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May 15, 2009 (Vol. 29, No. 10)

CGH Sheds Its Light on Disease Etiology

Diseases that Have Defied Description Can Now Be Described and Explained

  • Click Image To Enlarge +
    CNV distribution across the human genome, taken from the database of genomics variation.
    (Centre for Applied Genomics, Hospitals for Sick Children, University of Toronto)

    Array comparative genomic hybridization (CGH) is illuminating DNA copy number variations (CNV) throughout the genome to diagnose disease etiology and to help tailor treatment regimens for patients to improve health outcomes.

    In January 2007, the College of American Pathologists and American Society of Clinical Oncology (CAP/ASCO) published guideline recommendations for testing human epidermal growth factor receptor 2 (HER2) in the diagnostic workup  for all invasive breast cancers. About 15 to 20% of breast cancers are HER2-positive. As a predictive marker, HER2-positive tumors are associated with higher rates of breast cancer recurrence and mortality. Furthermore, HER2 status can help predict the success of using certain systemic or endocrine therapies.

    The CAP/ASCO recommendations were made following a study of previously published HER2 test data. The study found that patients with early-stage breast cancer and metastatic cancer benefited from trastuzumab (Herceptin) HER2-targeted therapy, but that interlaboratory variability in HER2 test results ran as high as 20%. Thus, some patients never received Herceptin, though they would have benefited from it, and others who got it would not have benefited and have been put at higher risk for cardiac problems.

    In normal (nondividing) cells one HER2 gene is on each of two copies of chromosome 17 and instructs a cell to manufacture HER2 protein. HER2 protein receptors on the cell’s surface program cell growth and division. In HER2-positive breast cancer, the cell has more copies of the HER2 gene and is amplified. Greater numbers of HER2 receptors on the cell’s surface send more messages for it to grow and divide more aggressively.

    The two most widely used methods in the clinic for HER2 testing are immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). Test results from both IHC and FISH have an impact on the treatment regimen for women with breast cancer.

  • Immunohistochemistry

    IHC, a protein assay, assesses the amount of HER2 protein receptors on a cancer cell’s surface. In HER2-positive tumor cells, HER2 protein production is greater compared with normal cells.

    A sample of breast cancer tissue is exposed to an antibody against HER2 protein receptors. The antibody reacts causing a color change in the sample. Degree of color change is evaluated; the darker the stain, the greater the amount of HER2 protein. Percent of stained cells and their color intensity determine the test score. The scoring scale for an IHC test ranges from 0 to 3+. Scores of 0 and 1+ are negative for HER2; a score of 2+ is borderline or equivocal; a score of 3+ is positive for HER2.

    Potential problems with IHC testing include damaging the sample during preparation, or subjectively judging the degree of color staining, which can adversely affect results.

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