Comprehensive Molecular Profiling of Intrahepatic and Extrahepatic Cholangiocarcinomas: Potential Targets for Intervention

Abstract

Various genetic driver aberrations have been identified among distinct anatomic and clinical subtypes of intrahepatic and extrahepatic cholangiocarcinoma, and these molecular alterations may be prognostic biomarkers and/or predictive of drug response. Tumor samples from patients with cholangiocarcinoma who consented prospectively were analyzed using the MSK-IMPACT platform, a targeted next-generation sequencing assay that analyzes all exons and selected introns of 410 cancer-associated genes. Fisher exact tests were performed to identify associations between clinical characteristics and genetic alterations. A total of 195 patients were studied: 78% intrahepatic and 22% extrahepatic cholangiocarcinoma. The most commonly altered genes in intrahepatic cholangiocarcinoma were (30%), (23%), (20%), (20%), and gene fusions (14%). A tendency toward mutual exclusivity was seen between multiple genes in intrahepatic cholangiocarcinoma including, and Alterations in CDKN2A/B and ERBB2 were associated with reduced survival and time to progression on chemotherapy in patients with locally advanced or metastatic disease. Genetic alterations with potential therapeutic implications were identified in 47% of patients, leading to biomarker-directed therapy or clinical trial enrollment in 16% of patients. Cholangiocarcinoma is a genetically diverse cancer. Alterations in and are associated with negative prognostic implications in patients with advanced disease. Somatic alterations with therapeutic implications were identified in almost half of patients. These prospective data provide a contemporary benchmark for guiding the development of targeted therapies in molecularly profiled cholangiocarcinoma, and support to the use of molecular profiling to guide therapy selection in patients with advanced biliary cancers. .

Comprehensive genomic profile of cholangiocarcinomas in China

“…Several studies have identified the different GAs in iCCA and exCCA. The most common mutations in iCCA were found to be IDH1/2, BAP1, KRAS, TP53, SMAD4 and ARID1A, whereas common mutations in exCCA were identified in KRAS, TP53, SMAD4, SKT11, ERBB2, PTEN, ATM and NF1 (10,44). TP53 may play a key role in enabling hepatocyte-derived iCCA (30,18), and KRAS mutations in the absence of TP53 mutations can drive exCCA (41,45).…”

“…Jiao et al (29) discovered frequent inactivating mutations of BAP1, ARID1A and PBRM1, with a high mutation rate in the sequenced tumor. Recently, Lowery et al (10) reported the genome profiling of patients with CCA, including 152 iCCA and 43 exCCA cases, from Caucasian (89.2%, 174/195), Asian (7.1%, 14/195), and African American (3.6%, 7/195) patients, and found that the most common mutations were IDH1, TP53, ARID1A, BAP1, KRAS, PBKM1, SMAD4 and ATM. In the present study, common high frequency mutations (>10%) of TP53, KRAS, SMAD4, TERT, ARID1A and CDKN2A were The top bar graph shows the gene mutation frequency of each sample, the percentages on the left represents the mutation frequency of each mutated gene, and the bar graph on the right shows the number of each mutated gene.…”

“…Moreover, KRAS mutations and the MAP/ERK pathway were significantly associated with progression-free survival (PFS) in iCCA, whereas BAP1 mutations and aberrations in the fibroblast growth factor (FGF) pathway were significantly correlated with PFS in exCCA (9). Based on the comprehensive molecular profiling of 194 patients with CCA, including Caucasian, Asian and African American patients, Lowery et al (10) demonstrated that almost 50% of the patients were accompanied by therapeutic somatic alterations. These studies indicate that molecular profiling can facilitate biomarker-based clinical trials in patients with CCA.…”

Anatomical, histomorphological and molecular classification of cholangiocarcinoma

“…Additionally, BAP1 mutations were found to be restricted to iCCA in some studies and BAP1 and IDH mutations were also found in HCC, suggesting an overlap of iCCA, cHCC-CCAs and HCC respectively a common cell-of-origin for at least some of these mass-forming, small-duct type iCCAs. 97,100,101 As cHCC-CCAs represent a separated tumour type, according to the current WHO classification, and mostly vary in their molecular profile significantly to iCCA, this will not be further discussed in this review. 30 Furthermore, TP53 mutations may be used as a surrogate marker for malignancy (eg by immunohistochemistry to discriminate untypical bile duct adenomas (BDA) from iCCA).…”

DGAT-onco: A powerful method to detect oncogenes by integrating differential mutational analysis and functional impacts of somatic mutations

“…The cancer data was selected by the following criteria: 1) This cancer type is included in the TCGA dataset; 2) The sample size is the largest of its cancer type; and 3) Its source is not from the TCGA. Finally, we obtained a total of 445,249 mutations from 19 cancer types (Armenia, et al, 2018;Bailey, et al, 2016;Dulak, et al, 2013;Imielinski, et al, 2012;Johansson, et al, 2016;Johnson, et al, 2014;Jones, et al, 2014;Kim, et al, 2015;Krauthammer, et al, 2012;Lowery, et al, 2018;Pereira, et al, 2016;Reddy, et al, 2017;Sato, et al, 2013;Schulze, et al, 2015;Soumerai, et al, 2018;Stransky, et al, 2011;Tyner, et al, 2018;Vasaikar, et al, 2019;Wang, et al, 2014), namely TS19 dataset.…”