Predisposition syndromes

1

What percent of childhood cancer is attributable to inherited mutations?

In a recent study of 1120 children and adolescents with cancer, germline mutations in cancer-predisposing genes were identified in 8.5% of the cases. With the exception of this small percentage of cases attributable to hereditary cancer syndromes or genetic syndromes such as Down syndrome, the etiology of most childhood cancers is unknown. Importantly family history does not appear to predict presence of cancer predisposition in the majority of hereditable pediatric cancers.

2

Discuss the importance of rare cancers attributable to inherited mutations to the practice of pediatric oncology.

Despite their rarity, these syndromes and their underlying genetics permit a greater understanding of the processes underlying the development of malignancy. In addition, by identifying children at risk because of inheritance of a genetic defect, we can screen these children for the tumors for which they are at risk and potentially decrease the morbidity and mortality from their malignancy.

3

A child referred to your service with presumed Wilms tumor is found to have tumor present in both of her kidneys. Describe the underlying genetic changes present when patients have bilateral Wilms tumor.

Wilms tumor is thought to originate from pluripotent embryonic renal precursors. Five to ten percent of children diagnosed with Wilms tumors present with bilateral disease and develop tumors at an earlier age (circa 2 years) than children with unilateral disease (average age at diagnosis, 5 years). Tumors of children with bilateral disease contain persistent nephrogenic rests (undifferentiated blast cells), which normally disappear shortly after birth. Their persistence in Wilms tumor suggests a constitutional abnormality in renal differentiation.

Most children with bilateral Wilms tumor have de novo germline mutations in WT1. WT1 is a tumor suppressor gene located on chromosome 11p13, which encodes a zinc finger transcription factor and is inactivated in the germline of children with genetic predisposition to Wilms tumor and in 15% of sporadic Wilms. WT1 is a critical regulator of organ-specific differentiation; its inactivation or disruption triggers malignant transformation in embryonic cell types. WT1 is expressed in glomerular precursors of the developing kidney, and mice who lack both copies of WT1 do not develop kidneys.

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