Abstract P4-12-09: Low-level constitutional mosaicism of a de novo BRCA1 gene mutation
Authors: Friedman Eitan , Efrat Noa , Soussan-Gutman Lior , Dvir Addie , Kaplan Yulia , Ekstein Tali , Nykamp Keith , Powers Martin , Rabideau Marina , Topper Scott 
Published: May 2015

Abstract
Background:
Germline mutations in the BRCA1 and BRCA2 genes detected in some high-risk breast/ovarian families are used to estimate cancer risk, plan cancer early detection schemes, and make decisions about risk reducing surgeries. The gold standard for detecting BRCA sequence changes has long been Sanger sequencing, but recently next-generation sequencing (NGS) technologies have emerged as an accurate and efficient alternative, with improved sensitivity for detection of mosaic events. Here we report the detection of low-level constitutional germline mosaicism (∼5%) for a de novo pathogenic BRCA1 mutation detected using deep sequencing of three different non-cancerous tissues; and a corresponding high-level detection (∼50%) in cancerous breast tissue. This is the first reported case of multiple tissue constitutional mosaicism in BRCA1 at this level of detection.
Patient and Methods:
The patient is a woman of mixed Jewish Ashkenazi - Bulgarian heritage, diagnosed with a large (8x10 cm), triple negative, high-grade invasive breast cancer in the right breast at age 43 years. Her cancer family history includes a daughter with acute lymphatic leukemia at age 18 months, a brother with a Central Nervous System (CNS) tumor at age 45 years, a father with a malignant CNS tumor at age 58 years, a maternal grandfather with a malignant tumor in his 70's, and two of this maternal grandfather's sisters who were diagnosed with breast cancer. The patient underwent neoadjuvant chemotherapy followed by bilateral mastectomy (therapeutic mastectomy for the right breast and a contralateral risk-reducing mastectomy). The patient underwent germline testing using NGS, sequencing of 29 hereditary cancer genes in DNA extracted from blood using Invitae’s Hereditary Cancer Panel. This testing was followed up with additional NGS testing of buccal and contralateral healthy breast tissue. The patient also underwent somatic mutation testing on her breast tumor.
Results:
NGS of DNA extracted from blood identified a pathogenic BRCA1 mutation, c.1953dupG (p.Lys652GlufX21), in 5% of reads (X450 coverage). No other pathogenic mutations were detected in other genotyped cancer susceptibility genes. Analysis of buccal tissue and normal breast tissue removed at initial surgery also identified this mutation in ∼5% of reads, and confirm that this individual is a constitutional mosaic for this mutation. Genetic analyses were subsequently performed on the breast cancer tissue using Genome Health platform (Foundation One) and the same mutation, c.1943dupG was detected in 47% of molecules. Sanger sequencing of BRCA1 and BRCA2 in DNA extracted from peripheral blood had not detected this mutation. Analysis of the maternal DNA did not reveal this mutation, and analysis of the father was not possible.
Conclusion:
This is the first reported case of a de novo constitutional mosaicism in BRCA1 at this level of detection and confirmed across multiple tissue types, and highlights the need to perform deep sequencing in individuals clinically suspected of having cancer predisposition, prior to considering risk-reducing surgery.
Citation Format: Eitan Friedman, Noa Efrat, Lior Soussan-Gutman, Addie Dvir, Yulia Kaplan, Tali Ekstein, Keith Nykamp, Martin Powers, Marina Rabideau, Scott Topper. Low-level constitutional mosaicism of a de novo BRCA1 gene mutation [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 P4-12-09.