A new study identified biomarkers based on methylation sites for the diagnosis of primary liver cancer (PLC). The biomarkers are also able to differentiate between hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), the two most common subtypes of PLC.

The study was published in the journal Aging. Yi Bai from Nankai University, Tianjin, China, and co-authors wrote that “distinguishing HCC from ICC plays a vital role in subsequent treatment options selection.” The treatment methods for HCC and for ICC are completely different.

The researchers first compared the methylation data between normal liver samples and samples of PLC including HCC and ICC to identify differentially methylated CpG sites. They then used three PLC-specific methylation sites (cg24035245, cg21072795, and cg00261162) to develop a model to diagnose PLC. If the diagnosis of PLC was considered, they used three other methylation sites (cg17769836, cg17591574, and cg07823562) to distinguish between HCC and ICC.

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Hepatic arteries of a liver with metastases.
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Learn more about cholangiocarcinoma diagnosis.

In HCC, the enrichment pathways were mainly related to biological processes such as protein folding, oxidative stress, and glutathione metabolism. In ICC, on the other hand, top pathways were related to immune response and embryonic hepatocyte maturation.

Importantly, the methylator phenotype correlated well with patients’ overall survival time and clinical factors involved in tumor progression.

The researchers also identified pathways related to DNA methylation-driven genes in HCC and ICC and performed methylator phenotype based on independent prognostic sites.

“Our study provides the biomarkers based on methylation sites not only for the diagnosis of PLC but also for distinguishing HCC from ICC,” the authors concluded.

PLC is the sixth most common type of cancer and the fourth leading cause of death from cancer. Factors that increase the risk of PLC include hepatitis virus infection, excessive alcohol consumption, autoimmune diseases, and aflatoxin. 


Bai Y, Tong W, Xie F, et al. DNA methylation biomarkers for diagnosis of primary liver cancer and distinguishing hepatocellular carcinoma from intrahepatic cholangiocarcinoma. Aging (Albany NY). Published online July 8, 2021. doi:10.18632/aging.203249