Abstract 15: Identifying patients with inherited cancer susceptibility through tumor profiling
Authors: Madlensky Lisa , Schwab Richard , Arthur Elisa , Coutinho Alice , Parker Barbara , Kurzrock Razelle 
Published: May 2015

Abstract
Purpose: To determine whether molecular tumor profiles can be used to identify patients who may be appropriate for germline genetic testing for known cancer predisposition syndromes.
Methods: Chart review of 250 consecutive cancer patients who had tumor profiling carried out through Foundation Medicine. Age of diagnosis, family cancer history, and other primary cancers were abstracted from the electronic medical records of a single institution. We considered APC, ATM, BRCA1, BRCA2, CDH1, CDKN2A, MEN1, MLH1, MSH2, MSH6, MUTYH, NF1, NF2, PALB2, PMS2, PTEN, RET, TP53, TSC1, TSC2, and VHL as our gene subset of interest for this study. We considered sequence variants as putative mutations, gene amplifications and losses were not considered.
Results: The first 49 cases reviewed comprised 13 breast cancer patients, 6 colorectal, 5 melanoma, 5 head/neck, 3 sarcomas, and 17 other tumor types. Of these, 19 patients (38%) had no mutations in any cancer predisposition genes; 22 (44%) had variants in the listed subset of genes, but these were classified as “unlikely to be deleterious germline” predisposition genes based on patient clinical and family history; and 8 (16%) had mutations that we classified as “possible” germline based on clinical and family history. The “unlikely” group includes 22 patients with 35 variants: TP53 (n=15), APC (n=5), PTEN (n=5), ATM (n=3), BRCA2 (n=1), CDKN2A (n=2), CDH1 (n=1), MSH6 (n=1), NF1 (n=1), and NF2 (n=1). The “possible” group includes five patients with early-onset cancers and/or a family history of cancer including core Li-Fraumeni Syndrome cancers; two patients with BRCA2 mutations (one is previously unreported but predicted to be deleterious; one is classified in the literature as probably benign but is controversial); and one melanoma patient with a CDKN2A mutation. Germline testing for the single-site mutations identified is being initiated for these patients. Data will be presented on the full cohort of 250 patients, some of whom have already had confirmatory germline testing.
Conclusions: A substantial subset of patients undergoing tumor profiling may have underlying germline mutations. Given that germline variants may have implications for 1) the patient's risk of additional cancers, 2) their family members cancer risks, and 3) selection of therapies, clearly delineating which variants in a tumor are germline and which are somatic is of great clinical importance. In our study, 60% of patients had variants in genes associated with hereditary cancer syndromes (50% excluding those with only TP53 variants), and 16% were considered appropriate candidates for confirmatory germline testing based on clinical features and/or family history. Therefore it is important that studies be performed to determine to what extent variants found by tumor sequencing reflect underlying germline aberrations of clinical significance.
Citation Format: Lisa Madlensky, Richard Schwab, Elisa Arthur, Alice Coutinho, Barbara Parker, Razelle Kurzrock. Identifying patients with inherited cancer susceptibility through tumor profiling. [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 15. doi:10.1158/1538-7445.CANSUSC14-15