Abstract P2-09-19: The performance of next generation panel testing in individuals assessed by a community-based genetics program
Authors: Daib S , Sedlacek S , Hamlington B , Brzeskiewicz L , Goetsch B , Tedesco K , Patel G , Sudhoff K , Mullineaux L , Langer L 
Published: May 2016

INTRODUCTION: Genetic testing identifies patients with an increased risk for hereditary cancer and assists in development of clinical management or cancer prevention strategies. Utilization of multigene panels for patients with a personal or family history of cancer has the ability to identify a significant number of pathogenic variants in high risk and moderate risk genes. Importantly, at-risk patients with previously negative single gene testing can be retested with multigene panels. We characterized the mutations found in patients who had inherited cancer multi-gene panel testing, including patients with negative BRCA testing, and explored the phenotypes associated with the most prevalently mutated gene.

METHODS: Patients were identified by a Community-Based Genetics Program and sent to a commercial laboratory for multi-gene panel testing. A retrospective query of multi-gene oncology tests was performed: patient history, family history and previous genetic test results were reported on the requisition. The following Genes were Utilized in the Inherited Cancer Panels: High risk genes (APC, BMPR1, BRCA1, BRCA2, CDH1, CDKN2A, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, TP53, VHL), moderate risk genes (ATM, CHEK2, PALB2), and genes with increase risk of unknown magnitude (AXIN2, BARD1, BRIP1, CDK4, FANCC, NBN, RAD51C, RAD51D, XRCC2). The combination of genes analyzed was depends on the panel ordered.

RESULTES:

529 individuals were tested with 38 individuals with pathogenic variant (PV) or variant expected to be pathogenic (VEP). Of the 529 individuals, 154 (29%) had previous testing and 12 (7.8%) had PV/VEP. Interestingly, 48% of PV/VEP were in the moderate risk genes ATM, PALB2, CHEK2, and CHEK2 being the most commonly mutated gene. The following table details the genes with Positive and VEP Results:

Table 1: Gene Distribution Patients with PV/VEPGeneN%CHEK21333.3BRCA2512.8BRCA1410.2MUTYH512.8PALB2410.2ATM25.13RAD51C12..56MLH112.56MSH212.56MSH612.56PTEN12.56BRIP112.56

The majority of patients with CHEK2 mutations had a personal history of breast cancer (69%), but the family histories exhibited varied phenotypic expression.

Personal and Family History for Patients with CHEK2 PV/VEP or VUS (N=26)SitePersoanl historyFamily historyBreast1819Uterine11Ovarian16Colon 9Lung 1Pancreatic 3Gastric 2Renal 2Lymphoma 4Brain 2Skin 2Esophageal 1Prostate 6Thyroid 2Gynecologic 1

CONCLUSION: Inherited cancer panels provide patients with genetic information that would otherwise be missed by single gene testing and provides access to risk assessment and medical management. Using multigene panels, PV/VEP were discovered in 7.8% of patients with previous negative BRCA testing. CHEK2, a moderate risk gene, was identified in 33% of patients with a PV/VEP. The phenotypic expression for CHEK2 is primarily breast cancer with a wide spectrum of solid and hematological tumors.

Citation Format: Daib S, Sedlacek S, Hamlington B, Brzeskiewicz L, Goetsch B, Tedesco K, Patel G, Sudhoff K, Mullineaux L, Langer L. The performance of next generation panel testing in individuals assessed by a community-based genetics program. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-19.