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 and Objective: IDH1/2, BAP1, ARID1A and PBRM1 have been reported as the most frequent mutant genes in ICCs, 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 IHC methods, and histological subtype of ICCs was determined by HE, Alcian blue and S100P staining.Results: IDH1/2 mutation was related to decreased TBIL (P=0.039), ferritin (P=0.000) and higher histological differentiation (P=0.024), and was associated with prolonged DFS (P=0.009) and a trend toward increased OS (P=0.126) in small duct type of ICCs. IHC result of MsMab-1 was generally consistent with DNA sequencing for IDH1/2 mutant in ICCs (κ= 0.691). Only BAP1 expression loss was correlated to prolonged DFS (P=0.031) and OS (P=0.041) in large duct type of ICCs.Conclusions: IDH1/2 mutation may be a favorable predictor and 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 of ICCs, while it is not necessary in large duct of ICCs. MsMab-1 was a relatively effective multi-specific antibody against IDH1/2 mutant in ICCs. BAP1 expression loss was related to an improved prognosis in large duct type of ICCs.

Download Full-text

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

10.21203/rs.2.22983/v2 ◽

2020 ◽

Author(s):

Bingqi Ma ◽

Huijuan Meng ◽

Ye Tian ◽

Yingying Wang ◽

Tianqiang Song ◽

...

Keyword(s):

Overall Survival ◽

Dna Sequencing ◽

Intrahepatic Cholangiocarcinoma ◽

Disease Free Survival ◽

Serum Total Bilirubin ◽

Isocitrate Dehydrogenase 1 ◽

Small Duct ◽

Preoperative Serum ◽

Disease Free ◽

Expression Loss

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 surviva l (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.

Download Full-text

Keratin 19‐expressing hepatocellular carcinoma and small‐duct type intrahepatic cholangiocarcinoma show a similar postoperative clinical course but have distinct genetic features

Histopathology ◽

10.1111/his.13884 ◽

2019 ◽

Vol 75 (3) ◽

pp. 385-393 ◽

Cited By ~ 2

Author(s):

Masayuki Akita ◽

Tetsuo Ajiki ◽

Takumi Fukumoto ◽

Tomoo Itoh ◽

Yoh Zen

Keyword(s):

Hepatocellular Carcinoma ◽

Intrahepatic Cholangiocarcinoma ◽

Clinical Course ◽

Keratin 19 ◽

Small Duct ◽

Genetic Features

Download Full-text

Pathogenesis and classification of intrahepatic cholangiocarcinoma: different characters of perihilar large duct type versus peripheral small duct type

Journal of Hepato-Biliary-Pancreatic Sciences ◽

10.1002/jhbp.154 ◽

2014 ◽

Vol 22 (2) ◽

pp. 94-100 ◽

Cited By ~ 76

Author(s):

Shinichi Aishima ◽

Yoshinao Oda

Keyword(s):

Intrahepatic Cholangiocarcinoma ◽

Type Versus ◽

Small Duct

Download Full-text

Prognostic implication of inflammation-based prognostic scores in patients with intrahepatic cholangiocarcinoma (iCCA) treated with first-line Gemcitabine plus Cisplatin (GEMCIS)

Annals of Oncology ◽

10.1093/annonc/mdx369.101 ◽

2017 ◽

Vol 28 ◽

pp. v244

Author(s):

H. Cho ◽

C. Yoo ◽

K-P. Kim ◽

H-M. Chang ◽

B-Y. Ryoo

Keyword(s):

Intrahepatic Cholangiocarcinoma ◽

Prognostic Scores ◽

First Line ◽

Prognostic Implication

Download Full-text

Prognostic Value of Inflammatory and Tumour Markers in Small-Duct Subtype Intrahepatic Cholangiocarcinoma after Curative-Intent Resection

Gastroenterology Research and Practice ◽

10.1155/2021/6616062 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Bingqi Ma ◽

Huijuan Meng ◽

An Shen ◽

Yuwen Ma ◽

Dianpeng Zhao ◽

...

Keyword(s):

Intrahepatic Cholangiocarcinoma ◽

Prognostic Value ◽

Cox Regression ◽

Disease Free Survival ◽

Carbohydrate Antigen ◽

Tumour Markers ◽

Histological Subtypes ◽

Curative Intent ◽

Lymphocyte Ratio ◽

Small Duct

Intrahepatic cholangiocarcinoma (ICC) is characterised by heterogeneity, and it can be subdivided into small-duct and large-duct types. Inflammatory and tumour markers could effectively predict prognosis in many cancers, but no similar studies have been conducted in the histological subtypes of ICC. A total of 102 and 72 patients with ICC undergoing curative-intent resection were retrospectively subclassified into large-duct and small-duct types by chemical staining, respectively. The prognostic value of inflammatory and tumour markers was studied for the first time in histological subtypes of ICC by using a Cox regression model. A novel predictor named prognostic inflammatory index (PII) was proposed and defined as neutrophil × monocyte / lymphocyte count (109/L). Survival analysis showed that PII, neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), CA242, and ferritin were all predictors of DFS and OS in patients with ICC ( P < 0.040 ). Subgroup analysis showed that PII, CA19-9, and ferritin were risk predictors of disease-free survival (DFS) and overall survival (OS) in small-duct type ICC ( P < 0.015 ). In addition, in small-duct type ICC, NLR and LMR were correlated with OS ( P < 0.025 ), whilst CEA and CA242 were correlated with DFS ( P ≤ 0.010 ). In conclusion, PII is a convenient and efficient inflammatory predictor of DFS and OS in ICCs and their small-duct type. NLR and LMR, rather than platelet-to-lymphocyte ratio, were correlated with OS in small-duct type ICC. In addition, ferritin may be a supplement to CA19-9 in stratifying the survival outcome of patients with small-duct type ICC.

Download Full-text

Loss of ARID1A induces a stemness gene ALDH1A1 expression with histone acetylation in the malignant subtype of cholangiocarcinoma

Carcinogenesis ◽

10.1093/carcin/bgz179 ◽

2019 ◽

Vol 41 (6) ◽

pp. 734-742 ◽

Cited By ~ 1

Author(s):

Jun Yoshino ◽

Yoshimitsu Akiyama ◽

Shu Shimada ◽

Toshiro Ogura ◽

Kosuke Ogawa ◽

...

Keyword(s):

Prognostic Factor ◽

Intrahepatic Cholangiocarcinoma ◽

Promoter Region ◽

Inverse Correlation ◽

Immunohistochemical Analysis ◽

Independent Prognostic Factor ◽

Histone Deacetylase 1 ◽

Histone H3k27 ◽

Cholangiocarcinoma Cell ◽

Frequent Mutations

Abstract Genomic analyses have recently discovered the malignant subtype of human intrahepatic cholangiocarcinoma (ICC) characterized by frequent mutations of chromatin remodeling gene ARID1A; however, the biological and molecular functions still remain obscure. We here examined the clinical and biological significances of ARID1A deficiency in human ICC. Immunohistochemical analysis demonstrated that the loss of ARID1A was an independent prognostic factor for overall survival of ICC patients (P = 0.023). We established ARID1A-knockout (KO) cells by using the CRISPR/Cas9 system from two human cholangiocarcinoma cell lines. ARID1A-KO cells exhibited significantly enhanced migration, invasion, and sphere formation activity. Microarray analysis revealed that ALDH1A1, a stemness gene, was the most significantly elevated genes in ARID1A-KO cells. In addition, ALDH enzymatic activity as a hallmark of cancer stem cells was markedly high in the KO cells. ARID1A and histone deacetylase 1 were directly recruited to the ALDH1A1 promoter region in cholangiocarcinoma cells with undetectable ALDH1A1 expression by chromatin immunoprecipitation assay. The histone H3K27 acetylation level at the ALDH1A1 promoter region was increased in cells when ARID1A was disrupted (P < 0.01). Clinically, inverse correlation between ARID1A and ALDH1A1 expression was also identified in primary ICC (P = 0.018), and ARID1A-negative and ALDH1A1-positve ICCs showed worse prognosis than only ARID1A-negative cases (P = 0.002). In conclusion, ARID1A may function as a tumor suppressor in ICC through transcriptional downregulation of ALDH1A1 expression with decreasing histone H3K27 acetylation. Our studies provide the basis for the development of new epigenetic approaches to ARID1A-negative ICC. Immunohistochemical loss of ARID1A is an independent prognostic factor in intrahepatic cholangiocarcinoma patients. ARID1A recruits HDAC1 to the promoter region of ALDH1A1, a stemness gene, and epigenetically suppresses ALDH1A1 expression with decreasing histone H3K27 acetylation in cholangiocarcinoma cells.

Download Full-text