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Liver Cancer Genomes Reveal Mutational Signatures Associated With Alcohol, Other Factors

NEW YORK (GenomeWeb) – A French research team has outlined mutational signatures associated with alcohol use and other environmental exposures in liver cancer using a large tumor genome collection.

The researchers tapped into more than 250 available liver cancer genome sequences — analyzed alongside dozens of new liver cancer genomes — for a study published online today in Nature Communications. From these data, they teased out 16 signatures with apparent ties to environmental exposures, including 10 mutational signatures and six signatures marked by specific structural rearrangements.

Along with signatures already described in other cancer types, the team noted that the so-called signature 16 profile appeared to be specific to liver cancer. That signature, which was characterized by enhanced mutation to the CTNNB1 gene and transcription-coupled damage, was particularly common in tumors from men with liver cancer and/or in individuals with a history of alcohol or tobacco use.

Senior author Jessica Zucman-Rossi, a researcher affiliated with INSERM, Paris Descartes University, and other centers, and her colleagues wrote that based on their results, "signature 16 is the real hallmark of liver cancers, operative in every tumor and accounting on average for 40 percent of all somatic mutations." They further noted that they found "a strong increase of this signature independently associated with male gender, alcohol and tobacco consumption," and that a similar signature was linked to alcohol use in a recent study of esophageal squamous cell carcinoma.

At least one form of liver cancer, hepatocellular carcinoma, is known to be more common in men, the team added. And several environmental risk factors — ranging from alcohol or aristolochic acid use to viral infection — have been implicated in hepatocellular carcinoma.

To explore the mutational processes and exposures contributing to liver cancer in more detail, members of the team at the National Genotyping Center in France and Integragen used paired-end sequencing on Illumina Genome Analyzer, HiSeq 2000, or HiSeq 2500 instruments to sequence 14 and 30 matched tumor and normal pairs, respectively.

Nearly three dozen of the tumors from the newly sequenced set were classified as hepatocellular carcinoma, the researchers noted, including cases corresponding with hepatitis C or hepatitis B virus infection, alcohol abuse, metabolic conditions, or other potential contributors.

Using the sequence set, the team tracked down thousands of single nucleotide changes, more than 750 small insertions and deletions, and dozens of structural variants per tumor, on average, along with insertions stemming from hepatitis B virus infections.

Adding in genome sequence data for 264 hepatocellular carcinoma tumors from individuals in Japan sequenced for the International Cancer Genome Consortium, the researchers began teasing out mutational signatures found in this form of liver cancer.

They saw signs that certain mutational or structural rearrangement signatures appeared to be limited to a small subset of the tumors, appearing in 5 percent or fewer cases considered. Other signatures — including signature 16, signature 4 (previously linked to tobacco exposure in cancers of the lung or larynx), or age-related signatures 1 and 5 — turned up in almost all of the hepatocellular carcinomas.

The analysis offered insights into some of the known mutational signatures. For example, the team identified almost 1,400 signature 4 mutations, on average, in liver cancer genomes from individuals with a history of smoking. But more than 1,000 signature 4 mutations were found in tumors from non-smokers as well, suggesting environmental exposures beyond tobacco use might contribute to that signature.

The researchers also got a look at liver cancer-specific signatures such as signature 16, which they analyzed in hundreds more tumors profiled by exome sequencing for the Cancer Genome Atlas project or for a hepatocellular carcinoma study that Zucman-Rossi and her colleagues published in Nature Genetics in 2015.

By digging into signature 16 and other signatures, the researchers got a look at some of the processes that can go awry en route to cancer. They also used their sequence data to track the evolution and expansion of specific tumor signatures in the liver cancers over the course of cancer development and tumorigenesis.