Genomic Profiling of Intrahepatic Cholangiocarcinoma: Refining Prognosis and Identifying Therapeutic Targets

Abstract

Background The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to determine the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection. Methods Multiplexed mutational profiling was performed using nucleic acids that were extracted from 200 resected ICC tumor specimens from 7 centers. The frequency of mutations was ascertained and the effect on outcome was determined. Results The majority of patients (61.5 %) had no genetic mutation identified. Among the 77 patients (38.5 %) with a genetic mutation, only a small number of gene mutations were identified with a frequency of >5 %: IDH1 (15.5 %) and KRAS (8.6 %). Other genetic mutations were identified in very low frequency: BRAF (4.9 %), IDH2 (4.5 %), PIK3CA (4.3 %), NRAS (3.1 %), TP53 (2.5 %), MAP2K1 (1.9 %), CTNNB1 (0.6 %), and PTEN (0.6 %). Among patients with an IDH1-mutant tumor, approximately 7 % were associated with a concurrent PIK3CA gene mutation or a mutation in MAP2K1 (4 %). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1-mutant tumors were more often bilateral (odds ratio 2.75), while KRAS-mutant tumors were more likely to be associated with R1 margin (odds ratio 6.51) (both P < 0.05). Although clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis. Conclusions Most somatic mutations in resected ICC tissue are found at low frequency, supporting a need for broad-based mutational profiling in these patients. IDH1 and KRAS were the most common mutations noted. Although certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly affect long-term prognosis.

Impressive response to dual BRAF and MEK inhibition in patients with BRAF mutant intrahepatic cholangiocarcinoma—2 case reports and a brief review

“…In this reports, we focus on two cases of ICC with BRAF mutation and demonstrate impressive clinical activity for a combination of BRAF and MEK inhibitors, dabrafenib and tramatenib. BRAF mutations are more common in ICC than extrahepatic cholangiocarcinoma or gallbladder cancer (4,5). The frequency of BRAF mutations in ICC have ranged between 1% to 22% among various cases series or population studies.…”

Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma

“…Before the implementation of next-generation sequencing technologies, our knowledge of the role of mutations in iCCA was limited, encompassing recurrent activating mutations in KRAS (19%), low frequency mutations in BRAF (5%), and EGFR (3%), and widely varying reports of loss-offunction mutations in the tumor suppressor TP53 (16%, range 1%-38%; Tables 1 and 2; refs. 31,[50][51][52][53][54][55][56][57][58][59][60][61][62][63][64]. While KRAS and TP53 mutations are relatively common in all CCA, mutations in IDH1/2 and BRAF are considerably more prevalent in iCCA (Table 1).…”

Comparing Clonality Between Components of Combined Hepatocellular Carcinoma and Cholangiocarcinoma by Targeted Sequencing

“…The genetic composition of each component of cHCC-CC had common mutations previously detected in intrahepatic cholangiocarcinoma (iCC) and HCC. According to NGS data, mutations of KRAS, v-raf murine sarcoma viral oncogene homolog B1 (BRAF), epidermal growth factor receptor (EGFR), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), PTEN and TP53 have been repeatedly identified in iCC (13)(14)(15)(16)(17)(18). In our study, all CC components of cHCC-CC had TP53 substitutions (4/4, 100%) usually found in ordinary iCC with frequency of 2.5-36% (13)(14)(15)(16)(17).…”

“…PTEN SNP/Indel is frequently reported in iCC (frequency at 0.6-11%) (13,15,16,18). PTEN deletion or loss of expression is frequently reported in HCC (28).…”