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DNA Sequence Analysis Links A Human Carcinogen to a Specific Mutation

Aug 7, 2013 - 2:47:52 PM

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Aristolochia growing in a wheat field
STONY BROOK, N.Y
., August 7, 2013 – Researchers at Stony Brook University and the Johns Hopkins Schools of Medicine have discovered a direct and causal effect of exposure to aristolochic acid (AA) – a   component of Aristolochia, a plant used in herbal remedies since ancient times – in the development of urothelial cancer. Reported online in Science Translational Medicine, “Mutational Signature of Aristolochic Acid Exposure as Revealed by Whole Exome Sequencing,” links a single human carcinogen to a specific mutation through genomic DNA sequencing. The study results could have broad implications on global health, as herbal medicines used traditionally in Asia have contained AA.

Stony Brook researchers, Drs. Arthur Grollman and Thomas Rosenquist, in collaboration with Dr. Kenneth Kinzler, Margaret Huang and their colleagues at the Johns Hopkins School of Medicine, used powerful sequencing methods to make this discovery. Their results revealed the mutational signature of AA and its causal relationship to the development of urothelial carcinoma of the upper urinary tract (UTUC). They point out that this mutational signature guides the development of new biomarkers for AA-induced cancers and demonstrates how genome-wide sequencing can be used to identify environmental exposures leading to cancer.

“Results of our study results not only points to aristolochic acid as being a cause of urothelial cancer, which is an important global health message, but also provides new methods for identifying environmental exposures to aristolochic acid,” said Arthur Grollman, MD, Distinguished Professor of Pharmacological Sciences at Stony Brook.

“The genome sequencing led to uncovering a biomarker of AA-induced disease in patients with UTUC, and the method may be applicable to identifying biomarkers for other specific forms of cancer,” added Thomas Rosenquist, PhD, a geneticist and Research Assistant Professor in the Department of Pharmacological Sciences at Stony Brook University School of Medicine.

Study co-authors Drs. Rosenquist and Kinzler sequenced the one percent of the genome that encodes for proteins, known as the exome, in DNA isolated from upper urothelial tract tumor tissue and non-tumor tissue of Taiwanese patients. One set included patients that were suspected of AA-exposure. A second group included known smokers. By comparing the non-tumor and tumor sequences, the researchers determined mutations unique to the tumors.

“We detected a very strong ‘mutational signature’ in the AA-associated tumors that was not found in the smoking-associated urothelial tumors or even in any of the more than 800 cancer exome sequences previously known,” said Dr. Rosenquist. “This mutational signature is therefore specific to AA-associated tumors and is  can be used as a biomarker to determine the involvement of  AA in Aristolochia-using populations.”

More specifically, Drs. Rosenquist summarized the key aspects of the molecular signature and how AA causes carcinogenic effects leading toward UTUC.
“The most striking aspect of the AA molecular signature is that the normally rare A-to-T mutation is the predominant DNA change in AA tumors. Indeed, we know that the metabolic intermediates of AA forms bulky adducts with deoxyadenosine that lead to A-to-T mutations. Our study shows that in AA-induced cancers, oncogenes and tumor suppressors show this normally rare A-to-T mutation and implicates AA in the initiation and promotion of the tumor.

“The fact that most of the mutated adenines are on the non-transcribed strand suggested a failure to repair the DNA adducts on this strand, accounting for the  persistence of DNA damage and contributing to the very high number of mutations observed in AA-induced cancers,” explained Dr. Rosenquist.

The study involved exome sequencing of tissue from 19 individuals with direct AA exposures  based on the population (151 Taiwanese patients) in a previous study by Dr. Grollman and colleagues, published in PNAS in 2012. In that study, Dr. Grollman and colleagues concluded that exposure to AA is a primary contributor to the incidence of UTUC in Taiwan and, by implication, other Asian countries where the use of Aristolochia herbals is widespread.

Taiwan stands out for having the highest rates of UTUC and chronic kidney disease in the world, and, 10 years ago, approximately one in three adults reported the use of Aristolochia herbs in Taiwan.

Dr. Grollman indicated that the next steps in the research will be to further analyze the signature mutation as a biomarker for UTUC recurrence, as well as develop methods to screen populations at risk of this disease.

Collaborators on the study and other co-authors include: Margaret Hoang, Jian He, Bert Vogelstein, and Nicholaas Papadopoulos of the Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center in Baltimore; Chung-Hsin Chen and Yeong-Shiau Pu of the National Taiwan University Hospital and College of Medicine; Robert J. Turesky of the Division of Environmental Health Sciences, Wadsworth Center, NYS Department of Health; and Noushin Niknafs, Christopher Douville and Rachel Karchin of the Department of Biomedical Engineering, Institute for Computational Medicine, The Johns Hopkins University; and Kathleen Dickman, Victoria Sidorenko, and Masaaki Moriya of the Department of Pharmacological Sciences at Stony Brook.

The research was supported by grants from the National Institutes of Health, The Virginia and D.K. Ludwig Fund for Cancer Research, the Commonwealth Foundation, Taiwan National Science Council, the Department of Health in Taiwan, Henry and Marsha Laufer and the Zickler Family Foundation.

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© Stony Brook University 2013

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