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Whole-Genome Sequencing Reveals Mutation Signature in Aristolochic Acid–Associated Upper Urinary Tract Cancer

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Key Points

  • Using whole-exome sequencing, researchers found an average of 753 mutations in each tumor from patients with upper urinary tract cancers who were exposed to aristolochic acid compared with 91 in tumors from patients in the nonexposed group.
  • Members of the toxin-exposed group had a large number of a particular, rare type of mutational signature in the ATCG chemical code of their DNA.

Genomic sequencing experts at Johns Hopkins partnered with pharmacologists at Stony Brook University to reveal a striking mutational signature of upper urinary tract cancers caused by aristolochic acid, a plant compound contained in herbal remedies used for thousands of years to treat a variety of ailments such as arthritis, gout, and inflammation. The findings were published in the August 7 issue of Science Translational Medicine.

Aristolochic acid is found in the plant family Aristolochia, a vine known widely as birthwort. Although the U.S. Food and Drug Administration first warned of its cancer-causing potential in 2001, botanical products and herbal remedies containing it can still be purchased online. Moreover, the vine has been found to be an environmental carcinogen through the contamination of food supplies of farming villages in the Balkans, where Aristolochia grows wildly in the local wheat fields. For years, scientists have known of some mutations in upper urinary tract cancer patients exposed to the plant toxin, but the genome-wide spectrum of mutations associated with aristolochic acid exposure remained largely unknown.

Study Details

For the current study, the Johns Hopkins and Stony Brook team used whole-exome sequencing on 19 Taiwanese patients with upper urinary tract cancer who were exposed to aristolochic acid, and seven patients with no suspected exposure to the toxin. The technique scours the exome, part of the human genome that contains codes for functional proteins, and can reveal particular mutations—in this case, those associated with cancer.

"Genome-wide sequencing has allowed us to tie aristolochic acid exposure directly to an individual getting cancer," said Kenneth Kinzler, PhD, Professor of Oncology in the Johns Hopkins Kimmel Cancer Center's Ludwig Center for Cancer Genetics and Therapeutics. "The technology gives us the recognizable mutational signature to say with certainty that a specific toxin is responsible for causing a specific cancer. 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."

High Level of Mutations in Toxin-Exposed Group

Specifically, Dr.Kinzler said they found an average of 753 mutations in each tumor from the toxin-exposed group compared with 91 in tumors from the nonexposed group. This level of mutation is more than that found in melanomas caused by ultraviolet radiation and lung cancer caused by smoking.

Members of the toxin-exposed group had a large number of a particular, rare type of mutational signature in the ATCG chemical code of their DNA. The predominant mutation type in the toxin-exposed tumors (72%) was an A substituted with a T. In one instance, the scientists used the mutational signature to uncover an artistolochic-related tumor in a patient who was unaware of prior exposure.

This study illustrates how genomic sequencing could also be used to pinpoint a culprit carcinogen in some cancer clusters, said Margaret L. Hoang, PhD, lead author of the study. Cancer clusters are defined as an unusually large number of similar cancers occurring within a specific group of people, geographic area, or period of time.

The research was funded by the Virginia and DK Ludwig Fund for Cancer Research, the Commonwealth Foundation and the Howard Hughes Medical Institute.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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