Molecular Detection of FGFR2 Rearrangements in Resected Intrahepatic Cholangiocarcinomas: FISH Could Be An Ideal Method in Patients with Histological Small Duct Subtype

Yining Zou; Kun Zhu; Yanrui Pang; Jing Han; Xin Zhang; Zhengzeng Jiang; Yufeng Huang; Wenyi Gu; Yuan Ji

doi:10.14218/JCTH.2022.00060S

Molecular Detection of FGFR2 Rearrangements in Resected Intrahepatic Cholangiocarcinomas: FISH Could Be An Ideal Method in Patients with Histological Small Duct Subtype

J Clin Transl Hepatol. 2023 Nov 28;11(6):1355-1367. doi: 10.14218/JCTH.2022.00060S. Epub 2023 Jul 27.

Authors

Yining Zou^{1

2}, Kun Zhu^{1

3}, Yanrui Pang^{1

4}, Jing Han^{1

4}, Xin Zhang^{1

4}, Zhengzeng Jiang^{1

4}, Yufeng Huang^{1

4}, Wenyi Gu^{1

4}, Yuan Ji^{1

4}

Affiliations

¹ Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.
² Department of Pathology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
³ Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
⁴ Fudan University, Shanghai, China.

Abstract

Background and aims: 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.

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.

Results: 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.

Conclusions: 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.

Keywords: Clinicopathological subgroups; Fibroblast growth factor receptor 2 (FGFR2); Fluorescence in situ hybridization (FISH); Intrahepatic cholangiocarcinoma; Prognosis.