Background and Aims: Biliary tract cancer (BTC) is a heterogeneous group of malignancies with poor prognosis arising from the epithelial cells of biliary tree. Recently it has been reported that specific molecular mutations are associated with different types of biliary tree carcinomas, supporting their pathologic and molecular heterogeneity. However, the pathogenic pathways involved in carcinogenesis of 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 PCC, 35 ICC, and 12 GBC), who underwent curative surgery in a single tertiary HPB surgery referral center, were assessed for mutational status in 56 cancer-related genes. Results: Considering the different types of BTC, the 5-years RFS rate was 16.7%. (median RFS, 7 months) in GBC, 42.9%. (median RFS, 26.4 months) in ICC, 19.7% (median RFS, 16.5 months) in PCC, p=0.166 (figure 3). The presence of mutations in ARID1A, BRAF, ERBB2, FGFR3, PIK3CA and TP53 genes was significantly associated with poor RFS compared with wild type tumors (median RFS of 11.5 months vs. 19.2 months, p=0.039; 3.0 months vs. 17.0 months, p= 0.002; 5.0 months vs 16.5 months, p=0.017; 5.1 months vs. 16.5 months, p=0.024; 11.1 months vs 18.5 months , p= 0.032 and 8.6 months vs 21.9 months , p = 0.003 respectively). At the multivariate analysis including clinical, pathological and molecular characteristics, the factors independently related with survival 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). Considering the pattern of recurrence, local recurrence occurred in 47 patients (73.4%) , while systemic recurrence occurred in 17 patients (26.4%) . Regarding the prognostic genes identified at the univariate analysis: ARID1A mutation was associated with a local and systemic recurrence in the 43% and 29% of cases, respectively; BRAF mutation was associated with a local and systemic recurrence in the 33% and 33% of cases, respectively; ERBB2 and FGFR3 mutation were always associated with a local recurrence; PIK3CA mutation was related with a local and systemic recurrence in the 72% and 14% of cases, respectively; and TP53 mutation was associated with a local and systemic recurrence in the 29% and 41% of cases. Regarding other genes with relatively high rate of mutation: BAP1 mutation was associated with a local and systemic recurrence in the 57% and 29% of cases, respectively; KRAS mutation was related with a local and systemic recurrence in the 42% and 10% of cases, respectively; PBRM1 mutation was associated in the 64% of cases with a local recurrence. 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
