Multigene mutational profiling of biliary tract cancer is related with pattern of recurrence in surgical resected patients

Abstract

Background and Aims: The pathogenic pathways involved in carcinogenesis of Biliary Tract cancer (BTC) are still to be fully defined, and data regarding the relationship between molecular alterations and pattern or timing of recurrence is lacking. The aim of the present study was to investigate the relationship between the mutational gene profile and the pattern of recurrence in BTCs. Patients and Methods: From September 1990 to December 2012, a total of 103 specimens of patients with BTC (56 perihilar cholangiocarcinoma, PCC, 35 intrahepatic cholangiocarcinoma ,ICC, and 12 gallbladder cancer, GBC), who underwent curative surgery in a single tertiary HPB surgery referral center, were assessed for mutational status in 56 cancer-related genes. Results: The5-years recurrence free survival (RFS) rate was 16.7% in GBC, 42.9% in ICC, 19.7% in PCC, p=0.166. The presence of mutations inARID1A, BRAF, ERBB2, FGFR3, PIK3CA and TP53 genes was associated with poor RFS compared with wild type tumors (p=0.039, p= 0.002; p=0.017, p=0.024, p= 0.032 and, p = 0.003 respectively). At the multivariate analysis including clinical, pathological and molecular characteristics, the factors independently related with RFS were: Radicality of surgery (OR 2.050, C.I. 1.104-3.807, p=0.023), LN status (OR 1.835, C.I. 1.006-3.348, p=0.048), mutational status of ARID1A(OR 2.566, C.I. 1.174-5.608, p=0.018) and TP53(OR 2.805, C.I. 4.432-5.496, p=0.003). Moreover ARID1A mutation was associated more frequently with local than systemic recurrence (43% and 29% of cases, respectively); otherwise TP53 mutation was associated more frequently with systemic than local recurrence (41% and 29% of cases, respectively). Conclusion: Our study reported specific prognostic genes for GBC, PCC and ICC that can identify patients with poor prognosis after curative surgery . Moreover, we analyzed the relationship between the mutational gene profile and the recurrence of BTCs. Disease-specific genes identified can be explored for new molecular therapies in clinical trial.