Molecular characteristics of inherited breast tumors
© Current Science Ltd 2000
Published: 12 March 2000
Germline mutations in genes involved in DNA double-strand break repair (DSBR) and DNA damage-induced checkpoint activation are associated with chromosomal breakage syndromes and (breast) cancer predisposition. These genes include TP53, CHK2, ATM, NBS1, Mre11 and the two major breast-cancer susceptibility genes BRCA1 and BRCA2. Breast tumors from BRCA1 and BRCA2 mutation carriers have explicit histopathological features and genetic alterations, distinct from other forms of inherited (BRCAx) and sporadic breast cancer. This suggests that transformation of DSBR-deficient cells follows abrogation of specific cell-cycle control and apoptosis mechanisms, and results in genetic instability and tumor progression along distinguishable pathways. Comparative genomic hybridization (CGH) analysis may give hints to the location of such genes by showing frequent loss of chromosome 4, 5q, 12q, 13q and Xq in BRCA1 tumors, and of 1p, 3p, 6q, 8p, 9p, 11q, 13q and Xq in BRCA2 tumors. Frequent copy number gains are seen at 1q, 6p, 8q, 10p, 16p and 17q in BRCA1 tumors, and at 1q, 8q, 16p, 17q, 19 and 20q in BRCA2 tumors. By extending the analyses to the level of gene expression, using cDNA microarrays containing 6500 sequence-verified human genes or ESTs, we have shown that BRCA1 and BRCA2 tumors can be separated into distinct clusters by multi-dimensional scaling and hierarchical dendrogram analysis of expression data. Genes consistently up or downregulated in each group of inherited breast cancer have been identified, and will be evaluated as diagnostic tools in new sets of tumors, also on the level of protein expression. The presumably heterogeneous group of BRCAx breast tumors exhibits, in general, a less aggressive phenotype, being typically of low malignant grade and steroid receptor-positive status. Further characterisation of gene alteration and expression profiles in these tumors may be used as a complement to traditional linkage analysis in the search for additional breast cancer susceptibility genes.