Unanticipated germline cancer susceptibility mutations identified by clinical exome sequencing of sequentially diagnosed pediatric solid tumor patients: the BASIC3 study. S. E. Plon1,2,3,4, S. Scollon1, K. Bergstrom1, T. Wang4, R. A. Kerstein1, U. Ramamurthy1, D. M. Muzny3, S. G. Hilsenbeck4, Y. Yang2, C. M. Eng2, R. A. Gibbs2,3, D. W. Parsons1,3,4 1) Dept Pediatrics, Baylor College of Medicine, Houston, TX; 2) Dept Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; 3) Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX; 4) Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX.

   Background: Germline data from clinical whole exome sequencing (WES) of cancer patients can provide clinically relevant findings with regard to cancer susceptibility. We prospectively determined whether germline cancer susceptibility findings in children can be predicted based on pathologic cancer diagnosis and family history information. Methods: The BASIC3 study investigates the clinical implementation of CLIA-certified germline and tumor WES in an ethnically diverse cohort of sequentially diagnosed children with CNS and non-CNS solid tumors. At subject entry, the study geneticist and genetic counselors record whether specific cancer genetic tests would be considered using current clinical practice based on the cancer diagnosis, age and family history. These data were then compared with the pathogenic mutations and variants of uncertain significance (VUS) in cancer genes identified by clinical WES. Results: The first 115 patients enrolled comprised 41 CNS and 74 non-CNS solid tumor diagnoses. Based on the information provided genetic testing was considered for 40/115 (35%) patients, including TP53 in 23 patients. Germline WES revealed pathogenic mutations in dominant cancer susceptibility genes in 10 patients, including 4 that were suggested at study entry (TP53, MSH2, DICER1, VHL), 6 that were not (BRCA1x2, BRCA2, CHEK2, APC, mosaic WT1) and one patient with liver disease and liver cancer homozygous for a novel TJP2 mutation. Eight patients were reported to carry single truncating mutations in recessive cancer disorder genes such as FANCL and WRAP53 all without clinical evidence of the disorder. Nearly all patients harbored VUS in cancer genes (98%; median = 3), including one likely pathogenic TP53 mutation and one Wilms tumor patient compound heterozygous for rare missense variants in DIS3L2. Conclusions: Diagnostic germline mutations were obtained in 9.6% (11/115) of sequentially diagnosed children with CNS and non-CNS solid tumors. Five of these patients carry mutations generally associated with adult cancer diagnoses and thus not prospectively recommended for testing. Comparison with 2000 WES results of non-cancer patients from the same lab suggests that BRCA1/2 mutations maybe enriched in this childhood cancer cohort (p=0.05 exact Fischers test). Further study is required to determine whether these cancer susceptibility mutations and variants are significantly enriched in childhood cancer patients. Supported by NHGRI/NCI-1U01HG006485.

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