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Breast cancer genome analysis highlights 4 subtypes, link to ovarian cancer

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New insights should advance future treatment


 

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Analyses from the Cancer Genome Atlas (TCGA) have confirmed the existence of four primary subtypes of breast cancer, each with its own biology and survival outlooks, according to a study published in the journal Nature.1

The standard molecular subtypes are:

  • luminal A tumors
  • luminal B tumors
  • basal-like cancer, also known as triple-negative breast cancer because most of these tumors test negative for three receptors: estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2)
  • HER2-enriched tumors.

In their analyses, funded by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both part of the National Institutes of Health (NIH), researchers described new insights into the four subtypes based on a comprehensive characterization of samples from 825 breast cancer patients.

Most breast Ca cases involve luminal tumors

The milk ducts of the human breast, lined with luminal cells, are the most common origin of breast cancers. Malignancies that arise from these cells are fed by estrogen, spurring growth. Treatment for luminal cancers is fairly uniform, with good outcomes for many patients, though some respond poorly. Therefore, luminal cancers are divided into type A (responsive to treatment) and type B (not as responsive).

Researchers theorize that women with luminal A tumors may respond well to hormonal (estrogen-blocking) therapy, whereas those with luminal B tumors may require chemotherapy in addition to hormonal therapy.

In general, luminal subtypes of breast cancer tumors had the lowest overall mutation rate but the largest number of genes observed to be significantly mutated. This finding suggests that each of the genes identified as significantly mutated in the luminal subtypes is more likely to be important in fueling cancer progression.

Triple-negative breast cancers linked to serous ovarian cancer

One of the most dramatic discoveries of this analysis was the marked genomic similarities between the basal-like subtype and serous ovarian cancer. The mutation spectrum—or types and frequencies of genomic mutations—were largely the same in both cancer types. Further analyses identified several additional common genomic features, such as gene-mutation frequency, suggesting that diverse genomic aberrations can converge into a limited number of cancer subtypes.

Computational analyses suggest that basal-like breast cancer and serous ovarian cancer might both be susceptible to agents that inhibit blood vessel growth, cutting off the blood supply to the tumor, as well as to compounds that target DNA repair, which include chemotherapy drugs such as cisplatin.

“The molecular similarity of one of the principal subtypes of breast cancer to that found in ovarian cancer gives us additional leverage to compare treatments and outcomes across these two cancers,” said Harold Varmus, MD, NCI director.

Two types of HER2-positive tumors?

When researchers analyzed the genomic findings from tumors determined to be HER2-positive by standard cellular tests, they found that only half of the samples were actually HER2-enriched. The other half were characterized as luminal subtypes, suggesting that there are at least two types of clinically defined HER2-positive tumors.

Overall, the scale of the TCGA program allows researchers to perform the integrative analyses that detect these complex patterns of genomic changes and interactions. This close inspection of the cancer genome has led to a deeper understanding of the mutations essential for cancer progression, and several new mutations were identified in the study.

“The data generated by the TCGA program comprise a vast resource that investigators will be analyzing for years to come,” said Eric D. Green, MD, PhD, NHGRI director. “The resource of information about breast cancer genomes will undoubtedly fuel myriad discoveries by the cancer research community.”

So far, TCGA research has published analyses of ovarian serous adenocarcinoma, colorectal adenocarcinoma, lung squamous cell carcinoma, and glioblastoma multiforme.

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