In one of the largest cancer genomics investigations reported to date, scientists have sequenced the whole genomes of tumours from 50 breast cancer patients and compared them to the matched DNA of the same patients' healthy cells. This comparison allowed researchers to find mutations that only occurred in the cancer cells.

Researchers uncovered incredible complexity in the cancer genomes, but also got a glimpse of new routes toward personalized medicine. The research was presented at the AACR 102nd Annual Meeting 2011, held April 2-6.

In all, the tumours had more than 1,700 mutations, most of which were unique to the individual, said Matthew Ellis, M.D., Ph.D., professor of medicine at Washington University School of Medicine in St. Louis and a lead investigator on the project.

"Cancer genomes are extraordinarily complicated," said Ellis. "This explains our difficulty in predicting outcomes and finding new treatments."

Washington University oncologists and pathologists at the Siteman Cancer Center collaborated with the university's Genome Institute to sequence more than 10 trillion chemical bases of DNA — repeating the sequencing of each patient's tumour and healthy DNA about 30 times to ensure accurate data.

The DNA samples came from patients enrolled in a clinical trial that Ellis is leading for the American College of Surgeons Oncology Group. All patients had estrogen-receptor-positive breast cancer. These cancer cells have receptors that bind to the hormone estrogen and help the tumours grow.

To slow tumour growth and make the tumours easier to remove, patients received estrogen-lowering drugs before surgery. But, for unknown reasons, this treatment does not always work; only 26 of the 50 tumour samples responded. Comparing the responders and those who were resistant might help explain why some ER-positive breast cancer patients do well with estrogen-lowering drugs and others poorly.

Confirming previous work, the researchers found that two mutations were relatively common in many of the patients' cancers. PIK3CA is present in about 40 percent of breast cancers that express receptors for estrogen and TP53 is present in about 20 percent. Ellis and colleagues found a third, MAP3K1, that controls programmed cell death and is disabled in about 10 percent of ER-positive breast cancers. The mutated gene allows cells that should die to continue living. Only two other genes, ATR and MYST3, harbored mutations that recurred at a similar frequency as MAP3K1 and were statistically significant.

"To get through this experiment and find only three additional gene mutations at the 10 percent recurrence level was a bit of a shock," he said.

In addition, they found 21 genes that were also significantly mutated, but at much lower rates — never appearing in more than two or three patients. Despite the relative rarity of these mutations, Ellis stressed their importance.

"Breast cancer is so common that mutations that recur at a 5 percent frequency level still involve many thousands of women," he said.

Ellis pointed out that some mutations that are rare in breast cancer may be common in other cancers and already have drugs designed to treat them. But such treatment is only possible when the cancer's genetics are known in advance. Ideally, the goal is to design treatments by sequencing the tumour genome when the cancer is first diagnosed, according to Ellis.

"We get good therapeutic ideas from the genomic information," he said. "The near term goal is to use information on whole genome sequencing to guide a personalized approach to the patient's treatment."

While many mutations are rare or even unique to one patient, Ellis said quite a few can be classified on the basis of common biological effects and, therefore, could be considered together for a particular therapeutic approach.

Ellis looks to future work to help make sense of breast cancer's complexity. But these highly detailed genome maps are an important first step.

"At least we're reaching the limits of the complexity of the problem," he said. "It's not like looking into a telescope and wondering how far the universe goes. Ultimately, the universe of breast cancer is restricted by the size of the human genome."

Source: AACR