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May 15, 2008 (Vol. 28, No. 10)

Applying aCGH to Molecular Diagnostics

Emerging Technology Has Promise for Analyzing Copy Number Variation

  • Use with Gene-Expression Arrays

    The complementary technologies of CGH and gene-expression arrays are already revealing unexpected connections in a subset of breast cancer patients, so-called triple negatives (not associated with estrogen receptors, progesterone receptors, and HER2), according to Dr. Baumbach-Reardon.

    “There are no helpful therapies for these women. We are already seeing significant differences across ethnicities. Our goal is to develop a signature profile that would be predictive of breast cancer for this subset of women. By assessing variations in copy number with CGH arrays, we hope to better understand the biological basis of ethnic-specific breast cancer disparities and to develop improved individualized diagnostic and therapeutic approaches.”

    Initially aCGH was used to analyze copy-number changes in tumors in order to identify the genes involved. An emerging application of this technology is to detect so-called “unbalanced constitutional rearrangements” in nontumorous tissue.

    “Several recent studies have mapped normal genomic variations, so called hot spots, using different high-resolution whole-genome screening platforms,” reports Karoly Szuhai, M.D., Ph.D., group leader, department of molecular cell biology, Leiden University Medical Center. “As a result, a collective database of genomic variants (DVV) was assembled that contained several normal variation loci. One problem is that this database is often consulted in screening for pathogenic alterations in order to exclude these normal variants. We showed that this could lead to false negative reporting.”

    Dr. Szuhai describes a patient with mild hearing loss and mental retardation who inherited a homozygous deletion from nonrelated heterozygous carrier parents. “Interestingly, other families have been identified with a comparable syndrome of hearing impairment that point to an involved gene at this locus. The frequency of a hemizygous deletion is about 1.4%.

    “The relatively high incidence of genomic variation of this region that is involved in both a syndrome and nonsyndromic hearing impairment points to it being an important locus for hearing loss. Furthermore, these studies point out the critical importance of a careful interpretation of results especially for cases involving normal variations at specific loci. This patient would have been shown to be negative by comparison to the DVV, whereas he actually does have a genetic aberration at this locus.”

    Despite these concerns, Dr. Szuhai says that aCGH will likely be the first choice for clinical diagnostics in the near future. “Array CGH is rapidly evolving. New and increasingly higher-resolution technologies for genome-wide screening are currently being developed. In addition, there is also a significant cost-and-benefit relationship in being able to use such an automated and quantitative measure of chromosomal aberrations.”

    Although many in the field feel that our understanding of benign and pathogenic genome variation is in its infancy, most expect rapid progress and even dramatic results will likely be realized in the years to come.

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