Decoding tumor genomes reveals clues to spread of deadly breast cancer

Using powerful DNA sequencing technology to decode the genomes of cancer patients, scientists at Washington University School of Medicine in St. Louis are getting an unprecedented look at the genetic basis of a highly lethal breast cancer that disproportionately affects younger women and those who are African-American.

They have decoded the genome of a 44-year-old African-American woman with so-called "triple negative" breast cancer and the genomes of her breast tumor and a metastatic tumor that quickly developed in her brain. By comparing the DNA sequences of the three genomes, the scientists identified 20 genetic changes in a subset of cells in the woman's breast tumor that likely played a role in the metastasis that killed her within months, they report April 15 in Nature.

The research suggests that sequencing entire genomes of cancer patients as well as their primary and metastatic tumors can reveal clues to the way the tumors spread and can set the stage for developing more effective drugs that target key genetic errors.

"We are getting an intimate look at the lethal spread of a breast cancer, which is now possible because we can sequence entire genomes quickly at a reasonable cost," says senior author Elaine Mardis, PhD, co-director of Washington University's Genome Center. "This work lays the foundation for understanding the genetic basis of tumor progression and metastasis, and for identifying new drug targets that can improve the outlook for women with this disease."

The patient, the first African-American to have her genome sequenced, had an aggressive, "basal-like" subtype of breast cancer. These genetically unstable tumors account for about 10 percent of all breast cancers and are often called triple-negative because they lack any receptors to which treatment can be targeted. They grow rapidly and typically do not respond well to chemotherapy.

That was the experience of the woman in this study. She initially received chemotherapy to shrink a large breast tumor and then had a mastectomy. When surgeons found evidence of treatment-resistant tumor cells in her lymph nodes, she received radiation therapy, but it did not halt the cancer. The tumor spread to the woman's brain, and she died within a year of her diagnosis.

In the current study, the researchers also sequenced the genome of the patient's breast tumor after growing it in a mouse, to determine whether the animal model can reproduce the genetic profile of the human cancer. The tumor was inserted into the mouse before the patient received cancer treatment.

"The tumor grown in the mouse was remarkably similar to the patient's own breast tumor," Mardis says. "The human tumor and the mouse counterpart shared all of the same mutations and the same fateful course: both spread to other sites. This similarity suggests that mouse models can be valid preclinical surrogates of metastatic disease to evaluate new cancer drugs."