April 3, 2011

DNA Decoded In 50 Breast Cancer Patients

Scientists have sequenced the whole genome of tumors from 50 breast cancer patients and compared them to the matched DNA of the same patients' healthy cells, according to a study released by Washington University School of Medicine. The comparison will allow researchers to find any mutations that only occurred in the cancer cells.

This is the single largest cancer genomics investigation ever conducted. The research was presented at the American Association for Cancer Research 102nd Annual Meeting 2011.

Although the cancer genomes were incredibly complex, researchers were able to get a glimpse into new routes towards personalized medicine, the study reports.

"Cancer genomes are extraordinarily complicated," says a lead investigator on the project, Matthew J. Ellis, MD, PhD, professor of medicine at Washington University School of Medicine in St. Louis.

"This explains our difficulty in predicting outcomes and finding new treatments."

There were more than 1,700 mutations in the tumors, which were unique to each individual, says Ellis.

The study confirmed Ellis and his colleagues' previous work. It found two relatively common mutations in many of the patients' cancers. PIK3CA mutation was present in 40% of breast cancers that are receptive to estrogen and TP53 mutation was found in 20% of breast cancers, the study reports.

A third mutation was also detected, MAP3K1. This mutated gene "controls programmed cell death," and is found to be disabled in 10% of estrogen-receptor-positive breast cancers. Cells that should die are allowed to continue living with this mutated gene.

Two other mutated genes, ATR and MYST3, recurred at a similar frequency to MAP3K1 and are 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," says Ellis.

21 more genes were found to be significantly mutated, but these never appeared in more than two or three patients.

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

Mutations that are rare in breast cancer may be common in other cancers that may already have drugs to treat them. However, such treatment is only if the cancer's genetics are known in advance, says Ellis.

"You may find the rare breast cancer patient whose tumor has a mutation that's more commonly found in leukemia, for example. So you might give that breast cancer patient a leukemia drug," he says.

The ideal goal is to design treatments for cancers by sequencing the tumor genome at first diagnosis.

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

DNA samples for this investigation came from patients enrolled in a clinical trial led by Ellis for the American College of Surgeons Oncology Group. Patients in the trial had estrogen-receptor-positive breast cancer, with cancer cells having receptors "that bind to the hormone estrogen and help the tumors grow."

Before surgery, patients from the clinical trial received estrogen-lowering drugs to slow tumor growth and make them easier to remove. However, not all patients' cancers were receptive to the estrogen.

By comparing patients who responded well to the estrogen-lowering drug and those who did not, researchers hope to find some answers.

Out of the 50 DNA samples, 24 were taken from patients who were resistant to the estrogen treatment, and 26 were samples from patients whose tumors responded to the estrogen.

More than 10 trillion chemical bases of DNA were sequenced. Each patient's tumor and healthy DNA sequences were repeated about 30 times to ensure accurate data.

This was a massive task, undertaken by Washington University oncologists and pathologists at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, and in collaboration with the university's Genome Institute.

"The computing facilities required to analyze this amount of data are similar in scale to those of the Large Hadron Collider, used to understand the workings of sub-atomic particles," Ellis states.

Future work is needed to make sense of breast cancer's complexity. Mapping these highly detailed genomes is a first step, Ellis says.

"At least we're reaching the limits of the complexity of the problem," he says. "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."


Image 2: The above Circos plot is a visual representation of the genomic disruptions in one of the breast cancers studied. Credit: Matthew J. Ellis, MD, PhD


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