Genetic predisposition and screening in pediatric cancer☆
Section snippets
Retinoblastoma
Retinoblastoma is the prototype tumor for understanding basic concepts in cancer genetics. Retinoblastoma may occur as either unilateral or bilateral disease with unifocal or multifocal tumors in each eye. Retinoblastoma is thought to be a single gene disorder caused by mutation of the RB1 gene. The hallmarks of cancer predisposition, including an unusually early age of onset, bilateral or multifocal tumors, a clustering of similar type of tumors in families, and a tendency to develop second or
Wilms' tumor
Wilms' tumor also occurs in both hereditable and nonhereditable forms [22]. An early model proposed a two-step model of tumorigenesis similar to retinoblastoma. Unlike retinoblastoma, however, multiple genetic loci have subsequently been implicated in Wilms' tumorigenesis. True familial Wilms' tumor accounts for only about 1% of all Wilms' tumor cases, but, as in retinoblastoma, children with bilateral disease are thought to have a genetic predisposition even without a preceding family history.
Li Fraumeni syndrome
Li Fraumeni syndrome (LFS), also known as breast sarcoma family cancer syndrome, is a rare autosomal dominant familial cancer syndrome characterized by early onset of bone or soft tissue sarcomas, breast cancer, brain tumors, and adrenocortical carcinoma. This syndrome was first described in 1969 by Li and Fraumeni who reported five families in which children with sarcomas had siblings or cousins who also had soft tissue sarcoma [46]. This syndrome was later expanded to include a variety of
Rhabdoid tumor syndrome
Rhabdoid tumor is a rare pediatric tumor of young infancy that may occur at any site but most often in the central nervous system, where it is also referred to as atypical-teratoid tumor, or in the kidney, where it was at one time considered a variant of Wilms' tumor but is now considered a distinct entity. Occasionally, infants develop distinct tumors at both sites, and it has been shown that the underlying genetic lesion is mutation of the hSNF5/INI1 gene [55], [56].
Rhabdoid tumor is a highly
Von Hipple-Lindau disease
Von Hipple-Lindau (VHL) disease is an inherited cancer-predisposition syndrome clinically characterized by hemangioblastoma of the retina, cerebellum, or spinal cord, by renal cell carcinoma, and by pheochromocytoma. In addition, pancreatic and renal cysts, endolymphatic sac tumors, papillary cystadenoma of the epididymis or broad ligament, and hemagiomas of visceral organs including adrenal, liver, and lung have been reported. Diagnosis of VHL disease is based on clinical features [57], [58].
Ataxia-telangiectasia
Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder which expresses the varieties of clinical features including cerebellar degenerative disease, humeral and cellular immune deficiency, telangiectasia, infertility, and increasing risk of leukemias as well as lymphomas. Genetic instability is the hallmark of this disease. The predisposition to cancer results from the genetic instability with accumulation of mutations or immune deficiency or both. Cancer is the second leading cause
Bloom's syndrome and related other rare syndromes
Bloom's syndrome is a rare autosomal recessive syndrome characterized by facial telangiectasia, photosensitivity, growth delay, and susceptibility to a variety of cancers. Other characteristics of this syndrome include a small narrow face, skin hypopigmentation and hyperpigmentation, a high-pitched voice, immunodeficiency, diabetes mellitus, small testes, a short menstrual period, and other minor anatomic anomalies [75].
A Bloom's syndrome registry has been established since 1960 to facilitate
Multiple endocrine neoplasia
The multiple endocrine neoplasias (MENs) are autosomal dominantly inherited cancer-predisposition syndromes divided into two types, MEN type 1 (MEN1) and MEN2. The MEN syndromes are characterized by two or more tumors of endocrine organs either in the same individual or within the immediate family. Individuals with MEN1 syndrome develop pituitary adenomas, parathyroid adenomas, as well as the neuroendocrine tumors (ie, pheochromocytoma and carcinoid tumors). The underlying genetic factor is
Familial adenomatous polyposis
Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited condition that predisposes to the formation of multiple adenomatous polyps in the colon and rectum of affected individuals. The incidence of this disease in the general population is approximately 1 in 8000. The polyps usually begin to develop in mid to late adolescence, with half of affected individuals having colonic polyps by the age of 18 years. An understanding of this disease is relevant to the pediatrician because
Genetic polymorphisms and pediatric cancers
Whereas the previous sections have dealt with the major predisposition syndromes, much of the genetic susceptibility to cancer may involve more subtle genetic factors that may influence cancer risks. It has been accepted that genetic and environmental factors are involved in tumorigenesis. Metabolic enzymes alter and then excrete the harmful xenobiotics and carcinogens. These agents include phase I enzymes, the cytochrome P-450 family of enzymes that activate substances that are then detoxified
Summary
Pediatricians are often the health care providers who first detect the signs and symptoms of childhood cancer. Although pediatric malignancies are rare diseases, early diagnosis is an important factor leading to high cure rates of many types of cancers including retinoblastoma, Wilms' tumor, hepatoblastoma, rhabdomyosarcoma, thyroid carcinoma, and other solid tumors. A number of familial cancer syndromes present with childhood cancers that can be recognized or diagnosed by pediatricians. The
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This work was supported by Children's Cancer Fund of Dallas and the Texas Advanced Research Program Grant No. 010019-0105-200.