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RESEARCH PRODUCT

A Comprehensive Tissue Microarray-Based FISH Screen of ALK Gene in Neuroblastomas

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The heterogeneity of neuroblastic tumors added to the immense biological complexity has led to an unprecedented scale of investigations and a growing list of molecular genetic targets for prognosis as well as therapy. Recently, Anaplastic Lymphoma Kinase (ALK) has been identified as a major predisposing gene as well as a potential therapeutic target for neuroblastoma. Individuals with ALK-related neuroblastoma susceptibility (i.e., heterozygous for an ALK mutation) are at risk of developing neuroblastic tumors. Aberrant copy number or mutations in ALK gene and overexpression of its protein tyrosine-kinase receptor have been related to poor prognosis of this disease, although a great degree of discrepancy exists regarding the clinical validation of these alterations. Molecular diagnostic laboratories currently evaluate only the tyrosine kinase domain (exons 21-28) of the ALK gene. To date, all reported disease-associated ALK mutations are located in the tyrosine kinase domain and the majority are thought to be drivers of an oncogenic process. However, these mutational studies are robust and are not feasible in the clinical setting especially on clinical samples of neuroblastoma. In addition, an effective clinical assay has not yet been validated for assessing whether the genetic status of ALK provides useful prognostic information for planning treatment strategy for neuroblastoma patients. A simple and cost-effective approach to implement in clinical practice would be to develop a test that can determine the DNA copy number alterations of ALK gene in clinical samples of neuroblastoma. Interphase fluorescence in situ hybridization (FISH) analysis of ALK gene with tissue microarrays would be an ideal example to suit the above mentioned objective. This review summarizes the role of FISH as a molecular genetic test in detecting copy number alterations of ALK gene in formalin-fixed paraffin embedded (FFPE) samples using our data on series of sporadic primary neuroblastomas.