ABSTRACT
Somatic inactivation of the remaining allele is a characteristic feature of cancers arising in BRCA1 and BRCA2 mutation carriers, which determines their unprecedented sensitivity to some DNA-damaging agents. Data on tumor-specific status of the involved gene in novel varieties of hereditary breast cancer (BC) remain incomplete. We analyzed 32 tumors obtained from 30 patients with non-BRCA1/2 BC-associated germ-line mutations: 25 women were single mutation carriers (7 BLM, 15 CHEK2 and 3 NBN/NBS1) and 5 were double mutation carriers (2 BLM/BRCA1, 1 CHEK2/BLM, 1 CHEK2/BRCA1 and 1 NBN/BLM). Losses of heterozygosity affecting the wild-type allele were detected in none of the tumors from BLM mutation carriers, 3/18 (17 %) CHEK2-associated BC and 1/4 (25 %) NBN/NBS1-driven tumors. The remaining 28 BC were subjected to the sequence analysis of entire coding region of the involved gene; no somatic mutations were identified. We conclude that the tumor-specific loss of the wild-type allele is not characteristic for BC arising in CHEK2, NBN/NBS1 and BLM mutation carriers. Rarity of "second-hit" inactivation of the involved gene in CHEK2-, NBN/NBS1- and BLM-associated BC demonstrates their substantial biological difference from BRCA1/2-driven cancers and makes them poorly suitable for the clinical trials with cisplatin and PARP inhibitors.
Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Cycle Proteins/genetics , Checkpoint Kinase 2/genetics , Mutation/genetics , Nuclear Proteins/genetics , RecQ Helicases/genetics , BRCA1 Protein/genetics , Biomarkers, Tumor/genetics , Female , Genetic Predisposition to Disease , Heterozygote , Humans , Loss of Heterozygosity , Neoplasm Staging , PrognosisABSTRACT
This case report describes a 35-year-old woman who was diagnosed with mixed epithelial/mesenchymal metaplastic carcinoma (carcinosarcoma) of the breast. Genetic analysis of blood DNA revealed a common founder mutation, BRCA1 5382insC. Examination of microdissected tumor samples determined that both epithelial and mesenchymal components contained deletion of the wild-type BRCA1 allele. This report exemplifies that even very uncommon breast tumor types may develop through biallelic inactivation of BRCA1 gene, that has to be considered in the genetic testing settings.
