Clinical Application of Microarray-Based Molecular Cytogenetics: An Emerging New Era of Genomic Medicine

Department of Pediatrics, Hayward Genetics Center, Tulane University School of Medicine, New Orleans, LA 70112, USA.
The Journal of pediatrics (Impact Factor: 3.79). 10/2009; 155(3):311-7. DOI: 10.1016/j.jpeds.2009.04.001
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    • "However, the requirement for arresting tumor cells in metaphases and the low resolution of conventional cytogenetics, and the targeted nature and limited number of probes that can be used in a single FISH assay often result in an underestimate of the severity and complexity of genomic alterations in cancer [25]. Microarray-based technology affords the capacity to examine the whole human genome on a single chip with a resolution as high as a few hundred base pairs, providing the most sensitive whole-genome screen for genomic CNAs [26]. In this multi-center clinical validation study, we evaluated the efficacy and reproducibility of microarray technologies for clinical oncology applications using three different microarray platforms and four different tissue types commonly used for clinical cancer testing. "
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    ABSTRACT: Cytogenomic microarray analysis (CMA) offers high resolution, genome-wide copy number information and is widely used in clinical laboratories for diagnosis of constitutional abnormalities. The Cancer Genomics Consortium (CGC) conducted a multiplatform, multicenter clinical validation project to compare the reliability and inter- and intralaboratory reproducibility of this technology for clinical oncology applications. Four specimen types were processed on three different microarray platforms-from Affymetrix, Agilent, and Illumina. Each microarray platform was employed at two independent test sites. The results were compared in a blinded manner with current standard methods, including karyotype, FISH, or morphology. Twenty-nine chronic lymphocytic leukemia blood, 34 myelodysplastic syndrome bone marrow, and 30 fresh frozen renal epithelial tumor samples were assessed by all six laboratories. Thirty formalin fixed paraffin embedded renal tumor samples were analyzed at the Affymetrix and Agilent test sites only. All study samples were initial diagnostic samples. Array data were analyzed at each participating site and were submitted to caArray for central analysis. Laboratory interpretive results were submitted to the central analysis team for comparison with the standard-of-care assays and for calculation of intraplatform reproducibility and cross-platform concordance. The results demonstrated that the three microarray platforms 1) detect clinically actionable genomic changes in cancer compatible to standard-of-care methods; 2) further define cytogenetic aberrations; 3) identify submicroscopic alterations and loss of heterozygosity (LOH); and 4) yield consistent results within and between laboratories. Based on this study, the CGC concludes that CMA is a sensitive and reliable technique for copy number and LOH assessment that may be used for clinical oncology genomic analysis.
    Cancer Genetics 08/2015; DOI:10.1016/j.cancergen.2015.08.002 · 2.98 Impact Factor
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    • "ROH is identified on microarray plots based on the presence of homozygous base calls with no change in the signal intensity, indicating the presence of two alleles [Kearney et al., 2011; Sund et al., 2012]. The presence of ROH can indicate uniparental disomy, ancestral parental relatedness, or parental consanguinity [Li and Andersson, 2009; Manning and Hudgins, 2010; Schaaf et al., 2011]. "
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    ABSTRACT: SNP microarrays are capable of detecting regions of homozygosity (ROH) which can suggest parental relatedness. This study was designed to describe pre- and post-test counseling practices of genetics professionals regarding ROH, explore perceived comfort and ethical concerns in the follow-up of such results, demonstrate awareness of laws surrounding duty to report consanguinity and incest, and allow respondents to share their personal experiences with results suggesting a parental relationship. A 35 question survey was administered to 240 genetic counselors and geneticists who had ordered or counseled for SNP microarray. The results are presented using descriptive statistics. There was variation in both pre- and post-test counseling practices of genetics professionals. Twenty-five percent of respondents reported pre-test counseling that ROH can indicate parental relatedness. The most commonly reported ethical concern was disclosure of findings suggesting parental relatedness to parents of the patient; only 48.4% reported disclosing parental relatedness when indicated. Fifty-seven percent felt comfortable receiving results suggesting parental consanguinity while 17% felt comfortable receiving results suggesting parental incest. Twenty percent of respondents were extremely/moderately familiar with the laws about duty to report incest. Personal experiences in post-test counseling included both parental acknowledgement and denial of relatedness. This study highlights the differences in genetics professionals' pre- and post-test counseling practices, comfort, and experiences surrounding parental relatedness suggested by SNP microarray results. It identifies a need for professional organizations to offer guidance to genetics professionals about how to respond to and counsel for molecular results suggesting parental consanguinity or incest. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 01/2014; 164(1). DOI:10.1002/ajmg.a.36206 · 2.16 Impact Factor
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    • "Recent advances of genetic techniques in animal models allow an analysis of the complex processes of embryonic development [65]–[67]. Genetic analyses of human patients have advanced greatly in recent years [68], [69]. Despite such advantages, the mechanisms for normal development and the pathogenic mechanisms for embryonic urinary systems remain obscure. "
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    ABSTRACT: Congenital diseases of the urinary tract are frequently observed in infants. Such diseases present a number of developmental anomalies such as hydroureter and hydronephrosis. Although some genetically-modified mouse models of growth factor signaling genes reproduce urinary phenotypes, the pathogenic mechanisms remain obscure. Previous studies suggest that a portion of the cells in the external genitalia and bladder are derived from peri-cloacal mesenchymal cells that receive Hedgehog (Hh) signaling in the early developmental stages. We hypothesized that defects in such progenitor cells, which give rise to urinary tract tissues, may be a cause of such diseases. To elucidate the pathogenic mechanisms of upper urinary tract malformations, we analyzed a series of Sonic hedgehog (Shh) deficient mice. Shh(-/-) displayed hydroureter and hydronephrosis phenotypes and reduced expression of several developmental markers. In addition, we suggested that Shh modulation at an early embryonic stage is responsible for such phenotypes by analyzing the Shh conditional mutants. Tissue contribution assays of Hh-responsive cells revealed that peri-cloacal mesenchymal cells, which received Hh signal secreted from cloacal epithelium, could contribute to the ureteral mesenchyme. Gain- and loss-of-functional mutants for Hh signaling revealed a correlation between Hh signaling and Bone morphogenetic protein (Bmp) signaling. Finally, a conditional ablation of Bmp receptor type IA (BmprIA) gene was examined in Hh-responsive cell lineages. This system thus made it possible to analyze the primary functions of the growth factor signaling relay. The defective Hh-to-Bmp signaling relay resulted in severe urinary tract phenotypes with a decrease in the number of Hh-responsive cells. This study identified the essential embryonic stages for the pathogenesis of urinary tract phenotypes. These results suggested that Hh-responsive mesenchymal Bmp signaling maintains the population of peri-cloacal mesenchyme cells, which is essential for the development of the ureter and the upper urinary tract.
    PLoS ONE 07/2012; 7(7):e42245. DOI:10.1371/journal.pone.0042245 · 3.23 Impact Factor
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