Molecular profiles of hereditary epithelial ovarian cancers and their implications for the biology of this disease

Abstract

BRCA1 and BRCA2 germline mutations account for the majority of hereditary ovarian cancers and comprise 10% of total cases. Ovarian cancers arising from these mutations exhibit both overlapping and distinct clinical and molecular features. The expression profiles of sporadic ovarian cancers show similarities to those of BRCA1 and BRCA2-related tumors suggesting that BRCA-related pathways may be involved in their development as well. The purpose of this review is to consider the available data on ovarian cancers in the context of other investigations of BRCA-related transcriptional alterations, and highlight areas for future research.

Figure 1

Overall expression differences between BRCA1‐linked, BRCA2‐linked, and sporadic ovarian epithelial cancers. (A) Unsupervised multidimensional scaling model based on the overall gene expression in BRCA1‐linked, BRCA2‐linked, and sporadic tumors. (B) The magnitude of differences in gene expression between various tumor groups as determined by the number of genes differentially expressed among the tumor groups when the uniform statistical cutoff P<0.0001 is applied. Figure reproduced with permission from Jazaeri et al. (2002).

Figure 2

BRCA1 and BRCA2‐discriminating genes also segregate sporadic ovarian cancers into two groups. (A) Hierarchical clustering of 110 non‐redundant genes with statistically significant differential expression between BRCA1‐linked (B1) and BRCA2‐linked (B2) tumors (modified F test, P<0.0001). The red and green intensities represent standard normal deviation (Z score) values from each gene's mean expression level (represented as black) across all 61 tumor samples. (B) Hierarchical clustering of sporadic and BRCA‐linked tumor samples based on the expression pattern of the 110 BRCA‐discriminating genes. The two major clusters correspond to BRCA1‐like (blue) and BRCA2‐like (orange) patterns of gene expression. B=BRCA1‐linked tumor; B2=BRCA2‐linked tumor; C=sporadic tumors. Tumor histology for each sample is indicated below the sample label as follows: S=serous; A=adenocarcinoma not otherwise specified; E=endometrioid; C=clear cell; M=mixed features. (C) Hierarchical clustering of sporadic samples in the absence of BRCA‐linked tumors. Note the maintenance of cluster integrity. Each sporadic sample is colored according to its cluster identity in B. The median age in years is shown for each major cluster. Figure reproduced with permission from Jazaeri et al. (2002).