Genomic imprinting and Wilms' tumor

Area of Science:

• Genetics
• Developmental Biology
• Oncology

Background:

• Wilms' tumors (WTs) exhibit selective loss of maternal and reduplication of paternal alleles on chromosome 11p15.5.
• This suggests imprinted genes in this region regulate tumor suppression and cell growth.
• H19 and IGF2 are key imprinted genes in 11p15.5, with H19 as a candidate tumor suppressor and IGF2 as a candidate oncogene.

Purpose of the Study:

• To review and extend data on the imprinting and expression status of H19 and IGF2 in WTs.
• To investigate the role of the bipaternal epigenotype in Wilms' tumorigenesis.
• To examine the impact of genetic alterations on other imprinted genes in the 11p15.5 region.

Main Methods:

• Review of existing data on gene imprinting and expression in Wilms' tumors.
• Analysis of loss of heterozygosity (LOH) and non-LOH pathways.
• Examination of H19 DNA methylation patterns.
• Assessment of KIP2 gene imprinting in relation to H19 and IGF2 alterations.

Main Results:

• A majority of WTs display a bipaternal epigenotype: H19 is inactive, and IGF2 is biallelically active.
• This epigenotype can result from LOH or non-LOH mechanisms, including H19 hypermethylation.
• The bipaternal endpoint affects at least H19, IGF2, and KIP2 imprinted genes.
• 11p15.5 LOH and H19 hypermethylation can occur early or late in tumor progression.

Conclusions:

• The bipaternal epigenotype is a common feature in Wilms' tumors.
• These genetic alterations appear to be permissive, rather than rate-limiting, for Wilms' tumorigenesis.
• Early genetic lesions do not correlate with tumor bilaterality or multifocality.