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Genome Sequencing Study Offers Clues about Basal-Like Breast Cancer Metastasis

By Andrea Anderson

NEW YORK (GenomeWeb News) – A Washington University-led research team reported today that they have sequenced a quartet of genomes originating from an African-American woman with basal-like breast cancer.

By sequencing the primary breast tumor, a brain metastasis, matched normal tissue, and a mouse xenograft developed from the primary tumor, the researchers were able to identify mutations shared in all of the tumors as well as genetic changes that were enriched — or found exclusively — in metastatic tissue. The research appears online today in Nature.

The team decided to study basal-like breast cancer because it is aggressive and tends to affect younger women and African-American women, co-senior author Elaine Mardis, co-director of Washington University's Genome Center, told GenomeWeb Daily News. Moreover, basal-like breast cancer tumors are estrogen receptor negative and respond poorly to chemotherapy.

The researchers used Illumina paired-end sequencing of DNA from a primary tumor from a 44-year-old woman with triple negative basal-like breast cancer who ultimately died from the disease.

They also sequenced DNA from a brain metastasis that formed after the woman received chemotherapy and radiation treatment, a first passage xenograft sample developed by implanting primary tumor tissue into an immunocompromised mouse, and matched normal DNA from the woman's blood. Roche 454 and Sanger sequencing were used to validate these results.

In the process, the researchers generated 38.8 times coverage of the haploid matched normal genome, 29 times coverage of the primary tumor genome, 32 times coverage of the brain metastasis genome, and 23.8 times coverage of the xenograft genome.

During their analyses of these genomes, the team identified 50 point mutations and small insertions or deletions that were present in one of the tumor genomes but not matched normal tissue, including 48 mutations found in all three tumors. They also found dozens of large deletions and a handful of inversions and translocations.

Among the genes affected: CSMD1, a gene shown to be mutated in some colorectal, head, and neck cancers that has also been linked to survival in invasive ductal breast cancer, JAK2 and NRK, genes mutated in some other breast cancers, and TP53, another known cancer-related gene.

Such results suggest the same genes are often mutated in cancers turning up at various sites in the body, Mardis noted. Additional cancer genome analyses may eventually yield clues about developing site-agnostic treatments.

And, the researchers explained, the mutations detected in the mouse xenograft model were very similar to those detected in the other tumor samples, consistent with the notion that such xenograft systems can be used to study human cancers in animals.

"The human tumor and the mouse counterpart shared all of the same mutations and the same fateful course: both spread to other sites," Mardis said in a statement. "This similarity suggests that mouse models can be valid preclinical surrogates of metastatic disease to evaluate new cancer drugs."

Of the 48 point mutations and small indels present in all three tumors, 20 were significantly enriched in the metastatic tumor, reflecting the fact that the metastatic tumor is made up of a subset of cells that have survived treatment, Mardis explained.

Compared with the other tumor samples, the team reported, the metastatic genome contained only two new point mutations — a missense mutation in SNED1 and a silent mutation in FLNC — and one deletion. That's far fewer differences than detected last fall by British Columbia researchers who sequenced an estrogen receptor positive, lobular breast cancer and metastasis.

For that study, though, researchers looked at a metastasis that formed nine years after cancer diagnosis, Mardis noted. In contrast, the brain metastasis sampled in the current study formed just eight months after the patient received radiation treatment.

Although the team hopes to sequence additional sets of primary, metastatic, and matched normal genomes, Mardis added, such metastatic samples are often difficult to obtain through tumor banks since metastases often are not surgically removed.

The work represents one aspect of a much larger cancer genome sequencing effort at Washington University, where researchers have reportedly sequenced roughly 150 matched tumor-normal samples, including breast, lung, ovarian, and brain cancers.

This January, researchers at Washington University announced that they were embarking on a collaboration with investigators at St. Jude Children's Hospital to sequence more than 600 pediatric tumor-normal samples.

"Moving forward, we'll be comparing tumor genomes from many patients with the same type of cancer to find common genetic alterations," Washington University Genome Center Director and co-senior author Richard Wilson said in a statement. "This comprehensive understanding of cancer can aid in the development of new approaches to cancer diagnosis and treatment."

Meanwhile, in a perspectives article set to appear in the same issue of Nature, members of the International Cancer Genome Consortium discussed the goals and progress being made by the group, touching on everything from ethics and data policies to clinical applications of cancer genome research. The ICGC aims to bring together genomic data on 50 cancer types and subtypes.

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