Abstract 11: Evaluating cancer susceptibility mutations and incidental findings from whole exome sequencing of sequentially diagnosed pediatric solid and brain tumor patients: Early results of the BASIC3 study

Advances in sequencing technologies allow for provision of genome-scale data to oncologists and geneticists caring for pediatric cancer patients but current experience with the clinical application of genomic sequencing is limited. The goal of the BASIC3 (Baylor Advancing Sequencing into Childhood Cancer Care) study is to determine the clinical impact of incorporating tumor and constitutional whole exome sequencing (WES) into the care of children with newly diagnosed solid tumors at Texas Children9s Cancer Center (target enrollment n=280). WES of patient blood and frozen tumor samples was conducted in the CLIA-certified Whole Genome Laboratory at Baylor College of Medicine using the vCrome 2.1 capture platform and Illumina paired-end sequencing. Reported WES germline findings were validated by a second platform and evaluated in parental blood samples if available, then deposited into the electronic medical record and disclosed to families by their oncologist and a genetic counselor. These disclosure visits are audio recorded and transcribed for analysis of the communication of WES results between parents and oncologists; in addition, the parents and oncologists are serially interviewed to determine preferences for reporting this complex information. Since the study opened in August 2012, 80% of 145 potentially eligible families have consented to enrollment. The first 100 patients comprise a diverse representation of diagnoses, including 32 with CNS tumors (32%) and 68 with non-CNS tumors (68%). The germline WES results (n=85 reported to date) included diagnostic findings in 10 cases including 7 patients with pathogenic mutations in dominant cancer susceptibility genes (all singletons except TP53 mutations identified in 2 patients). Only 3 of these 7 patients had genetic testing recommended clinically. There were 2 patients with mutations which identified the genetic cause of other (non-cancer) medical problems, and 1 study patient with mutations which explained both liver disease and hepatocellular carcinoma. Downstream testing of at-risk relatives has occurred rapidly in several families and cancer screening recommendations implemented in patients and family members. Seven medically actionable incidental findings unrelated to clinical phenotype have also been reported, predominantly in cardiovascular genes and mitochondrial DNA. The BASIC3 study demonstrates the feasibility of routine germline WES in the pediatric oncology clinic and a significant level of parental interest in receiving WES results. Early results suggest that clinically relevant susceptibility mutations can be identified in approximately 10% of unselected pediatric solid and brain tumor patients. This is a conservative estimate, as the WES data analysis does not currently report copy number variation in cancer susceptibility genes. A similar proportion of patients had incidental medically actionable mutations reported. The clinical utility of the germline WES data and the preferences of oncologists and parents for reporting of these results are under study. Supported by NHGRI/NCI 1U01HG006485. Citation Format: Sharon E. Plon, Sarah Scollon, Katie Bergstrom, Robin A. Kerstein, Murali Chintagumpala, Stacey L. Berg, Susan G. Hilsenbeck, Tao Wang, Surya Rednam, David Wheeler, Laurence McCullough, Richard Street, Amy L. McGuire, Reid G. Jeffrey, Donna M. Muzny, Christine M. Eng, Yaping Yang, Richard A. Gibbs, Donald W. Parsons. Evaluating cancer susceptibility mutations and incidental findings from whole exome sequencing of sequentially diagnosed pediatric solid and brain tumor patients: Early results of the BASIC3 study. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 11. doi:10.1158/1538-7445.CANSUSC14-11