title: Molecular classification of non-muscle-invasive bladder cancer (pTa low-grade, pT1 low-grade, and pT1 high-grade subgroups) using methylation of tumor-suppressor genes.
abstract: The role of epigenetics in distinguishing pathological and clinical subgroups in bladder cancer is not fully characterized. We evaluated whether methylation of tumor-suppressor genes (TSGs) would classify non-muscle-invasive (NMI) bladder cancer subgroups and predict outcome. A retrospective design included the following paraffin-embedded primary NMI tumor types (n = 251): pTa low grade (LG) (n = 79), pT1LG (n = 81), and pT1 high grade (HG) (n = 91). Methylation of 25 TSGs was measured using methylation-specific, multiplex, ligation-dependent probe amplification. The TSGs most frequently methylated in the overall series were STK11 (96.8%), MGMT2 (64.5%), RARB (63.0%), and GATA5 (63.0%). TSG methylation correlated to clinicopathological variables in each subgroup and in the overall NMI series. Methylation of RARB, CD44, PAX5A, GSTP1, IGSF4 (CADM1), PYCARD, CDH13, TP53, and GATA5 classified pTa versus pT1 tumors whereas RARB, CD44, GSTP1, IGSF4, CHFR, PYCARD, TP53, STK11, and GATA5 distinguished LG versus HG tumors. Multivariate analyses indicated that PAX5A, WT1, and BRCA1 methylation independently predicted recurrence in pTaLG, PAX6, ATM, CHFR, and RB1 in pT1LG disease; PYCARD, in pT1HG disease; and PAX5A and RB1, in the overall series. Methylation of TSGs provided a molecular classification of NMI disease according to clinicopathological factors. Furthermore, TSG methylation predicted recurrence in NMI subgroups.
authors.affiliation: Bladder Cancer Group, Proteomics Unit, CIC bioGUNE, Derio, Spain; Department of Urology, Central Hospital of Asturias, Oviedo, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Sacristan
authors.affiliation: Tumor Markers Group, Molecular Pathology Program, Spanish National Cancer Center, Madrid, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Gonzalez
authors.affiliation: Department of Urology, Central Hospital of Asturias, Oviedo, Spain.
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Fernández-Gómez
authors.affiliation: Department of Pathology, Central Hospital of Asturias, Oviedo, Spain.
authors.forename: Florentino
authors.initials: F
authors.lastname: Fresno
authors.affiliation: Department of Urology, Central Hospital of Asturias, Oviedo, Spain.
authors.forename: Safwan
authors.initials: S
authors.lastname: Escaf
authors.affiliation: Bladder Cancer Group, Proteomics Unit, CIC bioGUNE, Derio, Spain; Tumor Markers Group, Molecular Pathology Program, Spanish National Cancer Center, Madrid, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain. Electronic address: mscarbayo@cicbiogune.es.
authors.forename: Marta
authors.initials: M
authors.lastname: Sánchez-Carbayo
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D011379:Prognosis; D047368:Tumor Burden; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality / Q000473:pathology