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Liver Cancer Genomes Reveal Extent of Exposure to Mutagenic Herbal Remedy Compounds

NEW YORK (GenomeWeb) – New research is tallying the mutational toll taken by traditional medicines that contain aristolochic acid-producing plants such as Aristolochia or Asarum, focusing on aristolochic acid-related mutational signatures in liver cancer cases from Taiwan and other parts of Asia.

Researchers from Duke-NUS Medical School, the National Cancer Center Singapore, Singapore's Precision Medicine Institute, and elsewhere performed exome sequencing on matched tumor and normal samples from 98 individuals with a form of liver cancer called hepatocellular carcinoma. In a whopping 78 percent of the tumors, they uncovered a so-called AA mutational signature stemming from aristolochic acid and similar compounds.

When the team expanded its analysis to include another 1,400 hepatocellular carcinoma tumors from around the world, it saw over-representation of the AA mutational signature in cases from Asia and Southeast Asia, though it also turned up in a small subset of cases from Europe and North America. The study was published online today in Science Translational Medicine.

Based on the prevalence of the AA-associated signature in the liver cancer cases considered, the authors suggested that exposure to these mutagenic compounds "is geographically widespread."

"Asia, especially Taiwan, appears to be much more extensively affected, which is consistent with other evidence of patterns of AA exposure," they wrote. "We propose that additional measures aimed at primary prevention through avoidance of AA exposure and investigation of possible approaches to secondary prevention are warranted."

Just as mutational signatures can be used to retrace exposure to mutation-causing ultraviolet light or smoking exposures in skin or lung cancers, the team reasoned that identifying AA mutational signatures in liver cancer could offer a window into the use of traditional medicines containing mutagens such as aristolochic acid.

The compounds have been implicated in mutations forming via interactions at purine bases, the authors explained, as well as kidney toxicity and urothelial tract cancers. They noted that remedies containing AA have been banned in Taiwan for well over a decade.

Using the Illumina HiSeq 2500 instrument, the researchers sequenced protein-coding sequences captured with Agilent SureSelect V5 exome panels from matched tumor and normal samples for 98 Taiwanese hepatocellular carcinoma cases. The tumor set contained 26,800 single base mutations and nearly 650 short insertions and deletions detected in the tumors. And by profiling the cases with their mSigAct mutational signature software, the researchers uncovered 76 cases marked by alterations related to AA exposure. Those results were verified through cross-examination with an alternative mutational signature classification strategy.

From there, the team expanded its search for AA mutational signatures using available exome or genome sequences for another 1,400 hepatocellular carcinoma cases from China, Korea, Japan, Vietnam, France, Italy, Spain, and other sites in Southeast Asia and North America.

Compared with the initial set of liver tumors from Taiwan, the team found that the AA mutational signature was less prevalent in this expanded tumor set. Still, it turned up in 47 percent of the 89 hepatocellular carcinomas profiled from China and 29 percent of cases across Southeast Asia.

In the 209 tumors from North America, the researchers reported, 4.8 percent of cases harbored AA-related mutations. But in the 87 North American cases in individuals with documented Asian ancestry, the proportion of hepatocellular carcinoma liver cancers with AA-linked mutations rose to 22 percent. The team also saw the aristolochic acid mutational signature in some 1.7 percent of the 230 hepatocellular carcinomas considered from Europe.

"A higher proportion of [hepatocellular carcinomas] from Taiwan" expresses the AA mutational signature, the authors noted, though "this analysis of publicly available data showed widespread AA exposure in East and Southeast Asia and in self-identified Asians elsewhere."