Published online 2 April 2011 | Nature | doi:10.1038/news.2011.203


Fifty genome sequences reveal breast cancer's complexity

Decoding of ten trillion bases yields no simple patterns or silver bullets.

breast cancer tumourMammograms of a malignant breast tumor before (L) and after (R) 16 weeks of aromatase inhibitor therapy. The more we learn about breast cancer, the more complicated it becomes.Dr. Kim Wiele, Paul K. Commean and Joan Moulton, Electronic Radiology Laboratory, Washington University

The deeper researchers dive into the genetics of breast cancer, the more complicated their discoveries. And the latest, and deepest, dive is no exception.

Scientists led by Matthew Ellis at Washington University in St. Louis, Missouri, have sequenced the whole genomes of 50 patients' breast cancer tumours alongside matching DNA from the same patients' healthy cells in order to identify genomic alterations present only in the cancerous cells. Their findings, presented today at the Annual Meeting of the American Association for Cancer Research in Orlando, Florida, reveal that these cancers' genetic fingerprints are highly diverse; of the 1,700 gene mutations they found in total, most were unique to individual patients' tumours, and only three occurred in 10% or more. The genomic changes were also of all kinds, from single-nucleotide variations and frame shifts to translocations and deletions.

"The results are complex and somewhat alarming, because the problem does make you sit down and rethink what breast cancer is," says Ellis, leader of the breast cancer programme at the university's Siteman Cancer Center.

Nonetheless, he says, there is reason for optimism — not least because careful analysis of the data, combined with what is already known about the functions of the affected genes, yields a wealth of new therapeutic possibilities.

Big science

The sheer volume of the scientists' enterprise is impressive: they sequenced and analysed more than ten trillion bases, using a supercomputer of a power similar to that of the Large Hadron Collider at CERN, Europe's premier physics laboratory in Geneva, Switzerland. The tumours sequenced, with average 30-fold coverage, were from oestrogen-receptor-positive breast cancers. They came from participants of two clinical trials of oestrogen-lowering drugs known as aromatase inhibitors. Patients with breast cancer who are not responsive to these drugs have significantly worse outcomes, although the molecular basis for this is poorly understood. The scientists hoped that, by comparing the genome sequences of oestrogen-sensitive tumours (26 of the 50) to oestrogen-resistant cancers (24), they might find clues to the pathological basis for the difference.

They did find at least one association — for the breast-cancer-suppressor gene MAP3K1, the protein product of which accelerates programmed cell death. Mutations that disable this gene allow cells that should die to remain living. MAP3K1 mutations were present in about 10% of the tumours, and seemed to be associated with the aromatase inhibitor-sensitive, more favorable, type of disease, particularly when the same cancer carried another, previously described mutation in a gene called PIK3CA.

This was one of two mutations already associated with breast cancer that occurred frequently in the 50 tumours: PIK3CA was found in 43% of samples and the tumour suppressor TP53 turned up in about 15%. All told, about half the cancers carried a combination of these three mutations — leaving half with cancers arising from varying constellations of much rarer mutations.

Ellis says that the complexity of their results indicates that when it comes to developing therapeutics "very clearly the only way forward is the genome-first approach. No single blockbuster drug will answer the problem of endocrine-therapy resistance".


He adds that, because breast cancer is so common, even treatments targeting pathological mechanisms triggered by relatively rare mutations could benefit many thousands of women

"The fact they have sequenced cancers in the context of a clinical trial, that's what's really significant here," says Samuel Aparicio, a breast cancer researcher at the University of British Columbia and the BC Cancer Agency in Vancouver, Canada. This is because clinical trial data allow scientists to relate genomic findings to detailed data on, for instance, patient survival. "One knows exactly what happened to those patients," says Aparicio.

Ellis, for his part, says that he has already begun his next step: to repeat the experiment on at least 1,000 more tumours. "It's complicated and we're going to have to do many many more cases to understand how this all works," he says. "But certainly we have the methodology to begin to sort it out." 


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  • #60435

    Worried, this maybe massive waste of money.
    The genomic profile of established clinical cancers
    Bears very little relation to the driving original transformation. It is probably more important to study initiating events rather then the mendelian mess of advanced cancer.

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