Intrahepatic cholangiocarcinoma (ICC) is a subtype of primary liver cancer for which effective therapeutic agents are lacking. Fibroblast growth factor receptor 2 (
FGFR2) has become a promising therapeutic target in ICC; however, its incidence and optimum testing method have not been fully assessed. This study investigated the rearrangement of
FGFR2 in intrahepatic cholangiocarcinoma using multiple molecular detection methods. The samples and clinical data of 167 patients who underwent surgical resection of intrahepatic cholangiocarcinoma in Zhongshan hospital, Fudan university were collected. The presence of
FGFR2 gene rearrangement was confirmed using fluorescence in situ hybridization (FISH) and targeted next-generation sequencing (NGS).
FGFR2 protein expression was determined using immunohistochemistry (IHC). The concordance between the methods was statistically compared. PD-L1 expression was also assessed in this cohort. The clinicopathological characteristics and genomic profile related to
FGFR2 rearrangements were also analyzed to assist candidate-screening for targeted therapies.
FGFR2 rearrangement was detected in 21 of the 167 ICC cases (12.5%) using FISH. NGS analysis revealed that
FGFR2 rearrangement was present in 16 of the 20 FISH-positive cases, which was consistent with the FISH results (kappa value=0.696,
p<0.01). IHC showed that 80 of the 167 cases (48%) were positive for
FGFR2 expression, which was discordant with both FISH and NGS results. By comparison,
FGFR2-positivity tended to correlate with unique clinicopathological subgroups, featuring early clinical stage, histologically small duct subtype, and reduced mucus production (P<0.05), with improved overall survival (
p<0.05).
FGFR2-positivity was not associated with PD-L1 expression in ICCs. In genome research, we identified eight partner genes fused with
FGFR2, among which
FGFR2-BICC1 was the most common fusion type.
BAP1, CDKN2A, and
CDKN2B were the most common concomitant genetic alterations of
FGFR2, whereas
KRAS and
IDH1 mutations were mutually exclusive to
FGFR2 rearrangements. FISH achieved satisfactory concordance with NGS, has potential value for
FGFR2 screening for targeted therapies.
FGFR2 detection should be prioritized for unique clinical subgroups in ICC, which features a histological small duct subtype, early clinical stage, and reduced mucus production.
Full article