Abstract 2704: Pathogenic mutations and variants of unknown significance (VUS) in cancer predisposition genes are associated with over 10% of pediatric rhabdomyosarcoma: a report from the Children’s Oncology Group
Authors: Young Erin L. , Maese Luke , Robinson Rosann , Pflieger Lance , Moore Barry , Rynearson Shawn , Fowler Trent , Tavtigian Sean V. , Yandell Mark , Mason Clinton C. , Hawkins Douglas S. , Lupo Philip J. , Schiffman Joshua D. 
Published: July 2017

Abstract
Approximately 5% of rhabdomyosarcoma (RMS) cases are due to known cancer predisposition syndromes (e.g., Li-Fraumeni syndrome, Neurofibromatosis-1), but these estimates have not been confirmed in large-scale studies. Furthermore, no recommended germline testing protocols exist for RMS. We tested the hypothesis that germline mutation burden is greater than previously reported and present several new predisposition genes as potential drivers of pediatric RMS. We sequenced 59 cancer susceptibility genes in 213 children with RMS enrolled on one clinical trial (COG ARST0531), unselected for family history of cancer. Validation was performed with Sanger sequencing. Our analysis included determining the incidence of pathogenic variants in known RMS predisposition genes, followed by other cancer predisposition genes on our panel but not previously associated with RMS. In our cohort, 3.9% of unselected RMS cases harbor a pathogenic variant in a known predisposition gene (Table 1). Using VAAST, we next identified the top 10 genes possibly associated with RMS. Variants of uncertain significance (VUS) were restricted to rare variants (&lt;0.1%) with severe CADD and Polyphen2 scores, which added 16 additional patients (7.4%). To distinguish incidental findings from true correlations, we compared our allele frequencies to those in the GnomAD database (126,216 exome sequences and 15,136 whole-genome sequences). Including both pathogenic mutations and rare VUS, 10.8% of RMS cases carry a variant with potentially important clinical implications, suggesting that newly diagnosed RMS would benefit from multigene genetic testing. Future directions include linkage to clinical data such as family history, age at diagnosis, tumor stage/location/histology, and clinical outcome, as well as expanding both the RMS and control cohorts.
Table 1.List of genes with numbers of carriers identified in 213 rhabdomyosarcoma casesGeneCarriers%% of carriers in GnomADSIR95% CIP=valueTruncating Variants and Known Pathogenic MissenseATM00.42%---BAP100.87%0.05%---BRCA220.87%0.85%1.01(0.12-3.66)1.1736DICER110.43%0.06%7.75(0.20-43.19)0.2421MSH210.43%0.15%2.93(0.07-16.30)0.5790NF120.87%0.88%0.98(0.12-3.54)1.2088PMS200.87%0.18%---PTCH100.15%---TP5331.30%0.13%10.10(2.08-29.51)0.0070WT101.30%0.02%---Total93.90%3.42%1.14(0.52-2.16)0.7882Combined Analysis of Pathogenic Variants plus Variants of Uncertain Significance (VUS)ATM20.87%0.78%1.11(0.13-4.02)1.0734BAP120.87%0.22%3.89(0.47-14.05)0.1891BRCA220.87%1.52%0.57(0.07-2.06)1.7286DICER173.03%0.86%3.52(1.41-7.24)0.0089MSH210.43%0.78%0.56(0.01-3.10)1.6690NF120.87%1.70%0.51(0.06-1.84)1.8062PMS210.43%0.64%0.68(0.02-3.78)1.5425PTCH131.30%0.86%1.52(0.31-4.43)0.6348TP5341.73%0.25%6.93(1.89-17.76)0.0058WT110.43%0.31%1.40(0.04-7.81)1.0197Total2510.82%9.94%1.09(0.70-1.61)0.7232
Citation Format: Erin L. Young, Luke Maese, Rosann Robinson, Lance Pflieger, Barry Moore, Shawn Rynearson, Trent Fowler, Sean V. Tavtigian, Mark Yandell, Clinton C. Mason, Douglas S. Hawkins, Philip J. Lupo, Joshua D. Schiffman. Pathogenic mutations and variants of unknown significance (VUS) in cancer predisposition genes are associated with over 10% of pediatric rhabdomyosarcoma: a report from the Children’s Oncology Group [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 2704. doi:10.1158/1538-7445.AM2017-2704