title: Whole-exome sequencing of muscle-invasive bladder cancer identifies recurrent mutations of UNC5C and prognostic importance of DNA repair gene mutations on survival.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Using pTN staging, we case-matched 81 patients with resected ≥pT2 bladder cancers for whom perioperative 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%). Patients who were carriers of somatic mutations in DNA repair 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, Section of Hematology-Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: Kai Lee
authors.initials: KL
authors.lastname: Yap
authors.affiliation: Department of Medicine, Section of Hematology-Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Kiyotani
authors.affiliation: Department of Medicine, Section of Hematology-Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Antic
authors.affiliation: Department of Medicine, Section of Hematology-Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: Miran
authors.initials: M
authors.lastname: Jang
authors.affiliation: Department of Medicine, Section of Hematology-Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: Magdeline
authors.initials: M
authors.lastname: Montoya
authors.affiliation: Department of Medicine, Section of Hematology-Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: Alexa
authors.initials: A
authors.lastname: Campanile
authors.affiliation: Department of Medicine, Section of Hematology-Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: Poh Yin
authors.initials: PY
authors.lastname: Yew
authors.affiliation: Department of Medicine, Section of Hematology-Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: Cory
authors.initials: C
authors.lastname: Ganshert
authors.affiliation: Department of Urology, Iwate Medical University, Morioka, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Fujioka
authors.affiliation: Department of Surgery, Section of Urology, The University of Chicago, Chicago, Illinois.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Steinberg
authors.affiliation: Department of Medicine, Section of Hematology-Oncology, The University of Chicago, Chicago, Illinois. ynakamura@bsd.uchicago.edu podonnel@medicine.bsd.uchicago.edu.
authors.forename: Peter H
authors.initials: PH
authors.lastname: O'Donnell
authors.affiliation: Department of Medicine, Section of Hematology-Oncology, The University of Chicago, Chicago, Illinois. Department of Surgery, The University of Chicago, Chicago, Illinois. ynakamura@bsd.uchicago.edu podonnel@medicine.bsd.uchicago.edu.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016000:Cluster Analysis; D019295:Computational Biology; D004260:DNA Repair; D059472:Exome; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D000075386:Netrin Receptors; D011379:Prognosis; D011956:Receptors, Cell Surface / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality* / Q000473:pathology
chemical_list: D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; C115727:UNC5C protein, human