Novel tumor subgroups of urothelial carcinoma of the bladder defined by integrated genomic analysis
Menée sur 160 échantillons tumoraux prélevés sur des patients atteints d'un carcinome urothélial, dont 49 présentant une tumeur de haut grade de stade T1, cette étude identifie des altérations du nombre de copies de gènes dans plusieurs régions du génome en fonction de la présence de mutations dans les gènes FGFR3 et TP53
Purpose: There is a need for improved sub-classification of urothelial carcinoma (UC) at diagnosis. A major aim of this study was to search for novel genomic subgroups. Experimental Design: We assessed 160 tumors for genome-wide copy number alterations and mutation in genes implicated in UC. These comprised all tumor grades and stages and included 49 high-grade stage T1 (T1G3) tumors. Results: Our findings point to the existence of genomic subclasses of the "gold-standard" grade/stage groups. The T1G3 tumors separated into 3 major subgroups that differed with respect to the type and number of copy number events and to FGFR3 and TP53 mutation status. We also identified novel regions of copy number alteration, uncovered relationships between molecular events, and elucidated relationships between molecular events and clinico-pathological features. FGFR3 mutant tumors were more chromosomally stable than their wild-type counterparts and a mutually exclusive relationship between FGFR3 mutation and overrepresentation of 8q was observed in non-muscle-invasive tumors. In muscle-invasive (MI) tumors, metastasis was positively associated with losses of regions on 10q (including PTEN), 16q and 22q, and gains on 10p, 11q, 12p, 19p and 19q. Concomitant copy number alterations positively associated with TP53 mutation in MI tumors were losses on 16p, 2q, 4q, 11p, 10q, 13q, 14q, 16q and 19p, and gains on 1p, 8q, 10q and 12q. Significant complexity was revealed in events affecting chromosome 9. Conclusions: These findings may lead to improved biological understanding and the development of prognostic biomarkers. Novel regions of copy number alteration may reveal potential therapeutic targets.