(P 49) GENETIC INTERACTION BETWEEN SPRED3 AND SMARCB1 CAUSES EXPLOSIVE MULTIFOCAL MALIGNANT PERIPHERAL NERVE SHEATH TUMORS

Objective: Whole genome sequencing (WGS) can solve unexplained familial cancer patterns. Here we used WGS and functional studies to understand the genetic basis for an unfortunate family afflicted by highly penetrant and aggressive malignant peripheral nerve sheath tumors (MPNST).

Methods: A family with multiple members afflicted by aggressive, multifocal MPNST was identified as part of the International Sarcoma Kindred Study. One parent had a known SMARCB1 mutation causing a benign Schwannoma at age 30, while the second parent developed a glioblastoma multiforme at her 50s. Three children developed aggressive multifocal MPNST before 20 years, with all 3 succumbing by age 30. We applied WGS to the germlines of 4/5 family members, as well as more than 30 MPNST or atypical Schwannomas to identify genetic modifiers or de novo events which could explain the dramatic phenotype in the children. We then used cellular models to confirm the functional contribution of candidate genes, and to map the sequence of events leading to development of these cancers.

Results: We identified 15 genes carrying variants which could potentially explain the acceleration of phenotype in the children. Of these, we selected 6 for functional studies using the immortalized human neural progenitor ReN cell line. Using a variety of assays, including clonognenic expansion and differentiation, we show the novel gene, SPRED3, as the likely modifier. SPRED3 is a member of the Sprouty family of proteins that regulate growth factor-induced activation of the MAP kinase cascade. A related gene, SPRED1, is associated with Legius syndrome, sharing clinical features with Neurofibromatosis type 1. We then mapped the phylogenetic relationships between the MPNST within each individual to derive a probable sequence of events leading to tumor development, showing that the earliest events arose prior to day 15 in the embryo.

Conclusion: This study of a rare and tragic family has shed fundamental insight into the genetic basis of Schwannomas and MPNST.