Gene expression profiling of hereditary and sporadic ovarian cancers reveals unique BRCA1 and BRCA2 signatures.

The recent completion of the draft human genome sequence (1) presents countless opportunities to investigate genome function and the importance of alterations in the genetic code in both health and disease. Among the most rapidly adopted of the emerging genomic technologies, microarray hybridization permits the parallel determination of the expression of tens of thousands of genes in tissue samples (2). Microarray studies have proven to be of great value in further understanding the basic biology of cancer and have been used successfully to classify tumors into distinct, clinically relevant subgroups based on gene expression profiles and to identify potential biomarkers. Ovarian cancers differ from many other human tumors in displaying considerable disease heterogeneity, a poorly understood progression pathway, and few good tumor markers. In addition, ovarian cancers are usually diagnosed at a late stage, and the survival rate, therefore, is poor. Improved knowledge of the changes in gene expression associated with progression of ovarian cancer and with different forms of the disease, therefore, may lead to greater understanding of the underlying disease mechanisms and the development of possible intervention strategies. In this issue of the Journal, Jazaeri et al. used complementary DNA (cDNA) microarrays to examine the role of mutations in the BRCA1 and BRCA2 genes in ovarian carcinogenesis by comparing gene expression patterns in ovarian cancers that are associated with germline BRCA1 and BRCA2 mutations and expression patterns in sporadic ovarian cancers (3). The most striking finding was that the BRCA1and BRCA2-associated tumors displayed distinct gene expression profiles. Indeed, 110 genes of the approximately 6500 genes analyzed were found to be differentially expressed (P<.0001) between these two subtypes of ovarian cancer. This result is in agreement with previous studies illustrating differences in gene expression profiles between BRCA1and BRCA2-derived breast cancers (4,5). Remarkably, the gene expression profiles of the sporadic tumors appeared to share features of BRCA1or BRCA2-associated cancers, as illustrated by the segregation of the sporadic samples into two groups based on the expression pattern of the BRCA1 versus BRCA2 genes. In other words, each sporadic sample had a molecular profile similar to that of either the BRCA1or the BRCA2-associated tumors. The genes that separate the BRCA1versus BRCA2-associated ovarian cancers and the two subsets of sporadic tumors are involved in important cellular functions, such as signal transduction, RNA processing and translation, chemokine signaling, immune modification, and DNA repair. As such, they may represent important mediators of common genetic pathways in ovarian carcinogenesis, and further investigation of these genes may provide insight into the development of BRCA1and BRCA2-associated ovarian cancer. In agreement with the finding that the sporadic cancers shared gene expression features of either BRCA1 or BRCA2 tumors, it is not surprising that only a small number of genes were found to separate between the combined BRCA-associated group and the sporadic tumors (3). The separation of the sporadic tumors into BRCA1-like and BRCA2-like subgroups may be caused by the dysfunction of BRCA1 or BRCA2 proteins or downstream effector molecules in either of the pathways. With regard to clinical and pathologic features, BRCA-associated cancers are not clinically significantly different from sporadic cases, although the mean age at diagnosis has been reported to be lower in patients with BRCA1associated ovarian cancer (6). The observation that BRCAassociated gene expression profiles can be recapitulated in subsets of sporadic tumors indicates that molecular mechanisms common to both hereditary and sporadic ovarian carcinogenesis exist. As suggested, a possible explanation for this finding might be the disruption of BRCA function in sporadic tumors, either of the BRCA genes themselves, or of other key molecules in the same functional pathways. Loss of heterozygosity at the BRCA1 and BRCA2 loci among sporadic ovarian tumors is high (7), but somatic mutations in the BRCA genes are rare (8). Loss of BRCA1 expression through promoter hypermethylation has been reported in approximately 15% of breast and ovarian cancers (9,10). Of interest, BRCA1 hypermethylation in breast cancer is more common in the medullary subtype of breast cancer that is overrepresented in patients with BRCA1 germline mutations (9), emphasizing the clinical significance of BRCA1 deficiency in the development of breast cancer. The recent finding of a BRCA1-like gene expression profile in a sporadic breast cancer with BRCA1 promoter hypermethylation is consistent with a role for epigenetic alterations of BRCA1 in some sporadic cancers and illustrates the sensitivity of gene expression profiling in identifying unique expression profiles in subsets of tumors