Whole-exome sequencing of muscle-invasive bladder cancer identifies recurrent mutations of UNC5C and prognostic importance of DNA repair gene mutations on survival

Kai Lee Yap, Kazuma Kiyotani, Kenji Tamura, Tatjana Antic, Miran Jang, Magdeline Montoya, Alexa Campanile, Poh Yin Yew, Cory Ganshert, Tomoaki Fujioka, Gary D. Steinberg, Peter H. O'Donnell, Yusuke Nakamura*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Experimental Design: Using pTN staging, we case-matched 81 patients with resected -pT2 bladder cancers forwhomperioperative chemotherapy use and disease recurrence status were known. Whole-exome sequencing was conducted in 43 cases to identify recurrent somatic mutations and targeted sequencing of 10 genes selected from the initial screening in an additional 38 cases was completed. Mutational profiles along with clinicopathologic information were correlated with recurrence-free survival (RFS) in the patients.

Results: We identified recurrent novel somatic mutations in the gene UNC5C (9.9%), in addition to TP53 (40.7%), KDM6A (21.0%), and TSC1 (12.3%). Patientswho were carriers of somaticmutations inDNArepair genes (one or more of ATM, ERCC2, FANCD2, PALB2, BRCA1, or BRCA2) had a higher overall number of somatic mutations (P=0.011). Importantly, after a median follow-up of 40.4 months, carriers of somatic mutations (n=25) in any of these six DNA repair genes had significantly enhanced RFS compared with noncarriers [median, 32.4 vs. 14.8 months; hazard ratio of 0.46, 95% confidence interval (CI), 0.22-0.98; P=0.0435], after adjustment for pathologic pTN staging and independent of adjuvant chemotherapy usage.

Conclusion: Better prognostic outcomes of individuals carrying somatic mutations in DNA repair genes suggest these mutations as favorable prognostic events in muscle-invasive bladder cancer. Additional mechanistic investigation into the previously undiscovered role of UNC5C in bladder cancer is warranted.

Purpose: Because of suboptimal outcomes in muscle-invasive bladder cancer even with multimodality therapy, determination of potential genetic drivers offers the possibility of improving therapeutic approaches and discovering novel prognostic indicators.

Original languageEnglish (US)
Pages (from-to)6605-6617
Number of pages13
JournalClinical Cancer Research
Volume20
Issue number24
DOIs
StatePublished - Dec 15 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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