Yuri Nikiforov, MD, PhD
Vice Chair, Department of Pathology
Director, Molecular & Genomic Pathology
3477 Euler Way
Thyroid cancer genetics; chromosomal rearrangements; radiation-induced carcinogenesis; novel mutations in thyroid cancer; next-generation sequencing; thyroid fine-needle aspiration (FNA)
Dr. Nikiforov's research is focused on thyroid cancer genomics and mechanisms of chromosomal rearrangements and other mutations induced by ionizing radiation in thyroid cells and other cell types. Since 2000, Dr. Nikiforov's research activities have led to four scientific discoveries. These discoveries described below have resulted in more than 120 published papers and form the basis of Dr. Nikiforov's current work.
1.The discovery that genes involved in recurrent chromosomal rearrangements in cancer cells are localized in proximity to each other in the nuclei of normal human cells at the time of exposure to ionizing radiation or other genotoxic stress (Science, 2000, 290:138-141).
2.The discovery that BRAF oncogene can be activated as a result of chromosomal rearrangement (J Clin Invest, 2005,115:94-101).
3.The discovery that in thyroid cancer, chromosomal rearrangements represent the main mutational mechanism in tumors arising as a result of exposure to ionizing radiation, whereas point mutations are a mechanism of spontaneous (chemical) carcinogenesis (J Clin Invest, 2005,115:94-101).
4.The discovery of ALK activation in thyroid cancer as a result of STRN-ALK fusion (PNAS, 2014, 111:4233-8).
Current research activities of Dr. Nikiforov's lab are focused on further understanding the molecular mechanisms of radiation-induced carcinogenesis and chromosomal rearrangements in human cells. Specifically, the studies aim to establish the number of double-strand DNA breaks required for the formation of a chromosomal rearrangement after exposure to ionizing radiation and identify the DNA repair mechanisms involved in this process. The results of this research will allow better understanding of carcinogenesis induced by ionizing radiation and help to develop measures for alleviating and preventing the carcinogenic effect of radiation exposure. Another direction of Dr. Nikiforov's research is centered on finding novel mutations and gene fusions in thyroid cancer using next-generation sequencing and applying the current knowledge in molecular genetics of thyroid cancer to the clinical management of patients with thyroid nodules. Specifically, the studies in progress aim to define the diagnostic utility of molecular markers for preoperative diagnosis of cancer in thyroid fine-needle aspiration (FNA) biopsies and to characterize several novel chromosomal rearrangements discovered in thyroid cancer by next generation sequencing.
- Nikiforova MN, Stringer JR, Blough R, Medvedovic M, Fagin JA, Nikiforov YE. Proximity of chromosomal loci that participate in radiation-induced rearrangements in human cells. Science 2000, 290,138-141 (subject of an editorial by Savage JR. Cancer. Proximity matters. Science 2000, 290:62-63). PubMed Link
- Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA. High prevalence of BRAF mutations in thyroid cancer: Genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 2003, 63:1454-7. PubMed Link
- Ciampi R, Knauf JA, Kerler R, Gandhi M, Zhu Z, Nikiforova MN, Rabes HM, Fagin JA, Nikiforov YE. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J Clin Invest 2005,115: 94-101. (This paper was the subject of a commentary by Fusco A, et al. A new mechanism of BRAF activation in human thyroid papillary carcinomas. J Clin Invest 2005, 115:20-23.) PubMed Link
- Zuo H, Gandhi M, Edreira MM, Hochbaum D, Nimgaonkar VL, Zhang P, Dipaola J, Evdokimova V, Altschuler DL, Nikiforov YE. Downregulation of Rap1GAP through epigenetic silencing and loss of heterozygosity promotes invasion and progression of thyroid tumors. Cancer Res. 2010, 70:1389-97. PubMed Link
- Nikiforov YE, Ohori NP, Hodak SP, Carty SE, Lebeau SO, Ferris RL, Yip L, Seethala RR, Tublin ME, Stang MT, Coyne C, Johnson JT, Stewart AF, Nikiforova MN. Impact of mutational testing on the diagnosis and management of patients with cytologically indeterminate thyroid nodules: A prospective analysis of 1056 FNA samples. J Clin Endocrinol Metab. 2011, 96:3390-7. (This paper received the Endocrine Society's International Award for Publishing Excellence in the Journal of Clinical Endocrinology & Metabolism in 2011.) PubMed Link
- Gandhi M, Evdokimova VN, T Cuenco K, Nikiforova MN, Kelly LM, Stringer JR, Bakkenist CJ, Nikiforov YE. Homologous chromosomes make contact at the sites of double-strand breaks in genes in somatic G0/G1-phase human cells. Proc Natl Acad Sci U S A. 2012, 109:9454-59. PubMed Link
- Nikiforov YE, Nikiforova MN. Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol. 2011, 30:569-80. PubMed Link
- Jung CK, Little MP, Lubin JH, Brenner AV, Wells SA Jr, Sigurdson AJ, Nikiforov YE. The increase in thyroid cancer incidence during the last four decades is accompanied by a high frequency of BRAF mutations and a sharp increase in RAS mutations. J Clin Endocrinol Metab. 2014, 99:E276-85. PubMed Link
- Leeman-Neill RJ, Kelly LM, Liu P, Brenner AV, Little MP, Bogdanova TI, Evdokimova VE, Hatch M, Zurnadzy LY, Nikiforova MN, Yue NJ, Zhang M, Mabuchi K, Tronko MD, Nikiforov YE. ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer. Cancer 2014, 120:799-807. PubMed Link
- Kelly LM, Barila G, Liu P, Evdokimova VN, Trivedi S, Panebianco F, Gandhi M, Carty SE, Hodak SP, Luo J, Dacic S, Yu YP, Nikiforova MN, Ferris RL, Altschuler DL, Nikiforov YE. Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer. Proc Natl Acad Sci USA. 2014 Feb 3. 2014 Mar 18;111(11):4233-8. PubMed Link