Aristolochic Acid Research


Cancer genomics of aristolochic acid induced urinary tract carcinoma

Rosenquist, Sidorenko, Dickman

Image: Pie chartThe TP53 tumor suppressor gene in AA-induced urothelial tumors has an abnormally high rate of A-to-T mutations located primarily on the non-transcribed strand of DNA (Moriya, et al. 2011).  We are now collaborating with Drs. Vogelstein and Kinzler of Johns Hopkins University to sequence the whole exome of DNA obtained from urothelial cancer and matching normal tissue from Taiwanese patients exposed to AA. This study should allow us to establish the genome-wide mutational signature of AA and to identify driver mutations underlying upper urothelial carcinogenesis. Identifying the driver genes in UUC combined with the unique AA-mutation spectrum may yield tools for early detection of this tumor in at risk populations. Also we hope to gain insight into several open questions such as why only a subset of persons exposed to AA develops tumors. Also, although AA-DNA adducts accumulate to high levels in several tissues why do tumors develop only in the upper urinary tract?

  • Springer S, Chen C-H, Grollman A P, Turesky R J, Yun B H, Rosenquist T A, Pu Y-S, Kinzler K W, Vogelstein B, DickmanK G, Netto G J. Non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy. eLife, 2018. PMID29557778
  • Hoang M.L., Chen C.H., Chen P-C., Roberts N.J., Dickman K.G., Yun B.H., Turesky R.J., Pu Y-S., Vogelstein B., Papadopoulos N., Grollman A.P., Kinzler K.W., Rosenquist T.A. Aristolochic Acid in the etiology of renal cell carcinoma. Cancer Epidemiol Biomarkers Prev 113(35):9846-9851, (2016). PMID27555084
  • Hoang M.L., Kinde I., Tomasetti C., McMahon K.W., Rosenquist T.A., Grollman A.P., Kinzler K.W., Vogelstein B., Papadopoulos N. Genome-wide quantification of rare somatic mutations in normal human tissues using massively parallel sequencing. Proc Natl Acad Sci, 2016. PMID27528664
  • Rosenquist T.A., Grollman A.P. Mutational signature of aristolochic acid: Clue to the recognition of a global disease. DNA Repair 44:205-211, 2016. PMID27237586
  • Moriya M., Slade N., Brdar B., Medverec Z., Tomic K., Jelakovic B., Wu L., Truong S., Fernandes A., and Grollman A.P. TP53 mutational signature for aristolochic acid: an environmental carcinogen. Int J Cancer 129:1532-6, 2011.  PMID21413016