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Neurofibromatosis Type 1 and Cancer Susceptibility

Neurofibromatosis type 1 (NF1) is a common genetic disorder of deregulated cell growth, affecting approximately 100,000 Americans. People with NF1 are at an increased risk of developing a variety of benign and malignant tumors. There are limited therapies and no cures for NF1. At this time, it is essentially impossible to predict how severe the disorder will be in a given individual over time.

DCEG investigators in the Clinical Genetics Branch (CGB) seek to identify the additional genes (called “genetic modifiers”) that influence the wide variations in severity seen in individuals with NF1 by applying the principles of translational medicine. They have quantitatively phenotyped a cohort of 135 NF1 individuals from 93 families and collected multiple research biospecimens. 

Analyses of this cohort have yielded multiple novel insights including:

  • recognition of previously-unrecognized tumor associations in NF1, by identifying biallelic NF1 inactivation in glomus tumors, gastrointestinal stromal tumors (GISTs), and giant cell lesions of the jaw;
  • identification of candidate modifier genes influencing café-au-lait macule number;
  • the first genome-wide association study (GWAS) in NF1;
  • characterization of novel clinical features (phenotypes) in NF1, including its association with pulmonary hypertension.

They have also characterized several other phenotypes with features that significantly overlap those of NF1, including the Jaffe-Campanacci syndrome and Legius syndrome. Collaborations are underway with two multi-institutional groups seeking to identify genetic modifiers of tumor-related phenotypes in NF1.

Next-generation Sequencing for NF1

Investigators are also using next-generation sequencing (NGS) of NF1-associated plexiform neurofibromas. Plexiform neurofibromas are congenital neurofibromas (present at birth) affecting up to 50% of people with NF1, which grow unpredictably and can be locally destructive. They are regarded as pre-cancerous lesions from which malignant peripheral nerve sheath tumors (MPNSTs) arise. Investigators are using NGS of tumor/normal-tissue pairs to identify the somatic variation that influences risk of tumorigenesis in NF1, an effort modeled upon the NCI Cancer Genome Atlas.

A rigorous two-stage statistical design was developed to identify driver mutations in plexiform neurofibromas, using DNA from tumor/normal-tissue pairs. In collaboration with Drs. Brigitte Widemann and Javed Khan of the NCI Pediatric Oncology Branch, CGB is sequencing germline, plexiform neurofibroma and MPNST samples collected from the same individual with NF1, testing the hypothesis that sequencing of such “trios” will identify driver genes that promote plexiform and MPNST development.

Identifying Under-recognized Rare Cancers

CGB investigators have also undertaken a systematic literature review of all the NF1-associated case reports and case series published in the last 50 years, focusing on the types and numbers of cancers described. The goal is to identify under-recognized rare cancers putatively associated with NF1 for further clinical and molecular characterization.

Neurofibromatosis Type 1 (NF1) and Cancer Susceptibility – Research Publications

For more information, contact Douglas Stewart.

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