RESEARCH INTERESTS:
The overall goal of my laboratory is to understand the genetic basis of inherited susceptibility to cancer. At a basic level, we are interested in studying genes that normally control genomic stability and when disrupted lead to the instability seen in cancer cells including chromosome losses and gains or aneuploidy. These control mechanisms are conserved among all eukaryotes from yeast to man and mutations in checkpoint genes have been found in a large percentage of human tumors and in individuals with a predisposition to specific cancers.

Our basic science work has focused on the analysis of DNA damage checkpoint pathways in the budding yeast, S. cerevisiae. We have shown that there is an alternative checkpoint pathway that functions when proteins that regulate chromatin structure are disrupted. This unexpected finding suggests that there is a direct link between chromatin structure and the response to DNA damage, which we are exploring further.

As a novel approach to model variation in genomic instability in humans, we have performed genetic screens in diploid yeast strains to identify more subtle mutations which modify chromosome loss rates. These mutations are based on monitoring changes in chromosome loss rates in yeast that are heterozygous (mutant for only one copy) of each gene. We are developing novel statistical tools to analyze this data in collaboration with Marek Kimmel in the Department of Statistics at Rice University. Genes identified in this screen will be incorporated into epidemiologic studies of human cancer susceptibility. We are now using high throughput methods to screen a variety of strain backgrounds for their impact on spontaneous chromosome loss or mitotic recombination.

On a more translational level, we have carried out analyses of a variety of autosomal recessive cancer predisposition syndromes. Rothmund-Thomson Syndrome (RTS) is associated with a high incidence of osteosarcoma. We have determined that RTS patients who develop osteosarcoma carry deleterious mutations in the RECQL4 gene and we have identified that certain disease causing mutations are associated with mislocalization of the RECQL4 protein. Fanconi anemia is associated with bone marrow failure and cancer predisposition. We have found that cells from FA patients have abnormal mitochondria and are sensitive to oxidative stress due to dysfunction of mitochondrial peroxidase.

Most recently, we have initiated a project in collaboration with the Human Genome Sequence Center to develop a large scale parallel sequencing pipeline to identify the causative mutation or chromosome imbalance in families with unusual patterns of childhood cancer.

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SELECTED PUBLICATIONS:
1. Poland KD, Azim M, Folsom M, Goldfarb R, Naeem R, Korch C, Drabkin HA, Gemmill RM, Plon SE (2007). Constitutional Balanced t(3;8)(p14;q24.1) Translocation Results in Disruption of the TRC8 Gene and Predisposition to Clear Cell Renal Cell Carcinoma. Genes, Chromosome, Cancer, in press. [Epub ahead of print]

2. Burks LH, Yin J, Plon SE (2007). Nuclear import and retention domains in the amino terminus of RECQL4. Gene 391: 26-38.

3. Mukhopadhyay SE, Leung KS, Hicks MJ, Hastings PJ, Youssoufian H, Plon SE (2006). Defective mitochondrial peroxiredoxin 3 results in sensitivity to oxidative stress in Fanconi anemia. J. Cell Biol. 175: 225-235.

4. Hegde MR, Chong B, Blazo ME, Chin LHE, Ward PA, Chintagumpala MM, Kim JY, Plon SE, Richards CS (2005). A homozygous mutation in MSH6 causes Turcot Syndrome. Clin. Cancer Res. 11: 4689-4693

5. Scott KL, Plon SE (2005). CHES1/FOXN3 interacts with Ski-interacting protein and acts as a transcriptional repressor. Gene 359: 119-126.

6. Mendoza-Londono R, Kashork CD, Shaffer LG, Krance R, Plon SE (2005). Acute lymphoblastic leukemia in a patient with Greig cephalopolysyndactyly and interstitial deletion of chromosome 7 del (7)(p11.2 p14) involving the GLI3 and ZNF1A1 genes. Genes Chromosome Cancer 42: 82-86.

7. Blazo MA, Lewis RA, Chintagumpala MM, Frazier M, McCluggage C, Plon SE (2004). Outcomes of Systematic Screening for Optic Pathway Tumors in Children with Neurofibromatosis Type I. Am. J. Med. Genet. 127: 224-229.

8. Scott KL, Plon SE (2003). Loss of Sin3/Rpd3 Histone Deacetylase Restores the DNA Damage Response in Checkpoint-Deficient Strains of S. Cerevisiae. Mol. Cell. Biol. 23: 4522-4531.

9. Wang LL, Gannavarapu A, Kozinetz CA, Levy ML, Lewis RA, Chintagumpala MM, Plon SE (2003). Osteosarcoma in Rothmund-Thomson Syndrome is Associated with Truncating Mutations in RECQL4. J. Natl. Cancer Inst. 95: 669-674.

For more publications, see listing on Pub Med.

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CLINICAL INFORMATION:
Board Certifications:
American Board Medical Genetics

Primary Focus:
Cancer Genetics Syndromes, Breast Ovarian Cancer Susceptibility, von Hippel Lindau Syndrome, Neurofibromatosis, Retinoblastoma & Familial Adenomatous Polyposis

Professional Organizations:
Member, American Society Human Genetics
Member, American College Medical Genetics
Member, American Association Cancer Research

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CONTACT INFORMATION:
Sharon E. Plon, M.D., Ph.D.
Texas Children's Cancer Center
Feigin Center, Suite 830.20
6621 Fannin St. Mail Stop 3-3320
Houston, Texas 77030, U.S.A.

Kleberg Genetics Center
NEUROFIBROMATOSIS CLINIC
Texas Children's Hospital
6621 Fannin St. - Mail Stop 3-3370
Houston, Texas 77030, U.S.A.

Telephone: 832-824-4251 (Academic Office)
Fax: 832-825-4276
E-mail:

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