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Cancer is the most common cause of disease-related death in children beyond the newborn period. The unique biological features, the cell of origin, and the response to therapy of childhood cancers make them intriguing models with which to study and understand the process of human carcinogenesis. Tumors of childhood commonly reflect the embryonic precursor of the cell types in which they arise. The majority occur sporadically, and their etiology remains unclear. Obvious environmental influences to cancer initiation are not generally apparent. Some cancers, such as neuroblastoma, appear to arise even before birth, whereas a significant number of others present with a striking family history of cancer or coincide with congenital abnormalities, suggesting an important role for inherited causal genetic factors. Disorders such as xeroderma pigmentosum,1 which places children at increased risk for developing skin cancers, or Beckwith-Wiedemann syndrome,2 which is commonly complicated by the development of embryonal tumors, including Wilms tumor of the kidney, rhabdomyosarcoma, or hepatoblastoma, are examples of inherited disorders that confer an increased risk developing cancer. Cancer predisposition syndromes in which nonmalignant phenotypic features are not observed include hereditary retinoblastoma,3 Li-Fraumeni syndrome,4 and familial polyposis,5 while others such as von Hippel Lindau disease6 are associated with the coincident presentation of both benign and malignant neoplasms.

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With the advent of technologies that can provide highly sensitive genome-wide molecular analysis, as well as clinical oncologists and geneticists recognizing the value of carefully ascertaining family cancer histories, it is likely that both new cancer predisposition associations and novel cancer genes will continue to be discovered. Importantly, new genetic tests offer opportunities for presymptomatic diagnosis of syndromic associations and a greater role of clinical surveillance by pediatricians and family physicians for early cancer detection in high-risk individuals. Study of both sporadic childhood cancers and familial syndromes associated with childhood malignancies has led to the identification and functional characterization of numerous tumor suppressor genes (TSGs), oncogenes, and DNA repair genes. TSGs normally control cell proliferation by either inhibiting progression through the cell cycle or promoting apoptosis (programmed cell death). Inactivation of both alleles of a TSG by mutation or deletion causes uncontrolled proliferation, thereby contributing to tumorigenesis. In contrast, oncogenes normally potentiate cell proliferation, and mutation of one allele is sufficient to produce uncontrolled cell growth. Inactivation of DNA stability or repair genes permits cells that harbor damaged DNA to divide, potentially leading to malignant transformation of those cells.2 Nonrandom molecular and cytogenetic alterations are frequently observed in most childhood cancers. These markers are unique diagnostic identifiers and frequently provide prognostic value with respect to disease outcome and anticipated response to therapy. Importantly, many of these genetic markers also recapitulate normal developmental processes, and as such offer a window into the biological mechanisms of both carcinogenesis and normal embryologic growth and development (Table 443-1). This chapter addresses the diverse molecular mechanisms in several prototypical childhood cancers and cancer predisposition syndromes, highlighting the critical role of molecular and ...

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