16 May 2005
A team led by Cambridge researchers has identified a novel gene product, EMSY, which is reported to link the BRCA2 pathway of tumorigenesis to sporadic breast and ovarian cancer. Mutations in the genes BRCA1 and BRCA2 are known to account for the majority of familial cases of breast and ovarian cancer, but as 95% of these cancers are sporadic (non-familial), the search for new genes involved with breast-ovarian cancers is important. It has long been suspected that BRCA2 might also play a role in sporadic cancers, but the gene is virtually never mutated in such cases. A highly conserved region of the BRCA2 protein encoded by exon 3 of the gene, a transcriptional activation domain, is thought to play an important role in the normal tumour suppressor function of the protein; deletions of this region have been linked with familial cancers. The paper published in the latest edition of Cell [Hughes-Davies, L. et al. (2003) Cell 115, 523-535], reports isolation of the EMSY protein via interaction with the BRCA2 transcriptional activation domain. The EMSY protein is involved in the cellular DNA damage response, and suppresses the transcriptional activation function of BRCA2. Both proteins locate to regions of DNA damage within cells, suggesting that their functions are connected.
The EMSY gene maps to a region of chromosome 11 that is amplified in many breast and ovarian tumours. Samples from several hundred breast tumours were analysed for specific EMSY amplification using tissue microarrays: the gene was amplified in 13% of the tumours tested. Similarly, 17% of high-grade ovarian cancer samples (but none of the lower grade samples) showed amplification of EMSY; higher tumour grades suggest greater potential for malignancy of that tumour. Only a tiny proportion of other tumour types were found to have amplification of the gene. Amplification was also found to correlate with clinical outcome for some subsets of breast cancer, being associated with a poor prognosis in patients with node-negative disease (i.e. where the cancer had not spread to the lymph nodes at the time of diagnosis). The median survival period for these patients was 6.4 years in cases where EMSY amplification was present, compared with 14 years where there was no such amplification. Overexpression of EMSY in some sporadic breast and ovarian cancers is proposed to have a very similar tumorigenic effect to the deletion of the BRCA2 exon 3 in familial forms of the cancers.
Comment: The normal functions of EMSY and its interactions with BRCA2 require further exploration, as does the role of EMSY amplification in cancer. However, the identification of this novel cancer-associated gene has exciting prospects for gaining improved understanding of the pathways involved in the development of both familial and sporadic forms of breast and ovarian cancer. There are also potential implications for the development of novel treatments, diagnostic and prognostic tools.