Tumor and Constitutional Sequencing for Neurofibromatosis Type 1.

Abstract

<i>NF1</i> variants in tumors are important to recognize, as multiple mechanisms may give rise to biallelic variants. Both deletions and copy-neutral loss of heterozygosity (LOH) are potential mechanisms of <i>NF1</i> loss, distinct from point mutations, and additional genes altered may drive different tumor types. This study investigates whether tumors from individuals with neurofibromatosis type 1 (NF1) demonstrate additional gene variants and detects <i>NF1</i> second hits using paired germline and somatic sequencing. In addition, rare tumor types in NF1 may also be characterized by tumor sequencing. Sequences of 529 cancer driver genes were analyzed in 6,381 tumors, yielding 391 <i>NF1</i>-mutated tumors in which <i>NF1</i> LOH analysis was performed. Driver genes were evaluated by tumor type including malignant peripheral nerve sheath tumors and gliomas. <i>NF1</i> LOH was seen in 133 of 391 tumor samples in the cohort. Individuals with NF1 had more prevalent copy-neutral LOH (<i>P</i> < .0001), suggesting somatic intrachromosomal recombination. Osteosarcoma in NF1 also had <i>NF1</i> LOH and additional p53 alteration. <i>NF1</i> second hit data from tumors were informative for inferring deleteriousness of missense variants that were conflicting in ClinVar, potentially helping to add to <i>NF1</i> annotation. Although criteria for evaluating germline and somatic variants are different, deleterious effects on <i>NF1</i> function may be shared. Sequencing of NF1-associated tumors demonstrated a spectrum of second hits in <i>NF1</i> and the prevalence of copy-neutral LOH. Future work may be aimed at further understanding of LOH mechanisms and strategies to mitigate tumor risk.