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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 ...