title: Genomic characterization of high-risk non-muscle invasive bladder cancer.
abstract: The genetic mechanisms associated with progression of high-risk non-muscle-invasive bladder cancer (HR-NMIBC) have not been described. We conducted selective next-generation sequencing (NGS) of HR-NMIBC and compared the genomic profiles of cancers that responded to intravesical therapy and those that progressed to muscle-invasive or advanced disease. DNA was extracted from paraffin-embedded sections from 25 HR-NMIBCs (22 with T1HG; 3 with TaHG with or without carcinoma in situ). Ten patients with HR-NMIBC developed progression (pT2+ or N+) ("progressors"). Fifteen patients had no progression ("non-progressors"). Tissue from 11 patients with metastatic bladder cancer (BC) were analyzed for comparison. We found no difference in frequency of mutations of TP53, PIK3CA, or KMT2D between the primary tumors of progressors compared to non-progressors and metastatic tumors. An increased frequency of deletions of CDKN2A/B was identified in tumors at progression (37%) compared to non-progressors (6%) (p = 0.10). We found a significant decrease in total mutational burden (TMB) that has been associated with immunotherapy response comparing non-progressors, progressors and metastatic tumors at 15, 10.1 and 5.1 mutations/MB respectively (p = 0.02). This association suggests more advanced tumors have decreased neoantigen burden and may explain the mechanism of BCG response in non-progressors. We found no novel genetic drivers in progressors and HR-NMIBC had many genetic features similar to metastatic BC. Loss of CDKN2A/B may occur late during invasion of BC and may represent an important step in progression. Further research is necessary to evaluate TMB and loss of CDKN2A/B locus as a biomarker for progression of NMIBC.
authors.affiliation: Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Meeks
authors.affiliation: Developmental Therapeutics Program, Division of Hematology/Oncology, Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: Benedito A
authors.initials: BA
authors.lastname: Carneiro
authors.affiliation: Developmental Therapeutics Program, Division of Hematology/Oncology, Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: Sachin G
authors.initials: SG
authors.lastname: Pai
authors.affiliation: Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Oberlin
authors.affiliation: Northwestern University Department of Preventive Medicine, Chicago, IL, USA.
authors.forename: Alfred
authors.initials: A
authors.lastname: Rademaker
authors.affiliation: Foundation Medicine Inc, Cambridge, MA, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Fedorchak
authors.affiliation: Foundation Medicine Inc, Cambridge, MA, USA.
authors.forename: Sohail
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: Foundation Medicine Inc, Cambridge, MA, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Elvin
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Nike
authors.initials: N
authors.lastname: Beaubier
authors.affiliation: Developmental Therapeutics Program, Division of Hematology/Oncology, Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D023281:Genomics / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D012306:Risk; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology*
chemical_list: D015415:Biomarkers
keywords: bladder cancer; invasion; mutation burden; progression