Chapter 32 - Molecular testing in pediatric cancers

Abstract

Cancer is the leading cause of childhood death by disease after infancy, and its incidence, treatment, and outcome differ substantially from cancers in adults. Three of the most common childhood tumors are retinoblastoma, Wilms tumor (nephroblastoma), and neuroblastoma. These cancers arise from malignant transformation of developing cells (blasts) and are almost entirely restricted to the pediatric population. This chapter discusses the genetic basis of each of these tumor types, and the current role of molecular and cytogenetic testing in diagnosis, prognosis, and treatment. Retinoblastoma has a stable worldwide incidence of approximately 1/50,000 and accounts for 3% of all pediatric cancer diagnoses. The only known genetic locus affected in retinoblastoma is the RB1 gene at chromosome 13q14. Comprehensive molecular testing, including sequence analysis and deletion/duplication testing, has been demonstrated to identify mutation or deletion of RB1 in more than 95% of cases. Wilms tumor arises from nephrogenic rests of the developing kidney and represents approximately 7% of pediatric cancer diagnoses. An increased risk for Wilms tumor is associated with a number of predisposition syndromes, including Wilms tumor-aniridia-genitourinary abnormalities-intellectual disability, Denys-Drash syndrome, Beckwith-Wiedemann syndrome, Perlman syndrome, and Fanconi anemia subtypes D2 and N, among others. As the genetic etiology of the different syndromes varies, there are a large number of genetic loci underlying Wilms tumor predisposition. Molecular and cytogenetic testing is helpful for informing cancer risk and prognosis. Neuroblastoma, a solid tumor of the embryonic crest cells, accounts for approximately 10% of cancers but approximately 15% of cancer-related deaths among children. Genetic testing is useful for identifying germline mutations in predisposition syndromes, although these account for only 1%–2% of cases, and for identifying somatic alterations of prognostic significance. The best characterized acquired mutations include amplification of MYCN, ploidy status, and segmental chromosome abnormalities. Routine cytogenetic analysis and fluorescence in situ hybridization are essential for the proper characterization of neuroblastoma.