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Comprehensive Genomic Analysis Sheds New Light on Subtypes of Breast Cancer

Comprehensive genomic analysis of breast tumors has revealed four main subclasses of breast cancer, each of which has extensive genetic heterogeneity, said an international consortium of scientists in The Cancer Genome Atlas Network that includes scientists from the Baylor College of Medicine (BCM), and from 90 other institutions around the world. The result were published in an open article online on September 23, 2012 in Nature. "In the last 10 years, new technologies have allowed us to look at these tumors at a variety of different levels," said Dr. Chad Creighton, an associate professor in the National Cancer Institute-designated Dan L. Duncan Cancer Center at BCM, who worked on the analysis of the various genomic datasets, which included, for all genes, the sequence, expression, copy number, and any epigenetic silencing. Dr. Lawrence Donehower, professor of molecular virology and microbiology at BCM, concentrated on analysis involving a particular tumor suppressor gene called p53. "We took all these data and used them together to identify these four basic subtypes of tumors that we’ve known about for some time," said Dr. Creighton. "Among other things, this study aimed to get at the fundamental question of just how many subtypes of breast cancer there are, because that can determine treatment." "This is one of the largest multi-institutional and multi-platform efforts of this kind to date," said Dr. Donehower. For this report, members of the consortium evaluated tumors and tissue samples from 825 patients with breast cancer. Of these, 510 tumors from 507 patients underwent sequencing of the whole exome (the protein-coding portion of the genome) and identified 30,626 somatic mutations. (Somatic refers to cells or tissues other than the egg or sperm that make up the germ cells of the body.) The 35 genes judged "significantly mutated" by one analysis included nearly all the genes known to be mutated in breast cancer and several novel ones. The researchers also performed analysis of messenger RNA and microRNA (small single strands of genetic material that affect gene regulation), DNA methylation (the addition of a methyl molecule that usually turns a gene off), DNA copy number (alterations of the genome that can result in deletion of a gene or additional copies of gene) and of results obtained using a technique called reverse-phase protein array that evaluates the activities of proteins. When the results of these studies were taken together, the Cancer Genome Atlas consortium identified the subtypes as: luminal A breast cancers, which were the most heterogeneous or varied across all platforms; luminal B breast cancers that had a diversity of significantly mutated genes with TP53 and PIK3CA being the most frequent; HER2-based tumors, which express the protein HER-2 that is targeted by the drug trastuzumab (Herceptin®); and basal-like tumors or triple-negative breast cancers that lack the most common breast cancer drug targets—estrogen receptor, progesterone receptor, and HER-2. The study also noted that the different types do not seem to evolve from one another, said Dr. Creighton. For example, most luminal A breast cancers could not evolve into basal-like cancers, as luminal A cancers harbor a PIK3CA mutation that basal-like cancers lack. Understanding the genes involved in the different subtypes can give researchers targets for developing new treatments. "We wanted to understand what are the subtypes and what are the pathways that distinguish those subtypes," said Dr. Creighton. [Press release] [Nature article]