Abstract 2742: Potential burden of germline findings in targeted tumor sequencing using matched normal DNA

Tumor sequencing (TS) reveals germline variants, unless they are subtracted through a comparison of tumor and normal data. The genes analyzed in TS overlap significantly with genes associated with Mendelian disorders. Identification of pathogenic germline variation may have significant implications for the individual and their family; however, the prevalence of such variation in individuals undergoing TS is unknown. To determine the burden of germline variants in Mendelian disease genes identified in tumor-normal massively parallel sequencing, we analyzed 1570 cases, unselected for cancer type or family history, that had undergone TS with matched normal DNA using the 341-gene targeted capture panel employed at Memorial Sloan Kettering Cancer Center (MSK-IMPACT). The most frequent tumor types were breast carcinoma (n = 269, 17%), non-small cell lung cancer (n = 191, 12%), colorectal cancer (n = 116, 7%), prostate carcinoma (n = 97, 6%), esophago-gastric adenocarcinoma (n = 89, 6%), and soft tissue sarcoma (n = 80, 5%). Subjects had provided consent to IRB-approved protocols allowing sequencing of tumor and germline DNA. Analysis of the matched normal DNA samples was conducted in an anonymized manner under an IRB approved waiver. Curation of single nucleotide variants (SNVs) or indels employed Ingenuity® Variant Analysis (version 3.1.20141014), which uses an automated algorithm to classify genes into 5 classes of pathogenicity based on the American College of Medical Genetics (ACMG) draft guidelines. Variant classifications were reviewed and confirmed manually. Large deletions and duplications were curated manually. There are 26 genes on the MSK-IMPACT panel that are included in the ACMG 56-gene list recommended for return of results. In these 26 genes, there were 2 presumed pathogenic (likely pathogenic/pathogenic, LP/P) variants in 3 individuals (0.19%), 1 LP/P in 107 individuals (6.81%) and 0 LP/P in 1460 individuals (92.99%). There was 1 variant of uncertain significance (VUS) in 507 individuals (32.29%) and 2 or more VUS in 249 individuals (15.85%). Genes with the greatest number of unique LP/P variants were BRCA2, MUTYH, BRCA1, RET, TP53, MSH6, MSH2, SDHB, and APC. In the setting of tumor profiling, cancer predisposing germline variants may be relevant for guiding therapy and may provide personal and clinical utility with regard to future cancer risk-assessment and implementation of cancer prevention strategies including early-detection and risk-reduction strategies for the patient and at-risk family members. The detection of LP/P variants in genes of accepted clinical utility in the matched normal DNA of 7% of unselected individuals undergoing TS suggests that there may be a significant benefit in conducting secondary analysis for detection of these likely cancer-relevant germline findings. However, the challenges of classification and interpretation of VUS, present in almost half of the individuals, will need to be considered. Citation Format: Kasmintan A. Schrader, Donavan T. Cheng, Joseph Vijai, Meera Prasad, Michael F. Walsh, Ahmet Zehir, Tinu Thomas, Liying Zhang, Marc Ladanyi, Kenneth Offit, Michael F. Berger, Mark E. Robson. Potential burden of germline findings in targeted tumor sequencing using matched normal DNA. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2742. doi:10.1158/1538-7445.AM2015-2742