UNC Scientists Play Lead Role in Genome Breast Cancer Analysis

A team of scientists with The Cancer Genome Atlas program — including a large group from Carolina — has reported finding some of the genetic causes of the most common forms of breast cancer, resulting from the program’s genetic characterization of 800 breast tumors.

The findings offer a more comprehensive understanding of the mechanisms behind four subtypes of breast cancer and provide clues for new therapeutic targets. They also have identified a molecular similarity between one subtype of breast cancer and ovarian cancer.

The researchers analyzed tumors using two basic approaches. One used an unbiased and genome-wide approach; the second worked within the context of four previously known molecular subtypes of breast cancer — HER2-enriched, luminal A, luminal B and basal-like.

Both approaches arrived at the same conclusions, suggesting that even when given the tremendous genetic diversity of breast cancers, four main subtypes were observed. This study also is the first to integrate information from six analytic technologies, providing insights into these previously defined disease subtypes.

The findings are reported in the Sept. 23, 2012, online edition of the journal Nature. The paper listed more than 30 UNC authors.

The Cancer Genome Atlas program is a groundbreaking effort to genetically characterize the entire genome of 20 different cancer types, involving scientists from around the world. UNC’s Lineberger Comprehensive Cancer Center was one of the original consortium members and will receive more than $20 million in grants to fund this research. The Cancer Genome Atlas program is funded jointly by the National Cancer Institute and the National Human Genome Research Institute, both part of the National Institutes of Health.

UNC’s Charles Perou, corresponding author of the paper, said, “Through the use of multiple different technologies, we were able to collect the most complete picture of breast cancer diversity ever. These studies have important implications for all breast cancer patients and confirm a large number of our previous findings. In particular, we now have a much better picture of the genetic causes of the most common form of breast cancer, namely Estrogen-Receptor positive/luminal A disease. We also found a stunning similarity between basal-like breast cancers and ovarian cancers.

“This study has now provided a near complete framework for the genetic causes of breast cancer, which will significantly impact clinical medicine in the coming years as these genetic markers are evaluated as possible markers of therapeutic responsiveness.”

Perou is the May Goldman Shaw Distinguished Professor of molecular oncology and a member of the Lineberger Comprehensive Cancer Center.

Perou describes UNC’s role on the project as “extensive, including generating the RNA expression data, performing integrated data analyses and playing a major role in the writing of the paper and crafting of the new hypotheses coming from this work.”

The discoveries include findings of some of the likely genetic causes of the most common form of breast cancer, which is the Estrogen-Receptor positive luminal A subtype. Luminal A tumors are the No. 1 cause of breast cancer deaths in the U.S., accounting for approximately 40 percent. Finding the genetic drivers of this subtype is of paramount importance. The Cancer Genome Atlas program team found that the mutation diversity within this group was the greatest and that even specific types of mutations within individual genes were associated with the luminal A subtype. Some of these mutations may be directly targetable by a drug or drugs in clinical development, possibly offering new options for patients.

In addition, the team compared basal-like breast tumors (also known as triple-negative breast cancers) with high-grade serous ovarian tumors and found many similarities at the molecular level, suggesting a related origin and similar therapeutic opportunities. These data also suggest that basal-like breast cancer should be considered a different disease than ER-positive/luminal breast cancer; in fact, both basal-like breast cancer and ovarian cancer were more similar to each other than either was to ER-positive/luminal breast cancer.

Perou added: “Cancer is, of course, a complex disease that includes many types of alterations, and thus, no one technology can identify all of these alterations; however, by using such a diverse and powerful set of technologies in a coordinated fashion, we were able to identify the vast majority of these alterations.”

Katherine Hoadley ’06 (PhD), study co-author, said: “Our ability to compare and integrate data from RNA, microRNA, mutations, protein, DNA methylation, and DNA copy number gave us a multitude of insights about breast cancer. In particular, highlighting how distinct basal-like breast cancers are from all other breast cancers on all data types. These findings suggest that basal-like breast cancer, while arising in the same anatomical location, is potentially a completely different disease.”

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