Genomic Profiling of Combined Hepatocellular Carcinoma and Cholangiocarcinoma

December 2021, Vol 2, No 4

The combination of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) is a rare primary liver malignancy known as combined HCC and CCA (cHCC-CCA). The morphologic features of cHCC-CCA pose challenges for evidence-guided management.

“The two most frequent forms of primary liver carcinomas (HCC and CCA) are ontologically, morphologically, and clinically distinct. However, as evoked by its name, cHCC-CCA is a poorly understood, aggressive rare primary liver cancer that exhibits morphologic characteristics of both HCC and CCA,” Karthikeyan Murugesan, MS, of Foundation Medicine, and colleagues noted in a recent study.1 “As such, cHCC-CCA is an extremely challenging disease regarding both diagnosis and management.”

For the study, Ms Murugesan and colleagues used comprehensive genomic profiling in a large series of patients with HCC, CCA, or cHCC-CCA as part of routine clinical care to identify genomic alterations enriched in HCC and CCA. Based on their findings, they built a machine-learning model to classify cHCC-CCA as HCC-like or CCA-like, by integrating genomic-derived data.

They analyzed the genomic profiles of 73 patients with cHCC-CCA, 4975 with CCA, and 1470 patients with HCC, all generated from a targeted exome next-generation sequencing assay used in the course of clinical care. The cases were reviewed for genomic alterations, tumor mutational burden, microsatellite instability status, genomic loss of heterozygosity, chromosomal aneuploidy, genomic ancestry, and hepatitis B virus (HBV) infection.

Among the cHCC-CCA cases, the researchers observed a median of 4 genomic alterations per tumor. Frequently altered genes in this cohort were TP53 (65.8%), TERT (49.3%), and PTEN (9.6%), and 24.6% of cHCC-CCA cases harbored potentially targetable genomic alterations. Other genomic alterations predominantly associated with CCA and with HCC include, but are not limited to, TERT, FGFR2, IDH1, and the presence of HBV infection.

Based on these features, a machine-learning model was trained to classify a cHCC-CCA case as CCA-like or as HCC-like. In total, 16.4% (12/73) of the cHCC-CCA cases were classified as CCA-like, 57.5% (42/73) cases as HCC-like, and the remaining 26.3% (19/73) of cases were classified as ambiguous. In addition, the model accurately classified more than 70% of cHCC-CCA cases as CCA-like or HCC-like using only genomic features.

“The concept of cHCC-CCA itself should continue to be critically evaluated as to what the implications are for etiology of CCA-like and HCC-like cHCC-CCA,” the investigators concluded. “The genomic testing platform combined with the ML [machine learning]-classifier developed here allow for easy classification of cHCC-CCA in the course of clinical care by use of a clinically validated test. However, further investigation is needed to identify the clinical impact of these findings.”


  1. Murugesan K, Sharaf R, Montesion M, et al. Genomic profiling of combined hepatocellular cholangiocarcinoma reveals genomics similar to either hepatocellular carcinoma or cholangiocarcinoma. JCO Precis Oncol. 2021;5:1285-1296.

Related Items

Optimization of Diagnosis and Biomarker Testing in Intrahepatic Cholangiocarcinoma
June/July 2022, Vol 3, No 2
Barriers exist to the adoption of precision medicine, requiring consideration of best practices and current gaps in standard practices, a recent review article suggests.
Pertuzumab plus Trastuzumab a Promising Combination in Patients with HER2-Positive Metastatic Biliary Tract Cancer
December 2021, Vol 2, No 4
The HER2-targeted therapies pertuzumab and trastuzumab have improved patient outcomes in several cancer types.
Genomic Sequencing Study Reveals Precancerous Changes Involved in the Development of Gallbladder Cancer
December 2021, Vol 2, No 4
The overall survival of gallbladder carcinoma (GBC), the most common cancer of the biliary tract, is poor, largely because of delayed diagnosis.
Important Role of Screening for Genomic Alterations in Cholangiocarcinoma
September/October 2021, Vol 2, No 3
Comprehensive molecular profiling has demonstrated a diverse landscape of oncogenic genomic alterations in cholangiocarcinoma (CCA), which are often the drivers of CCA. In a recent review article, Tanios S. Bekaii-Saab, MD, FACP, Vice Chair and Section Chief for Medical Oncology, Department of Internal Medicine, Mayo Clinic Cancer Center, Phoenix, AZ, and colleagues provided an overview of the molecular heterogeneity of CCA, discussing the role of molecular tests for the diagnosis of patients with intrahepatic CCA, and the implications of the genomic alterations in the treatment of patients with this aggressive disease.
National Survey Pinpoints Reasons Oncologists Do Not Order Molecular Testing
September/October 2021, Vol 2, No 3
Multimarker tumor panel testing is beneficial in helping to inform treatment choice in precision oncology. However, little is known about the clinic-based and organizational factors related to multimarker tumor panel testing, and why oncologists may not choose this testing.
Role of Intraductal Treatment and Endoscopic Oncologists in the Management of Unresectable Extrahepatic Cholangiocarcinoma
September/October 2021, Vol 2, No 3
Although cholangiocarcinoma (CCA) is a rare cancer that originates in the bile ducts, its incidence rate continues to rise in the United States, and many patients are diagnosed late, with unresectable tumor and poor prognosis. The majority of patients with extrahepatic CCA, including the perihilar subtype, require referral to a center with expertise in endoscopic retrograde cholangiopancreatography (ERCP) and interventional radiology, because of the complexities in obtaining a definitive diagnosis and durable biliary drainage.

Subscribe Today!

To sign up for our newsletter or print publications, please enter your contact information below.

I'd like to receive: