title: BRCA1/2-negative hereditary triple-negative breast cancers exhibit BRCAness.
abstract: BRCA1/2-associated breast cancers are sensitive to poly(ADPribose) polymerase (PARP) inhibitors and platinum compounds mainly due to their deficiency in DNA repair via homologous recombination (HR). However, approximately only 15% of triple-negative breast cancers (TNBCs) are BRCA1/2-associated. TNBCs that exhibit BRCAness (a phenotype reflecting impaired HR in BRCA1/2-negative tumors) are also regarded sensitive to PARP inhibitors and platinum compounds. Thus, we hypothesized that hereditary BRCA1/2-negative TNBCs may exhibit BRCAness. To find a subset of hereditary BRCA1/2-negative TNBCs among 360 TNBCs, we first identified a group of 41 hereditary TNBCs by analyzing the family histories of the patients. Next, we tested this group for the presence of germline BRCA1/2 mutations, and finally, we compared the expression levels of 120 genes involved in HR and five other major mechanisms of DNA damage repair between BRCA1/2-associated and BRCA1/2-negative subgroups of hereditary TNBCs using real-time PCR arrays. Approximately 73% of the hereditary TNBCs were BRCA1/2-associated and 27% were BRCA1/2-negative. The expression levels of the analyzed genes showed no significant differences between these two subgroups indicating the BRCAness of the BRCA1/2-negative hereditary TNBCs and thereby distinguishing a novel subset of TNBCs as a potential target for PARP inhibitors or platinum-based therapy. The results show the significance of family history in selecting patients with TNBC for therapies directed at incompetent DNA repair (e.g., PARP inhibitors and/or platinum-based therapies) and indicate that a relatively simple strategy for broadening the target group for these modes of treatment is to identify patients with hereditary TNBCs.
authors.affiliation: Department of Pathology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Domagala
authors.affiliation: Department of Pathology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Hybiak
authors.affiliation: Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Cezary
authors.initials: C
authors.lastname: Cybulski
authors.affiliation: Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Lubinski
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D059765:Homologous Recombination; D006801:Humans; D008875:Middle Aged; D010641:Phenotype; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000737:chemistry; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012042:Registries; D011795:Surveys and Questionnaires; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases
keywords: BRCA1/2; BRCAness; PARP inhibitors; breast cancer; triple-negative