Abstract P3-04-02: Molecular analysis of breast cancers from individuals with hereditary cancer syndromes secondary to mutations in BRCA1, BRCA2, ATM, CHEK2, and PALB2
Authors: Blum JL , Wong S , Pearson EJ , Nair A , Snipes GJ , Briones N , Baker A , Cropp CD , Carpten JD 
Published: February 2018

Abstract
Background: Despite a growing understanding of the somatic landscape of breast tumors from BRCA1 and BRCA2 mutation carriers, less is known about breast tumors from carriers of germline mutations in other homologous recombination and DNA repair pathway genes such as ATM, CHEK2, and PALB2.
Methods: We identified 44 clinically annotated breast cancer cases that included carriers of germline mutations in BRCA1 (n=9), BRCA2 (n=9), ATM (n=5), CHEK2 (n=7), and PALB2 (n=6) from the Hereditary Cancer Risk Program at BUMC. Sporadic breast cancers cases (n=8) were also collected. Genomic DNA and RNA were extracted from macro-dissected FFPE tumor sections, adjacent normal FFPE tissue, along with constitutional genomic DNA from blood. Expanded whole exome sequencing (WES) was performed on normal/tumor pairs and RNA-seq from tumors for each case. Bioinformatics analysis was performed using industry standard methods for somatic characterization.
Results: All germline mutations were confirmed by WES. Somatic mutational analysis and copy number profiling from WES revealed the greatest similarities among BRCA1 and CHEK2 carriers. As expected, TP53 mutations were found in 8 of 9 BRCA1 carriers as all were triple negative subtype. We also detected somatic TP53 mutations in tumors from 4 of 7 CHEK2 carriers. Somatic TP53 mutations were found in only 1 of 7 BRCA2 tumors and 1 of 4 PALB2 tumors tested. Furthermore, BRCA1 and CHEK2 tumors showed trends of having higher mutation burden. Analysis of copy number BRCAness demonstrated stronger similarities between BRCA1, ATM, CHEK2, and PALB2 tumors. BRCA2 tumors were unique with fewer events and characterized by specific amplifications including 11q23 (CCND1) and 17q23 (BRIP1). Hierarchical clustering of RNA-seq data revealed strong clustering of BRCA1 tumors compared to all other tumors, predominantly attributed to breast cancer subtype. Furthermore, pathway analysis of genes that distinguish BRCA1 mutation positive versus non-BRCA mutated tumors showed strong correlation to pro-inflammatory and immune pathway signatures.
Conclusions: Molecular analysis of 44 breast cancers from individuals with inherited predisposition to breast cancer via BRCA1, BRCA2, ATM, CHEK2, and PALB2 germline mutations demonstrated strongest somatic similarities between BRCA1 and CHEK2 tumors although all BRCA1 were TNBC and all CHEK2 tumors were ER positive. Marked differential gene expression differences in RNA expression patterns were observed in BRCA1 mutation carriers compared with all other groups analyzed. Our study is among the first to interrogate the profile of non-BRCA mutated hereditary breast cancers.
Citation Format: Blum JL, Wong S, Pearson EJ, Nair A, Snipes GJ, Briones N, Baker A, Cropp CD, Carpten JD. Molecular analysis of breast cancers from individuals with hereditary cancer syndromes secondary to mutations in BRCA1, BRCA2, ATM, CHEK2, and PALB2 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-04-02.