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Late Effects of Treatment for Childhood Cancer (PDQ®): Treatment - Health Professional Information [NCI] - Subsequent Neoplasms

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Subsequent Neoplasms and Genetic Susceptibility

Literature clearly supports the role of chemotherapy and radiation in the development of SNs. However, interindividual variability exists, suggesting that genetic variation has a role in susceptibility to genotoxic exposures, or that genetic susceptibility syndrome confers an increased risk of cancer, such as Li-Fraumeni syndrome. Previous studies have demonstrated that childhood cancer survivors with either a family history of cancer, but more so, presence of Li-Fraumeni syndrome, carry an increased risk of developing an SN.[48,49] The risk of SNs could potentially be modified by mutations in high-penetrance genes that lead to these serious genetic diseases (e.g., Li-Fraumeni syndrome).[49] However, the attributable risk is expected to be very small because of the extremely low prevalence of mutations in high-penetrance genes. Table 1 below summarizes the spectrum of neoplasms, affected genes, and Mendelian mode of inheritance of selected syndromes of inherited cancer predisposition.

Table 1. Selected Syndromes of Inherited Cancer Predispositiona

SyndromeMajor Tumor TypesAffected GeneMode of Inheritance
WAGR = Wilms tumor, aniridia, genitourinary anomalies, mental retardation.
a Adapted from Strahm et al.[50]
Adenomatous polyposis of the colonColon, hepatoblastoma, intestinal cancers, stomach, thyroid cancerAPCDominant
Ataxia-telangiectasiaLeukemia, lymphomaATMRecessive
Beckwith-Wiedemann syndromeAdrenal carcinoma, hepatoblastoma, rhabdomyosarcoma, Wilms tumorCDKN1C/NSD1Dominant
Bloom syndromeLeukemia, lymphoma, skin cancerBLMRecessive
Fanconi anemiaGynecological tumors, leukemia, squamous cell carcinomaFANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCGRecessive
Juvenile polyposis syndromeGastrointestinal tumorsSMAD4/DPC4Dominant
Li-Fraumeni syndromeAdrenocortical carcinoma, brain tumor, breast carcinoma, leukemia, osteosarcoma, soft tissue sarcomaTP53Dominant
Multiple endocrine neoplasia 1Pancreatic islet cell tumor, parathyroid adenoma, pituitary adenomaMEN1Dominant
Multiple endocrine neoplasia 2Medullary thyroid carcinoma, pheochromocytomaRETDominant
Neurofibromatosis type 1Neurofibroma, optic pathway glioma, peripheral nerve sheath tumorNF1Dominant
Neurofibromatosis type 2Vestibular schwannomaNF2Dominant
Nevoid basal cell carcinoma syndromeBasal cell carcinoma, medulloblastomaPTCHDominant
Peutz-Jeghers syndromeIntestinal cancers, ovarian carcinoma, pancreatic carcinomaSTK11Dominant
RetinoblastomaOsteosarcoma, retinoblastomaRB1Dominant
Tuberous sclerosisHamartoma, renal angiomyolipoma, renal cell carcinomaTSC1/TSC2Dominant
von Hippel-Lindau syndromeHemangioblastoma, pheochromocytoma, renal cell carcinoma, retinal and central nervous tumorsVHLDominant
WAGR syndromeGonadoblastoma, Wilms tumorWT1Dominant
Wilms tumor syndromeWilms tumorWT1Dominant
Xeroderma pigmentosumLeukemia, melanomaXPA, XPB, XPC, XPD, XPE, XPF, XPG, POLHRecessive

Drug-metabolizing enzymes and DNA repair polymorphisms

The interindividual variability in risk of SNs is more likely related to common polymorphisms in low-penetrance genes that regulate the availability of active drug metabolites or are responsible for DNA repair. Gene-environment interactions may magnify subtle functional differences resulting from genetic variations.

Drug-metabolizing enzymes

Metabolism of genotoxic agents occurs in two phases. Phase I involves activation of substrates into highly reactive electrophilic intermediates that can damage DNA, a reaction principally performed by the cytochrome p450 (CYP) family of enzymes. Phase II enzymes (conjugation) function to inactivate genotoxic substrates. The phase II proteins comprise the glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase-1 (NQO1), and others. The balance between the two sets of enzymes is critical to the cellular response to xenobiotics; for example, high activity of a phase I enzyme and low activity of a phase II enzyme can result in DNA damage.

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WebMD Public Information from the National Cancer Institute

Last Updated: February 25, 2014
This information is not intended to replace the advice of a doctor. Healthwise disclaims any liability for the decisions you make based on this information.
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