Frequency and Prognostic Value of IDH Mutations in Korean Patients With Cholangiocarcinoma

Abstract

The molecular profile of cholangiocarcinoma (CC) remains elusive. The prognostic value of isocitrate dehydrogenase (IDH) mutations in CC is controversial, and there have been few relevant studies in Asian populations. In the present study, we investigated the frequency and prognostic significance of IDH mutations in Korean patients with CC. CC specimens were collected from patients who underwent surgical liver resection between 2004 and 2019. Clinical and pathological data were retrospectively reviewed from medical records. Mutational IDH profiling was performed by peptide nucleic acid-mediated PCR clamping in 206 surgical specimens; IDH-mutant samples were confirmed by next-generation sequencing (NGS). Of the 195 patients with CC, six (3.13%) were found to exhibit IDH1 (n = 5) or IDH2 (n = 1) mutations. Among patients with IDH1 mutations, four had R132C (c.394C>T) and one had R132G (c.394C>G) mutations. One patient had R172W (c.514A>T) mutations in IDH2. All IDH-mutant samples were of intrahepatic origin, and patients with IDH mutations had physiological to low serum levels of carbohydrate antigen 19-9 (CA19-9). No association between IDH mutation status and long-term survival outcomes was observed. The frequency of IDH mutations was considerably lower than the 10-20% reported in previous studies. The frequency and pattern of IDH mutations in CC are likely to vary among patients with different ethnicities. These findings suggest that characterization of the oncogenic mutation profile in different populations is of high clinical importance.

The regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer

“…In 2021, a next-generation sequencing study involving 20 common solid tumors (more than 28,000 patients in total) showed that the incidence of IDH1/2 mutation is only 1.3%, and the mutation frequency in lung cancer, colorectal cancer, liver cancer, stomach cancer, and other solid tumors is only 0.5%–3% 20 . The unique solid tumor with IDH1/2 mutation frequency exceeding 5% is cholangiocarcinoma (low incidence) 36 , 37 . In addition, IDH1/2 mutation frequency is also high in rare cancers such as chondrosarcoma (38%–86%), undifferentiated carcinoma of the paranasal sinuses (49%–82%), and angioimmunoblastic T-cell lymphoma (20%–30%) 38 .…”

Biology of IDH mutant cholangiocarcinoma

“…Correlations between IDH mutations in iCCA and clinical outcome parameters have been inconsistent across different studies, perhaps due to issues of sampling bias, heterogeneity in populations, various clinical stages, and limited specimen numbers. [109][110][111][112][113][114][115] On the other hand, mIDH iCCAs show distinct histological and molecular features. iCCAs can be classified histologically into small duct and large duct subtypes.…”

Recent advances of IDH1 mutant inhibitor in cancer therapy

“…The IDH1 mutation is the substitution of arginine 132 by other amino acids, including R132 H/C/L/S ( Golub, et al, 2019 ). Particularly, R132H and R132C are the most common mutation types, with mutation’s frequency ranging from 4.3% to 33% ( Kim, et al, 2020 ).…”