NIKIFOROV LABORATORY
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Research Projects

1. Studies of Molecular Alterations in Thyroid Cancer:
           
         
Since 2001, we have studied mover than 1,000 thyroid tumor samples to detect the prevalence of known genetic alterations in thyroid
cancer (such as RAS point mutations, RET/PTC rearrangements, BRAF point mutations, PAX8-PPAR gamma rearrangement) and to identify novel
genetic alterations in thyroid tumors. As part of this study, we have identified and functionally characterized two novel chromosomal rearrangements,
AKAP9/BRAF and HOOK3/RET, and identified the loss of RAP1GAP function in thyroid tumors due to LOH and promoter hypermethylation .This
will
improve our understanding of the molecular mechanisms of thyroid cancer and help to set up diagnostic methods for thyroid tumors.

2. Molecular Profiles of Thyroid Cancer in the U.S. from 1973-2008:
          The reasons for the sharp increase in thyroid cancer incidence remain unknown. In collaboration with Dr. Elaine Ron from NIH and other
investigators, we launch a study to determine the changes in the mutational profile of thyroid cancer in the U.S. for the last 30 years. We will test
tumors from different decades for RET/PTC rearrangement (frequently associated with radiation exposure), BRAF mutation (chemical carcinogensis,
possible high iodine intake), and RAS mutations. This multi-institutional study led by our laboratory will help to understand the reasons for the
increased incidence of thyroid cancer in the U.S.

3. Role of Nuclear Architecture in Generation of Chromosomal Rearrangements: 
         
We have previously demonstrated the existence of spatial proximity between the genes involved in RET/PTC rearrangement in the interphase
nuclei of normal thyroid cells, which is likely to predispose to the generation of RET/PTF rearrangement after exposure to ionizing radiation and to other
genotoxic agents. We continue this direction to understand why specific chromosomal loci are non-randomly located with respect to each other. We
hypothesized that this is due to high-order chromatin folding that exists during the interphase and we work on demonstrating it using various approaches
including FISH, EM, immunofluorescence, and others.

4. Generation of RET/PTC Rearrangement after Radiation Exposure: 
          
We have recently established an in-vitro model of the generation of RET/PTC rearrangements after exposure to ionizing radiation in
human HT Ori-3 cells. This is a unique model of carcinogenic chromosomal rearrangement induced by ionizing radiation in human cells in a
dose-dependent manner. We use this model to understand the mechanisms of chromosomal rearrangements after radiation exposure and
to identify the genes that predispose individuals to radiation-induced thyroid cancer. Specifically, we aim to understand how many DNA breaks
are needed to generate the rearrangement and what DNA repair mechanism is involved in the function.

5. Development of Molecular Test for Thyroid Fine Needle Aspirations (FNA) Specimens:
          
The preoperative diagnosis of thyroid cancer relies on the cytologic evaluation of fine-needle aspiration (FNA) samples. However,
the diagnostic accuracy of FNA using routine cytological examination is limited, especially in the diagnosis of follicular neoplasms. We
have developed a molecules test based on detection of mutations to improve the preoperative diagnosis of thyroid cancer in thyroid FNA samples,
which has been introduced into routine clinical practice at UPMC. Currently, in collaboration with Dr. Marina Nikiforova, we work on improving
the current test by adding a number of miRNA markers.


6. SNP Array Analysis of Thyroid Cancer:
 
          
We use SNP array to identify and characterize chromosome region losses and gains in thyroid cancer. This project is expected to allow us to
identify new genes important for thyroid carcinogenesis. We will focus particularly on the follicular variant of papillary carcinoma, which frequently
imposes diagnostic difficulty and is poorly characterized from the molecular stand point.


7. Role of Fragile Sites in Regeneration of Chromosomal Rearrangements:
 
          
In collaboration with Dr. Yuh-Hwa Wang from Wake Forest University, we conduct a research program to understand the role of fragile
DNA sites in the generation of chromosomal rearrangement. This project is expected to elucidate the mechanisms of RET/P5C rearrangement in human
cells not exposed to ionizing radiation.

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