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Studies Profile Mutation Patterns in Kidney Cancers Linked to Herbal Compound Use

NEW YORK (GenomeWeb News) – A pair of studies appearing online today in Science Translational Medicine suggest that kidney tumors stemming from exposure to a plant compound once used in Chinese medicine are characterized by both rampant somatic mutation rates and a distinct mutational signature that may help in their detection.

Aristolochic acid, a natural product found in several Aristolochia plant species, has historically been included in traditional medicinal preparations meant to boost weight loss and treat a range of conditions such as arthritis, inflammation, and menstrual symptoms.

Over time, though, epidemiological and other studies have revealed that individuals exposed to the compound — either medicinally or through contaminated food products — were prone to kidney damage and a form of kidney cancer called upper urinary tract urothelial cell carcinoma, or UTUC.

Consequently, herbal preparations containing Aristolochia have been banned for a decade or more in Asia, Europe, and North America, though prescription records in Taiwan suggest nearly a third of that country's population may have taken concoctions containing the compound in the years leading up to such restrictions.

Past research suggests UTUC tumors associated with aristolochic acid tend to harbor mutated forms of TP53 and a slew of adenine to thymine substitutions. Moreover, an aristolochic acid metabolite called aristolactam has been implicated in the formation of adducts that slightly alter DNA's structure.

Even so, there is still relatively little known about the suite of genetic changes associated with aristolochic acid exposure and the kidney cancers it's suspected of causing.

To delve into this in more detail, an international team led by investigators in Singapore, the US, and Taiwan used Illumina's HiSeq 2000 to do whole-genome sequencing on matched tumor-normal samples from a woman with aristolochic acid-associated UTUC.

Using the Illumina GAIIx instrument, they also did exome sequencing on tumor-normal pairs from another eight individuals with the disease and on samples from a human renal cell line that had or had not been exposed to aristolochic acid.

As they reported in one of two related studies out today, members of that group found that the somatic mutation rates in aristolochic acid-associated UTUC tumors exceeded those previously described for smoking-associated lung cancers, UV radiation-induced skin cancers, liver fluke-related forms of bile duct cancer, or gastric cancer tumors attributed to Helicobacter pylori infections.

Along with mutations to TP53, a gene implicated in aristolochic acid-associated UTUC in the past, the team found that tumors linked to the herbal remedy compound contained recurrent changes affecting the histone demethylase gene KDM6A and the ARID1A and SETX genes, which code from chromatin modifiers.

Sequences from all nine aristolochic acid-associated tumors tested were prone to adenine to thymine substitutions, a mutation signature that was especially common on non-transcribed strands of DNA.

Such changes also tended to turn up around splice sites in coding sequences, suggesting aristolochic acid-related mutations may alter the ways that some messenger RNAs are cut and slapped back together after transcription — a pattern that the researchers verified through RNA sequencing.

"Exposures to exogenous carcinogens are known to leave their imprints as mutational patterns in cancer genomes," authors of the study noted. "Characterizing these signatures not only sheds light on the molecular mechanism of carcinogenesis but may also provide a genomic tool to detect the carcinogen's involvement in cancers not previously known to be linked to the carcinogen."

By taking a peek at genome and exome sequence data for almost 100 hepatocellular carcinomas, for instance, researchers picked up an aristolochic acid-like mutation signature in a handful of the hepatocellular carcinoma cases, hinting that the herbal compound could be a culprit in some liver cancers, too.

"Although definitive evidence of [aristolochic acid] exposure in these patients is currently unavailable, these results suggest a potential role for [aristolochic acid] in a subset of [hepatocellular carcinomas]," they noted.

Reporting in the same issue of Science Translational Medicine, a team from the US and Taiwan unearthed the characteristic aristolochic acid-associated adenine to thymine transversion signature in its own exome sequencing analysis of samples from more than two-dozen individuals with UTUC.

Using the Illumina GAIIx instrument, the researchers sequenced protein-coding sequences from matched tumor and normal samples that had been captured with Agilent SureSelect kits. Those samples came from 26 Taiwanese individuals with UTUC, including 19 who'd been exposed to aristolochic acid. The remaining seven individuals had no known aristolochic acid exposures, but did have a history of smoking.

Exome sequence data from those samples again revealed very high rates of somatic mutation in the aristolochic acid-associated tumors, researchers reported, with nearly three-quarters of the single base substitutions in those UTUCs involving adenine to thymine swaps.

Hundreds of genes were mutated in the tumors linked to aristolochic acid use, they noted, making it tricky to pin down the alterations most pertinent to kidney cancer.

Even so, the group saw that the aristolochic acid-associated tumors were prone to mutations involving genes known for roles as tumor suppressors or oncogenes. Chromatin modification genes turned up in that analysis, too, including not only KDM6A but also MLL2 and CRENBBP.

By sifting through the exome sequences with an eye out for the aristolochic acid mutation signature, meanwhile, the researchers determined that at least one of the UTUC cases originally attributed to smoking was likely related to aristolochic acid exposure as well, consistent with the notion that certain mutation patterns may help in linking some cancers to past environmental exposures.

"Genome-wide sequencing has allowed us to tie aristolochic acid exposure directly to an individual getting cancer," the Johns Hopkins Kimmel Cancer Center's Kenneth Kinzler, co-senior author on the study, said in a statement.

"The technology gives us the recognizable mutational signature to say with certainty that a specific toxin is responsible for causing a specific cancer," he said. "Our hope is that using the more targeted whole-exome sequencing process will provide the necessary data to guide public health decisions related to cancer prevention."

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