Genetic Factors that Affect Tumorigenesis in NF1

摘要

Neurofibromatosis type 1 affects 1/4000 individuals worldwide and predisposes to the growth of both benign and malignant tumors. Our research is focused on NF1 microdeletions that are associated with an early onset, and subsequent heavy burden, of cutaneous neurofibromas and predispose to MPNST. We found that these deletions arise by homologous recombination between 51 kb repeat elements (NR1REP) that flank the NF1 gene. We identified recombination hotspots where 69% of NF1 microdeletions occur and developed robust and sensitive assays to detect microdeletions in a patient blood sample. We analyzed the structure and sequence of four NFIREP paralogs in the genome and described sequence features that may mediate recombination at these sites. We developed new quantitative PCR assays that will detect nonrecurrent NF1 microdeletions that occur either in the germline or in somatic tissues including tumors. Our data make substantial contributions to understanding how NF1 microdeletions occur, create important assays and resources to determine whether some individuals are more susceptible, and which deleted sequences may cause the severe tumor phenotype of these patients.