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Chinese Liver Cancer Atlas Reveals Potential Drivers, Mutational Histories

NEW YORK – New research suggests that at least some of the genomic alterations and mutational signatures found in hepatocellular carcinoma (HCC) cases in China are distinct from those previously described in liver cancer in other populations.

As part of the Chinese Liver Cancer Atlas (CLCA) effort, the researchers did deep whole-genome sequences for nearly 500 HCC tumors, achieving an average of 120-fold genome coverage — work they reported in Nature on Wednesday. The 494 participants considered for the study included individuals with a history of smoking or alcohol use, or with hepatitis B virus (HBV) or hepatitis C virus (HCV) infections.

"Although [the] Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium have analyzed the genomic complexity of HCC at unprecedented scale, whole genome analysis of hepatitis B virus (HBV)-dominated Chinese HCC is limited, which precludes detailed investigations for HCC progression and prevention," co-first and co-corresponding author Lei Chen, a researcher with the National Center for Liver Cancer/Eastern Hepatobiliary Surgery Hospital, said in an email.

Nearly 95 percent of the CLCA samples were marked by HBV infection, compared to just shy of 31 percent in a set of 248 PCAWG-HCC tumors, Chen said, noting that the Chinese cases also tended to be higher grade and were less frequently linked to alcohol use, smoking, or HCV infection.

Together with matched control blood samples sequenced to an average depth of 36-fold and RNA sequencing profiles for 239 of the HCC tumors, the tumor genomes made it possible to find candidate driver mutations, mutational signatures, and mutation events found within or across tumor subclones.

Along with clues to HCC in individuals from China, the team further compared the findings to HCC features previously reported by PCAWG and the Cancer Genome Atlas (TCGA) teams to find common and distinct genomic alterations.

"These findings shed light on the genomic alterations and processes that are enriched in the tumors of Chinese individuals with HCC," the authors reported. Still, they explained, "many potential driver events, including candidate driver genes, mutational processes, and clustered alterations were shared among our CLCA cohort, the PCAWG-HCC, and TCGA-HCC cohort, suggesting universal processes of HCC pathogenesis."

For example, the team's genomic analyses flagged half a dozen new candidate driver genes — FGA, HNF1A, PRDM11, CDKN1B, BMP5, and ECHS1 — and 28 potential drivers falling in noncoding portions of the genome, including TERT promoter, NEAT1 lncRNA, and RMRP lncRNA promoter sites previously found in the PCAWG-HCC cohort.

Along with follow-up assays focused on the fibrinogen alpha chain-coding gene FGA, the researchers relied on clonal and timing analyses to distinguish between chromothripsis, chromoplexy, and kataegis events present across tumors or within specific subclones.

"The identification of subclonal kataegis, chromothripsis, and chromoplexy showed that these catastrophic genomic alterations could occur with variable timing during HCC evolution," the authors reported, "consistent with the reported combined punctuated and gradual clonal evolution in HCC."

When it came to mutational signatures found in the CLCA tumors, meanwhile, the investigators unearthed five previously unappreciated mutational signatures — from aristolochic acid exposure-related indel and doublet base signatures to a single-base substitution signature found in more than 57 percent of CLCA cases but just 0.3 percent of PCAWG-HCC cases.

The authors noted that additional research will be needed to explore interactions between immune and stromal cells in the microenvironment and the tumor alterations they detected and called the CLCA study "a valuable resource that provides important biological insights into HCC carcinogenesis and clinical implications to HCC diagnosis and treatment."