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 | $156,749 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2013 | 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 | |||
Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors | |||
Abstract | |||
Neurofibromatosis type 1 (NF1) is a common (approximately 100,000 Americans) genetic disorder of dysregulated cell growth. People with NF1 also develop malignant cancers. There are limited therapies and no cures for NF1. At this time it is essentially impossible to predict the severity of the disorder. In this study we seek to identify the genes that influence the wide variability in severity seen in patients with NF1. We apply the principles of translational medicine to find genetic modifiers of severity in NF1. We have a cohort of 135 NF1 individuals quantitatively phenotyped from 93 families, and multiple research biospecimens. 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 café-au-lait macule number; and, 3) the first genome-wide association study (GWAS) in NF1. 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 two-stage 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 are collaborating with Dr. Brigitte Widemann (NCI) 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. |