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Studies Explore Genetics Behind Hepatitis B and C Virus-Associated Liver Cancers

NEW YORK (GenomeWeb News) – A pair of studies in the early, online version of Nature Genetics are highlighting the types of genetic mutations that underlie the liver cancer hepatocellular carcinoma, including forms of the disease related to hepatitis B and hepatitis C virus infection.

For the first of these studies, International Cancer Genome Consortium members from RIKEN, Japan's National Cancer Center Research Institute, and other centers in Japan used whole-genome sequencing to track down mutations in HBV-positive, HCV-positive, and non-hepatitis-related hepatocellular carcinoma samples.

Using the Illumina GAII and HiSeq 2000 platforms, the team sequenced 27 liver tumors from 25 patients to an average depth of nearly 40 times. These samples were then compared with genome sequences from matched normal white blood cell samples that had been sequenced to almost 33-fold depth, on average.

Included in the researchers' analysis were 11 HBV-related tumors, 14 HCV-related tumors, and two tumors from individuals who were not infected with HBV or HCV.

Two individuals tested in the study had more than one liver cancer, study authors noted, apparently due to multicentric tumor formation rather than metastases.

"Although no common somatic mutations were identified in the multicentric tumor pairs," they wrote, "their whole-genome substitution patterns were similar, suggesting that these tumors developed from independent mutations, although their shared etiological backgrounds may have strongly influenced their somatic mutation patterns."

In their subsequent analyses, members of the team identified genes that were recurrently affected by somatic mutations or copy number alterations across the entire set of liver cancers. They also explored some of the genetic features associated with the various forms of hepatocellular carcinoma, including breakpoint analysis of the HBV-positive tumors.

The investigators noted that both genes and long, non-coding RNAs with roles in chromatin regulation were frequently mutated in the liver tumors tested. In addition, they saw an over-representation of chromatin regulators amongst the potential driver genes identified in subsequent liver cancer cell line experiments, which involved individually knocking down candidate genes with small interfering RNAs.

Nevertheless, genome sequence, gene expression, and other analyses on the tumors indicated that a wide range of mutations can contribute to virus-related liver cancer — heterogeneity that the authors attributed to potential differences in carcinogen exposure, DNA repair defects, and the cell type in which the tumors originated.

"Considering the high complexity and heterogeneity of [hepatocellular carcinomas] of both etiological and genetic aspects," they concluded, "further molecular classification is required for appropriate diagnosis and therapy in personalized medicine."

In another Nature Genetics study, an international team led by investigators at BGI-Shenzhen and a not-for-profit company called the Asian Cancer Research Group, created by Eli Lilly, Merck, and Pfizer, focused on finding recurrent sites of HBV integration in liver cancer genomes.

"A deep understanding of the recurring HBV insertions in [hepatocellular carcinoma] will help the research community identify novel molecular targets in liver cancer, for which effective treatments are still limited," co-senior author John Luk said in a statement.

Luk, who was affiliated with the National University of Singapore and the University of Hong Kong when the study was performed, is currently head of oncology at the Roche R&D Center in Shanghai.

Luk and his colleagues used the Illumina HiSeq 2000 to do massively parallel sequencing on 81 HBV-positive hepatocellular carcinoma samples from Chinese liver cancer patients, comparing the copy number patterns in the tumors with those in seven HBV-negative liver tumors and in normal liver tissue adjacent to the tumors.

Consistent with HBV's role in liver cancer risk, the researchers found far more viral integration sites in the genomes of the liver cancers than in sequences from nearby normal tissue, with copy number alterations in the tumors often falling at breakpoints introduced by HBV integration.

When they looked at the spots that were most frequently affected by HBV-related changes, the investigators uncovered recurrent integration sites in and around new and known cancer genes, including TERT4, MLL4, CCNE1, SENP5, ROCK1, and FN1.

Moreover, the team reported, HBV integration tended to alter the expression of these genes, hinting that the virus increases chromosomal instability while simultaneously dialing up the activity of oncogenes and/or curbing the expression of tumor suppressors.

Through additional analyses that included microarray profiling, transcriptome sequencing, and Sanger sequencing, the researchers not only verified their initial findings, but also found evidence that HBV integration patterns may provide clues to help predict liver cancer survival.

In particular, their results indicated that elevated numbers of HBV integration sites in tumors corresponded to younger hepatocellular carcinoma onset, larger tumors, higher-than-usual blood marker levels, more aggressive disease, and poorer patient outcomes.