Molecular mechanism in urothelial carcinoma with FGFR3 mutation.

Abstract

e16548 Background: Specific genomic alterations in the FGFR (fibroblast growth factor receptor) family are well-known to be characteristic driver events of urothelial carcinoma and is a therapeutic target. However, molecular mechanism differences of urothelial carcinoma (UC) stratified by the FGFR mutation status has not yet been described. Methods: Patients diagnosed with UC were enrolled in the study. Tumor tissue and matching blood were sequenced by next-generation sequencing (NGS) techniques with Acornmed panel with 808 cancer-related genes. Results: A total of 368 patients with UC were enrolled including 75 patients with FGFR2/3 mutation and 293 patients with FGFR2/3 wildtype. In FGFR2/3 mutation cohorts, the five most frequently mutated genes were FGFR2/3 (100%), KMT2D (56%), KMT2C (35%), CREBBP (32%) and FAT1 (31%). For FGFR2/3 wildtype cohorts, the five most frequently mutated genes were TP53 (46%), KMT2D (41%), BRD4 (23%), ARID1A (15%), and KMT2C (14%). 87 frequently mutated genes were significant difference between FGFR2/3 mutation and FGFR2/3 wildtype cohorts, such as KMT2D, KMT2C, STAG2, CREBBP and FAT1, excluding the FGFR2/3 gene. Signature 1 for spontaneous deamination of 5−methylcytosine and signature 22 for exposure to aristolochic acid (AA) existed in both cohorts. Although there were APOBEC Cytidine Deaminase signatures in both groups, they were projected to different COSMIC signatures (signature 2 and 13, respectively). Signature 10 for defects in polymerase POLE (4.81%) were only observed in the FGFR2/3 mutation cohorts. In the FGFR2/3 mutation cohorts, mutated genes were mainly enriched in the cancer pathway, PI3K-Akt signaling pathway, and Ras signaling pathway. However, in the FGFR2/3 wildtype cohorts, the primary pathways included the cancer pathway, PI3K-Akt signaling pathway, and Rap1 signaling pathway. Conclusions: There were characterized the genomic differences and similarities, stratified by the TP53 status, which may reflect the UC patients with TP53 mutation harbored specific molecular mechanism.