ZIA CP010144 - 10567 (ZIA) | |||
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Title | Clinical and Genetic Studies of Neurofibromatosis Type 1 | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Stewart, Douglas | NCI Program Director | N/A |
Cancer Activity | N/A | Division | DCEG |
Funded Amount | $118,220 | Project Dates | 01/30/2010 - 00/00/0000 |
Fiscal Year | 2014 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Biochemical Epidemiology (45.0%) Cancer (100.0%) Neurofibromatosis (100.0%) |
Brain (50.0%) Sarcoma (50.0%) |
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Research Type | |||
Endogenous Factors in the Origin and Cause of Cancer Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors |
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Abstract | |||
Neurofibromatosis type 1 (NF1) is a common genetic disorder of dysregulated cell growth. People with NF1 also develop malignant cancers. Analyses of our cohort have yielded multiple novel insights including: 1) recognition of novel tumor associations in NF1, by identifying biallelic NF1 inactivation in glomus tumors and gastrointestinal stromal tumors (GISTs); 2) identification of candidate modifier genes influencing caf?-au-lait macule number (to be published in PLOS Genetics in 2014); 3) the first genome-wide association study (GWAS) in NF1 (fine-mapping underway, 2014); 4) numerous papers on NF1 phenotype refinement (publication on Jaffe-Campanacci syndrome, 2014; ongoing work on cephalometric analysis); and 5) analysis of NF1-genotype-phenotype analysis (with Brigitte Widemann, CCR, NCI). I am also using next-generation sequencing (NGS) and genomics to sequence NF1-associated tumors. We are using NGS of tumor/normal-tissue pairs to identify somatic variation (the ?neurofibrome?) that affect risk of tumorigenesis in NF1, an effort modeled upon the NCI/NHGRI Cancer Genome Atlas. We have developed a statistically rigorous design to identify driver mutations in plexiform neurofibromas, using DNA from tumor/normal-tissue pairs. Plexiform neurofibromas (PN) are congenital neurofibromas affecting up to 50% of people with NF1, which grow unpredictably and can be locally destructive. They are viewed as pre-malignant lesions from which malignant peripheral nerve sheath tumors (MPNSTs) arise. We have started a new project to sequence atypical neurofibromas with Eric Legius (Leuven, Belgium) and Dr. Widemann. Atypical neurofibromas are a poorly understood tumor like PN but with greater malignant potential. We are also collaborating with Dr. Widemann in a new protocol to collect PN and MPNST from the same patient. Lastly, our work on NF1 tumor sequencing has lead to collaborations to sequence brain tumors from patients with NF2. " |