo. Compared with a cohort of non-RA-MIBC analyzed in parallel, there was no difference in tumor mutational burden, but RA-MIBCs had a significantly increased number of short insertions and deletions (indels) consistent with previous radiation exposure. We identified mutation signatures characteristic of APOBEC-mediated mutagenesis, aging, and homologous recombination deficiency. The frequency of mutations in many known bladder cancer genes, including TP53, KDM6A, and RB1, as well as copy number alterations such as CDKN2A loss was similar in RA-MIBC and non-RA-MIBC.

Conclusions: We identified unique mutational properties that likely contribute to the distinct biological and clinical features of RA-MIBC.

Patient summary: Bladder cancer is a rare but serious diagnosis following radiation for prostate cancer. We characterized genetic features of bladder tumors arising after prostate radiotherapy, and identify similarities with and differences from bladder tumors from patients without previous radiation.

Keywords: Bladder cancer; DNA sequencing; Genomics; Mutational signatures; Prostate cancer; Radiation; Radiation-associated cancer; Second malignancy.

Fig. 1 –

Overall survival of patients in the RA-MIBC cohort compared with that in MIBC patients from the TCGA cohort. Survival times were calculated from the date of surgery (cystectomy or TURBT). MIBC = muscle-invasive bladder cancer; OS = overall survival; RA BC = radiation-associated MIBC cohort; RA-MIBC = radiation-associated MIBC; TCGA = The Cancer Genome Atlas; TURBT = transurethral resection of the bladder tumor.

Fig. 2 –

Mutational landscape of the RA-MIBC cohort. (A) Tumor mutational burden (TMB), mutational signatures, select clinical characteristics, and alterations in select bladder cancer genes for each tumor in the cohort (n = 22). (B) TMB was not significantly different but similar between the RA-MIBC and non–radiation-associated MIBC cohorts. CNA = copy-number alteration; EBRT = external beam radiation therapy; MIBC = muscle-invasive bladder cancer; NAC = neoadjuvant chemotherapy; NMIBC = non–muscle-invasive bladder cancer.

Fig. 3 –

Mutational features of RA-MIBC. (A) Five mutational signatures were identified in the RA-MIBC cohort. Signatures 1 and 5 (age related) were present in all 22 tumors, signatures 2 and 13 (APOBEC-mediated mutagenesis) were identified in 21 tumors, and signature 3 (homologous recombination deficiency) was identified in eight tumors. Signature 18 (unknown etiology) was identified in two tumors (not shown). There were significant differences in the number of single nucleotide variants (SNVs) across mutational signatures (Kruskal-Wallis, p < 0.001), and signature 5 had a significantly higher number of SNVs than all other signatures (Wilcoxon rank sum, adjusted p < 0.001). (B) Mutations in select DNA repair genes in the RA-MIBC cohort (only tumors with at least one alteration in a listed DNA repair gene are included [n = 18]). (C) The RA-MIBC cohort had a significantly higher ratio of short insertions/deletions (indels) to SNVs than the nonradiated MIBC cohort (left). The ratio of deletions to SNVs as well as the number of deletions per megabase (Mb) were also significantly higher in the RA-MIBC cohort than in the non–radiation-associated MIBC cohort (middle and right panels). MIBC = muscle-invasive bladder cancer; RA BC = radiation-associated MIBC cohort; RA-MIBC = radiation-associated MIBC.