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A new gene for breast/ovarian cancer (12/2003)

A new human breast and ovarian cancer gene has just been described by investigators in the last issue of the journal Cell1. The gene, called EMSY, also characterises a subset of breast cancer with poorer survival, which makes it a potentially important diagnostic tool.

The work by Luke Hughes-Davies and Margarida Ruas at the Cancer Research UK/Welcome Trust Institute, Cambridge, UK and David Huntsman at the Vancouver General Hospital, Canada suggest that EMSY is involved in DNA repair. Furthermore, the team of investigators report that EMSY seems to lead to ovarian and breast cancer by inactivating a gene involved in DNA repair. Unrepaired DNA mutations can then lead to disease.

Despite many years of study and significant progress in understanding the mechanisms of susceptibility to disease, ovarian and breast cancers remains an important cause of death among women. In breast cancer alone, there were more than 1.2 million cases diagnosed last year and at the age of 60, as many as 1 out of 23 women are in risk of suffering of the disease.
Two types of breast and ovarian cancers exist: inherited, where the patient belongs to a family with previous cases of the disease (also called familial cancer) or sporadic, where patients have no recorded family history of the disease.   Sporadic cancers comprise the majority of the breast/ovarian cancers with 95% of the cases, while the remaining 5%, are familial cancers.

In familial breast and ovarian cancer, two major genes have been associated with susceptibility to disease: BRCA-1 and BRCA-2. Both genes seem to be involved in DNA repair and mutation in either of them confers a lifetime risk of cancer (60- 85% to breast cancer and 15-40% of ovarian cancer).

In sporadic cases of breast/ovarian cancer, however, it has been extremely difficult to link mutations in these genes with disease. And, although recent results seem to suggest that BRCA-1 can be found inactivated without being mutated in some sporadic breast/ovarian cancers, nothing similar has been found for BRCA-2.

But now, Hughes-Davies, Ruas and Huntsman describe a new gene, EMSY, which produces a protein that binds to BRCA-2 and suppresses its activity and consequently could have a role in cancer. They also discovered that this gene localises in a chromosomal region long associated with sporadic ovarian and breast cancer. 

Following these results, the team of investigators analysed more than 1800 sporadic breast cancer tissues and discovered that mutation in EMSY that led to the presence of extra copies of the gene, was associated with disease -13% of the cases analysed showed this EMSY amplification. Hughes-Davies, Ruas and Huntsman also found a correlation between extra copies of EMSY and a subset of breast cancer with worst diagnosis.

Furthermore, when sporadic ovarian cancers were analysed, EMSY amplification was present in 17% of the cases and seemed to be linked to cancers with higher malignancy, a result similar to the one observed in familial ovarian cancers with BRCA-2 mutations.

These are very important results because they show, for the first time, that inactivation of BRCA-2 is implicated in cases of sporadic cancer. The disease mechanism involves EMSY, a gene that when overactive/amplified interferes with the capacity of BRCA-2 to repair damaged DNA and leads to disease.

The team of investigators say “We have cloned EMSY, a novel human breast and ovarian cancer gene… We have found that EMSY amplification is indeed seen in both sporadic breast and ovarian cancers, and it has a strong adverse effect on breast cancer survival, particularly in women who did not have nodal involvement at diagnosis.”

The last ten years have been a remarkable period for the genetics of breast and ovarian cancer. Two new genes, BRCA-1 and 2, were described, in which mutations associate with inherited breast/ovarian cancer.  However, the reason behind sporadic breast/ovarian cancer cases has remained a mystery for researchers. And although recent results seem to indicate that non-inherited alterations in BRCA-1 are involved in some sporadic cases of both ovarian and breast cancer nothing was found for BRCA-2.

But now Hughes-Davies, Ruas and Huntsman found a new gene, EMSY that demonstrates, for the first time, that BRCA-2 is involved, not only in familial ovarian and breast cancer, but also in sporadic ovarian breast cancer cases. Furthermore, EMSY mutation and so BRCA-2 disruption seems to characterise a subset of sporadic breast cancer with a much poorer diagnosis which can be useful as additional information in determining appropriate strategies for prevention and early detection of breast and ovarian cancers in high-risk women. Moreover, understanding of the mechanism behind disease, in this case behind sporadic breast/ovarian cancer, is crucial in the development of treatments.


Cell (2003) vol (115), p-523-535 http://www.cell.com/content/article/abstract?uid=PIIS0092867403009309&highlight=ruas

Original paper’s authors
Margarida Ruas - margarida.ruas@pharmacology.ox.ac.uk
Luke Hughes-Davies - lh205@cus.cam.ac.uk


Margarida Ruas is a Portuguese scientist who now works in elucidating the mechanism of how a new chemical messenger (NAADP) controls calcium signals within the cell in the department of Pharmacology at the University of Oxford, Oxford, United Kingdom


In collaboration with the Observatório da Ciência e do Ensino Superior (OCES)
Financed by the Fundação para a Ciência e Tecnologia (FCT)