Abstract P4-12-02: Spectrum of mutations identified in a 25-gene hereditary cancer panel for patients with breast cancer
Authors: Sharma Lavania , Moyes Kelsey , Abernethy John , McCoy Heidi , Saam Jennifer , Landon Michelle , Wenstrup Richard 
Published: May 2015

Abstract
Introduction: With the advancements of next generation sequencing, patients with a personal and/or family history of cancer that may not be suggestive of one cancer syndrome may be offered testing for mutations in multiple cancer-predisposing genes simultaneously. The focus of this analysis was to determine the spectrum of gene mutations observed in patients with a personal history of breast cancer.
Methods: A commercial diagnostic laboratory database was queried for patients with a personal diagnosis of breast cancer who underwent a 25-gene hereditary cancer panel from September 4, 2013 through April 17, 2014. The panel includes highly penetrant cancer predisposing genes BRCA1, BRCA2, TP53, PTEN, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, BMPR1A, CDH1, CDKN2A, MUTYH, SMAD4, STK11 and moderately penetrant genes CHEK2, PALB2, ATM, NBN, BARD1, BRIP1, CDK4, RAD51C and RAD51D. Sequencing and large rearrangement was performed for all the genes in the panel. All patient data regarding clinical history was obtained by health care provider report on the test requisition forms.
Results: A total of 3584 patients with a personal history of breast cancer were identified. Of these, 13.8% met the NCCN guidelines for genetic testing for both Hereditary Breast and Ovarian Cancer syndrome (HBOC) and Lynch syndrome (LS), while 80.3% met criteria for only HBOC and 1.2% met only for LS. 10.4% of females and 18.9% of males with breast cancer were positive for at least 1 deleterious or suspected deleterious mutation, of which mutations in BRCA1 and BRCA2 comprised 40.2%. In this cohort, 59.8% of the mutations were detected in other genes (see table below). Of the patients who did not meet either testing criteria, mutations were found in BRCA2 (2), APC (2), BARD1 (1), CHEK2 (1), MSH2 (1), NBN (1), and TP53 (1).
Interestingly, we also identified 15 patients with two mutations in our cohort. BRCA1 or BRCA2 accounted for one of the mutations in 9 out of 15 patients and 6 patients had two mutations in other genes.
Gene% of Total MutationsBRCA121.2%BRCA219.0%CHEK211.3%ATM9.7%PALB27.2%NBN6.6%APC5.6%BARD13.3%PMS22.6%BRIP12.3%MSH62.0%TP531.5%MSH21.3%RAD51C1.3%CDH11.0%RAD51D1.0%CDKN2A1.0%PTEN1.0%MLH10.5%Biallelic MUTYH0.3%SMAD40.3%
Conclusions: Testing patients using a 25-gene panel identified 234 mutations outside of BRCA 1 and BRCA 2 (157). That is a 149% increase in mutations identified over BRCA 1 and BRCA 2 testing alone. Mutations in moderately penetrant breast cancer genes (including CHEK2, ATM, PALB2 and NBN) comprised 34.8% of total mutations and 6.4% of mutations were in LS genes. Additionally, panel testing identified mutations in more than one gene in 4.0% of patients, which would not have been identified by single-syndrome testing. Panel testing provides a broader understanding of hereditary cancer in breast cancer patients both by identifying mutations in more genes and identifying patients with mutation in more than one gene. This approach can provide more guidance both for management of the patient and the patient's family members.
Citation Format: Lavania Sharma, Kelsey Moyes, John Abernethy, Heidi McCoy, Jennifer Saam, Michelle Landon, Richard Wenstrup. Spectrum of mutations identified in a 25-gene hereditary cancer panel for patients with breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-12-02.