Abstract 772: The molecular landscape of dermal neurofibromatosis
Authors: Gosline Sara JC , Knight Pamela , Yu Thomas , Prasad Nripesh , Jones Angela , Shrestha Shristi , Boone Braden , Levy Shawn E. , Link Andrew J. , Galassie Allison C. , Weinberg Hubert , Friend Stephen , La Rosa Salvatore , Guinney Justin , Bakker Annette 
Published: July 2016

Abstract
Background: Neurofibromatosis type I (NF1) is a genetic disorder that disrupts neurological tissue growth and can lead to a diverse set of symptoms including systematic growth of benign tumors, learning disorders and bone deformities. It is a rare disease occurring in only 1 in 3,000 people worldwide. While the disease has been linked to loss of function in the NF1 gene - a known tumor suppressor - there is a high degree of phenotypic diversity in the NF1 patient population, making it difficult to identify the underlying cause of the disease and treat it effectively. In this work we seek to improve overall knowledge of dermal NF1 through global molecular characterization of the disease.
Methods: We have collected four dermal neurofibromas and peripheral blood from each of 11 NF1 patients. We analyzed each sample using (1) Whole genome sequencing (WGS) on the Illumina HiSeq X platform, (2) Illumina OMNI2.5 Arrays (3) RNA-Sequencing on an Illumina HiSeq v4 machine and (4) iTRAQ-labeled proteomics. WGS data for both tumor and blood samples from each patient were used to identify patient-specific germ-line mutations as well as tumor-specific somatic mutations in each sample. Single nucleotide polymorphisms identified by the OMNI Arrays were used to identify copy number alterations in both blood and tumor samples. RNA-Seq data and proteomics data were mapped to transcripts and proteins respectively.
Results: Preliminary analysis of this data illustrates a diverse genomic landscape of NF1. Hierarchical clustering of copy number alterations largely show samples clustering by tissue, suggesting that most copy number alterations are somatic and not shared across the germline. However, there are two patients that show germline copy number alterations, including one patient with loss in the NF1 region. WGS analysis suggests similar diversity with each patient possessing a distinct combination of germline and somatic mutations of NF1 and other cancer-related genes. Cluster analysis of the RNA-Seq data shows no patient-specific clusters, suggesting that that each tumor executes a unique transcriptional program.
Conclusion: This work represents a first-ever attempt to profile the diversity of dermal neurofibromatosis at a molecular level. Preliminary analysis of the data underscores the complexity of this disease and explains, in part, previous difficulty in identifying effective treatments. Ongoing work includes expanding the analysis to include more patient samples and other types of NF1-derived tumors. As an orphan disease, NF1 has been poorly characterized compared to more common cancers. To rectify this, the Children's Tumor Foundation and Sage Bionetworks are collaborating to make NF1 data available to the public to accelerate research and the drug discovery pipeline. We expect that this data will be a resource for other NF1 researchers to assist in the study of this disease at the molecular level. All data and preliminary results are publicly available at http://www.synapse.org/dermalNF
Citation Format: Sara JC Gosline, Pamela Knight, Thomas Yu, Nripesh Prasad, Angela Jones, Shristi Shrestha, Braden Boone, Shawn E. Levy, Andrew J. Link, Allison C. Galassie, Hubert Weinberg, Stephen Friend, Salvatore La Rosa, Justin Guinney, Annette Bakker. The molecular landscape of dermal neurofibromatosis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 772.