Molecular profiles suggest two types of liver cancer should be treated as one


CT scan showing liver tumors in a patient with hepatocellular carcinoma (HCC)

A comprehensive molecular analysis of two types of liver cancer, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), has identified common molecular subtypes that can be found among patients with either disease. Although HCC and ICC are considered separate diseases, the finding suggests that a unified clinical approach could benefit patients with both types of liver cancer.

Worldwide, liver cancer is the second-leading cause of cancer death, the first of which is lung cancer. What’s more, says Xin Wei Wang, Ph.D., Deputy Chief of CCR’s Laboratory of Human Carcinogenesis, “it is the only cancer type to continuously show increased incidence and mortality in the United States for more than two decades. And it keeps increasing.”

About 80 percent of liver cancers diagnosed in the United States are HCC, which originates from the liver’s primary cells, hepatocytes. ICC, which develops from cholangiocytes (cells that line bile ducts), is much less common. “It’s thought that these are two different tumor types and two different diseases,” Wang says. “They have different clinical guidelines, and different drugs are recommended for treatment.”

Treatment options are limited for both diseases, however, and the prognosis for patients with liver cancer is generally poor. There is an urgent need for new therapies, particularly in Thailand, where liver cancer is a primary cause of cancer-related mortality in men, says Mathuros Ruchirawat, Ph.D., Vice President of the Chulabhorn Research Institute in Bangkok.

To better understand the disease, Wang and other CCR scientists have been collaborating with researchers and clinical centers in Thailand. Through the Thailand Initiative for Genomics and Expression Research in Liver Cancer (TIGER-LC), the consortium is collecting tissue samples and clinical data from individuals with and without liver cancer to create a comprehensive biorespository for study. The consortium consists of researchers and clinicians from five cancer hospitals in Thailand and plans to enroll 6,000 people in order to identify biomarkers and genomic risk factors linked to early onset of HCC and ICC. Unlike in the rest of the world, the most common form of liver cancer in northeastern Thailand is ICC, so the consortium has created a unique opportunity to investigate similarities and differences between that disease and HCC.

In research reported June 22, 2017, in the journal Cancer Cell, Wang and his colleagues, including researchers at the Chulabhorn Research Institute led by Her Royal Highness Princess Chulabhorn Mahidol of Thailand, Ph.D., and Ruchirawat analyzed the genetic sequences, gene activity and metabolic profiles of 199 tumor samples from patients in Thailand, including both HCCs and ICCs. CCR visiting fellow Jittiporn Chaisaingmongkol, Ph.D., who is now at the Chulabhorn Institute, is first author of the paper and had a leading role in the analysis.

The team used the data to identify subtypes of each disease with common molecular features. Surprisingly, Wang says, the molecular features that defined certain subsets of ICCs closely resembled subsets of HCC.

“Those subtypes not only have very similar gene expression matrices and similar tumor biology, they also have similar clinical outcomes,” Wang says. The team examined additional tumor samples and found that several of the subtypes they had identified in the original analysis were represented among patients of all ethnicities, but some occurred only among Asians.

Finally, the team investigated whether any of the molecular subtypes they identified were associated with possible risk factors for liver cancer. Liver fluke infections are prevalent in Thailand, and researchers have suspected they might contribute to the unusually high rates of ICC in that country, whereas hepatitis B and C infections and alcohol consumption are considered risk factors for HCC. None of these factors, however, were linked to any liver cancer subtype uncovered by the team.

Recognizing the molecular nature of liver cancer’s overlapping subtypes could help researchers more effectively treat liver cancers, regardless of whether a patient has been diagnosed with HCC or ICC. In the near term, Wang says, the findings will help researchers identify patients with particularly aggressive liver cancers and recommend appropriate treatments. Additionally, genetic mutations that the team has identified as possible drivers of specific subtypes will point researchers toward strategies for drug development.

Summary Posted: 06/2017