Genomic profiling of breast tumours in relation to BRCA abnormalities and phenotypes

• Published in: Breast cancer research : BCR Vol. 11; no. 4; p. R47
• Main Authors: Stefansson, Olafur Andri, Jonasson, Jon Gunnlaugur, Johannsson, Oskar Thor, Olafsdottir, Kristrun, Steinarsdottir, Margret, Valgeirsdottir, Sigridur, Eyfjord, Jorunn Erla
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 01-01-2009; National Library of Medicine - MEDLINE Abstracts; BioMed Central
• Subjects: Biomarkers, Tumor - analysis; BRCA mutations; Breast cancer; Breast Neoplasms - chemistry; Breast Neoplasms - classification; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Chromosome abnormalities; Cluster Analysis; Comparative Genomic Hybridization; Complications and side effects; Female; Gene Dosage; Gene Expression Profiling; Genes, BRCA1; Genes, BRCA2; Genetic aspects; Genetic susceptibility; Genomic Instability; Genotype; Health aspects; Humans; Oligonucleotide Array Sequence Analysis; Phenotype; Risk factors; Sequence Deletion; Iceland
• ISSN: 1465-5411; 1465-542X
• DOI: 10.1186/bcr2334

Germline mutations in the BRCA1 and BRCA2 genes account for a considerable fraction of familial predisposition to breast cancer. Somatic mutations in BRCA1 and BRCA2 have not been found and the involvement of these genes in sporadic tumour development therefore remains unclear.
The study group consisted of 67 primary breast tumours with and without BRCA1 or BRCA2 abnormalities. Genomic alterations were profiled by high-resolution (~7 kbp) comparative genome hybridisation (CGH) microarrays. Tumour phenotypes were analysed by immunohistochemistry on tissue microarrays using selected biomarkers (ER, PR, HER-2, EGFR, CK5/6, CK8, CK18).
Classification of genomic profiles through cluster analysis revealed four subgroups, three of which displayed high genomic instability indices (GII). Two of these GII-high subgroups were enriched with either BRCA1- or BRCA2-related tumours whereas the third was not BRCA-related. The BRCA1-related subgroup mostly displayed non-luminal phenotypes, of which basal-like were most prominent, whereas the other two genomic instability subgroups BRCA2- and GII-high-III (non-BRCA), were almost entirely of luminal phenotype. Analysis of genome architecture patterns revealed similarities between the BRCA1- and BRCA2 subgroups, with long deletions being prominent. This contrasts with the third instability subgroup, not BRCA-related, where small gains were more prominent.
The results suggest that BRCA1- and BRCA2-related tumours develop largely through distinct genetic pathways in terms of the regions altered while also displaying distinct phenotypes. Importantly, we show that the development of a subset of sporadic tumours is similar to that of either familial BRCA1- or BRCA2 tumours. Despite their differences, we observed clear similarities between the BRCA1- and BRCA2-related subgroups reflected in the type of genomic alterations acquired with deletions of long DNA segments being prominent. This suggests similarities in the mechanisms promoting genomic instability for BRCA1- and BRCA2-associated tumours, possibly relating to deficiency in DNA repair through homologous recombination. Indeed, this feature characterized both familial and sporadic tumours displaying BRCA1- or BRCA2-like spectrums of genomic alterations. The importance of these findings lies in the potential benefit from targeted therapy, through the use of agents leading to DNA double-strand breaks such as PARP inhibitors (olaparib) and cisplatin, for a much larger group of patients than the few BRCA1 and BRCA2 germline mutation carriers.