Dataset Information

Distinct clinical and prognostic implication of IDH1/2 mutation and other most frequent mutations in large duct and small duct subtypes of intrahepatic cholangiocarcinoma.

ABSTRACT:

Background

Isocitrate dehydrogenase 1/2 (IDH1/2), BAP1, ARID1A and PBRM1 have been reported as the most frequent mutant genes in intrahepatic cholangiocarcinoma (ICC), and their relationships with clinicopathological features and prognosis were researched in this study.

Methods

We collected clinical data of 130 ICC patients from January 2012 to December 2017. The IDH1/2 mutation and loss of BAP1, ARID1A and PBRM1 expressions were detected by DNA sequencing or immunohistochemical methods, and histological subtype of ICCs was determined by hematoxylin-eosin, Alcian blue and S100P staining.

Results

IDH1/2 mutation was related to decreased preoperative serum total bilirubin (P = 0.039), ferritin (P = 0.000) and higher histological differentiation (P = 0.024), and was associated with prolonged disease-free survival (P = 0.009) and a trend toward increased overall survival (P = 0.126) in small duct type of ICCs. Immunohistochemical staining results of MsMab-1 were generally consistent with DNA sequencing for IDH1/2 mutant in ICCs (κ = 0.691). Only BAP1 expression loss was correlated to prolonged disease-free survival (P = 0.031) and overall survival (P = 0.041) in large duct type of ICCs.

Conclusions

IDH1/2 mutation is a favorable predictor and may be related to iron metabolism in small duct type of ICCs. Furthermore, we suggest that the detection of IDH1/2 mutation is indispensable to determine targeted therapy in small duct type ICCs, while it is not necessary in large duct of ICCs. MsMab-1 is a relatively effective multi-specific antibody against IDH1/2 mutant in ICCs. BAP1 expression loss was correlated with improved prognosis only in large duct type ICCs.

SUBMITTER: Ma B

PROVIDER: S-EPMC7161164 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Publications

Distinct clinical and prognostic implication of IDH1/2 mutation and other most frequent mutations in large duct and small duct subtypes of intrahepatic cholangiocarcinoma.

Ma Bingqi B Meng Huijuan H Tian Ye Y Wang Yingying Y Song Tianqiang T Zhang Ti T Wu Qiang Q Cui Yunlong Y Li Huikai H Zhang Wei W Li Qiang Q

BMC cancer 20200415 1

<h4>Background</h4>Isocitrate dehydrogenase 1/2 (IDH1/2), BAP1, ARID1A and PBRM1 have been reported as the most frequent mutant genes in intrahepatic cholangiocarcinoma (ICC), and their relationships with clinicopathological features and prognosis were researched in this study.<h4>Methods</h4>We collected clinical data of 130 ICC patients from January 2012 to December 2017. The IDH1/2 mutation and loss of BAP1, ARID1A and PBRM1 expressions were detected by DNA sequencing or immunohistochemical m ...[more]

PMID: 32293336

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Project description:Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer. It is defined by cholangiocytic differentiation and has poor prognosis. Recently, epigenetic processes have been shown to play an important role in cholangiocarcinogenesis. We performed an integrative analysis on 52 iCCAs using both genetic and epigenetic data with a specific focus on DNA methylation components. We found recurrent isocitrate dehydrogenase 1 (IDH1) and IDH2 (28%) gene mutations, recurrent arm-length copy number alterations (CNAs), and focal alterations such as deletion of 3p21 or amplification of 12q15, which affect BRCA1 Associated Protein 1, polybromo 1, and mouse double minute 2 homolog. DNA methylome analysis revealed excessive hypermethylation of iCCA, affecting primarily the bivalent genomic regions marked with both active and repressive histone modifications. Integrative clustering of genetic and epigenetic data identified four iCCA subgroups with prognostic relevance further designated as IDH, high (H), medium (M), and low (L) alteration groups. The IDH group consisted of all samples with IDH1 or IDH2 mutations and showed, together with the H group, a highly disrupted genome, characterized by frequent deletions of chromosome arms 3p and 6q. Both groups showed excessive hypermethylation with distinct patterns. The M group showed intermediate characteristics regarding both genetic and epigenetic marks, whereas the L group exhibited few methylation changes and mutations and a lack of CNAs. Methylation-based latent component analysis of cell-type composition identified differences among these four groups. Prognosis of the H and M groups was significantly worse than that of the L group. Conclusion: Using an integrative genomic and epigenomic analysis approach, we identified four major iCCA subgroups with widespread genomic and epigenomic differences and prognostic implications. Furthermore, our data suggest differences in the cell-of-origin of the iCCA subtypes.

Project description:BackgroundSerum biomarkers are often used as part of preoperative prediction strategies to help assess a patient's surgical risk and prognosis. The high-sensitivity modified Glasgow prognostic score (HS-mGPS) has been shown to offer better predictive accuracy compared to the traditional Glasgow prognostic score (GPS) and the modified Glasgow prognostic score (mGPS) in various cancers, but its ability to predict outcomes in patients with resected intrahepatic cholangiocarcinoma (ICC) has not been well-studied. The aim of the study was to investigate the prognostic value of HS-mGPS in ICC and its subtypes.MethodsThis study was a single-center retrospective study. All patients who were pathologically diagnosed with ICC after surgery in Nanjing Drum Tower Hospital from 2012 and 2022. Relevant laboratory data such as serum C-reactive protein (CRP), albumin (ALB), neutrophils, lymphocytes, and platelets were included. Overall survival (OS) information was collected, serum CRP and ALB level were used for scoring GPS, mGPS and HS-mGPS. Univariate and multivariate analyses were conducted to identify factors influencing prognosis by using Kaplan-Meier (KM) curve and Cox proportional hazards models. Additionally, through histological analysis, ICC was classified into large duct type (LD-type) and small duct type (SD-type), and the performance of the three scoring systems in these subtypes was examined.ResultsA total of 185 patients were included in this study, 57 cases were of the LD-type, and 128 cases were of the SD-type. Tumor subtypes was a significant factor influencing prognosis for all ICC patients [hazard ratio (HR) =1.76, 95% confidence interval (CI): 1.036-2.994, P=0.04]. HS-mGPS demonstrated a better ability to predict outcomes compared to GPS and mGPS, and was an independent prognostic factor of OS (HR =2.1, 95% CI: 1.001-4.374, P=0.049). HS-mGPS was also more effective in predicting prognosis for SD-type ICC compared to GPS and mGPS (HR =3.13, 95% CI: 1.018-9.604, P=0.046), while it was ineffective for LD-type ICC. Further analysis revealed that SD-type ICC with higher HS-mGPS scores typically had larger tumors and poorer differentiation, while LD-type ICC showed no significant differences.ConclusionsHS-mGPS provides a more accurate prognostic indication for SD-type, but its effectiveness for LD-type requires further investigation with larger sample sizes. Therefore, for preoperatively biopsy-diagnosed SD-type ICC, the HS-mGPS has a certain level of prognostic predictive potential.

Dataset Information

Distinct clinical and prognostic implication of IDH1/2 mutation and other most frequent mutations in large duct and small duct subtypes of intrahepatic cholangiocarcinoma.

Background

Methods

Results

Conclusions

Publications

Distinct clinical and prognostic implication of IDH1/2 mutation and other most frequent mutations in large duct and small duct subtypes of intrahepatic cholangiocarcinoma.

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