Suspected and confirmed germline variants from tumor-only somatic sequencing of 864 gastrointestinal malignancies.

Abstract

e13131 Background: Targeted tumor-only somatic sequencing informs therapies and is becoming a routine part of cancer care. It also identifies patients with possible germline variants who require confirmatory genetic testing. The aim was to identify patients with suspected and confirmed germline variants whose GI tumors underwent somatic sequencing. Methods: 864 patients with GI tumors who had Foundation One (FO) somatic sequencing from 4/2003-3/2018 were evaluated. Inclusion criteria for suspected germline variants were: a) allele frequency ≥ 35% in hereditary cancer genes and b) pathogenic variants by FO and/or ClinVar. Variants in commonly mutated somatic genes ( TP53, KRAS, CDKN2A) were excluded in patients over age 40. Recommendation of genetic evaluation and germline test results were recorded. Patient, family, and tumor characteristics were compared using univariate analysis. Results: 199 of 864 patients had suspected germline pathogenic variants. 50 patients were recommended genetic evaluation, and 26 patients underwent genetic testing. A germline pathogenic variant was confirmed in 15 patients. Among all patients suspected to have germline variants, 8% were confirmed by genetic testing. Patients under age 40 and those with family cancer history were more often referred for testing (Table). Patients with variants in BRCA1, MLH1, MSH2, PMS2, POLE and TP53 were more often referred for testing. Conclusions: A quarter of patients carried a somatic pathogenic variant with allele frequency ≥35% in a hereditary cancer gene. 25% of these patients were recommended for genetic evaluation. Younger patients and those with family history were more often referred. 8% of patients with suspected germline variants were confirmed by genetic testing. These results provide “real world” experience in using somatic only tumor testing to identify patients with germline pathogenic variants who then might benefit from future cancer screening and genetic testing in family members. Comparison of characteristics by recommendation to undergo genetic testing based on somatic tumor sequencing results. [Table: see text]