Abstract 3003: Exome analysis of known hereditary cancer genes in 122 children with rhabdomyosarcoma
Authors: Wegman-Ostrosky Talia , Patidar Rajesh , Sindiri Sivasish , Shern Jack , Hawkins Douglas S. , Catchpoole Daniel , Wei Jun S. , Skapek Stephen , Khan Javed , Stewart Douglas R. 
Published: July 2017

Abstract
Introduction. Rhabdomyosarcoma (RMS) accounts for 5% of all pediatric cancer and is the most prevalent soft tissue tumor in childhood and adolescents. RMS is thought to arise from primitive mesenchymal stem cells directed towards myogenesis. Between 7-33% of RMS cases arise from a hereditary cancer syndrome, like LFS or NF1. We analyzed germline genetic variants in hereditary cancer genes in 122 children with RMS.
Methodology. In 122 children with RMS and 1001 cancer-free adults, we examined germline exome data to determine the frequency of genetic variants in 51 cancer genes known to underlie syndromes associated with RMS. DNA was extracted from blood or buccal cells using standard methods. Exome enrichment was performed with NimbleGen SeqCap EZ Human Exome Library v3.0+UTR, on an Illumina HiSeq. Annotation of each exome variant was performed using a custom software pipeline. We evaluated all variants that passed quality controls with a population minor allele frequency (MAF) &lt;0.1%. The cataloging of the variants was based on the ACMG classification as pathogenic (P), likely pathogenic (LP), or variable of unknown significance.
Results We compared the age, gender, histologic type and localization of the primary RMS of the patients with and without P/LP variants in the 51 genes. In the patients without P/LP variants, the mean age of diagnosis was 5 years and the most frequent site of diagnosis was head and neck. In the group with P/LP variants, the mean age of diagnosis was 10 years, and the most frequent site was pelvis.
In the 51 genes that were analyzed we found 9 P and 12 LP variants in 15 genes: TP53, ATM, MSH6, PMS, DICER1, FANCA, RECQL4, PTEN, WRN, RB1, BUB1B, RET, APC, FANCM and TSC2; genes with 2 variants include WRN, PTEN, BUB1B, FANCA and RET. Most of the variations were stopgain, follow by missense, frameshift insertion and splicing genetic variations. Ten of this genes are associated with an autosomal dominant pattern of inheritance. In one 15-year-old female patient with an alveolar RMS in the paraspinal area we found P/LP variants in PTEN and PMS2. The frequency of P/LP variants in cases was 16% and 3% in controls.
Conclusions. To our knowledge, this is the first study where multiple germline variation where analyses in children with RMS. We found P/LP variation in 16% of all the cases (pending orthogonal confirmation); the mean age of diagnosis was 10 years old and their primary tumor site was in the pelvis (50%). Identification of P/LP variation in genes underlying RMS-associated syndromes has implications for follow-up, screening and management of these patients and their families. We acknowledge the Children’s Oncology Group in helping to assemble the RMS cohort.
Citation Format: Talia Wegman-Ostrosky, Rajesh Patidar, Sivasish Sindiri, Jack Shern, Douglas S. Hawkins, Daniel Catchpoole, Jun S. Wei, Stephen Skapek, Javed Khan, Douglas R. Stewart. Exome analysis of known hereditary cancer genes in 122 children with rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3003. doi:10.1158/1538-7445.AM2017-3003