Loss of Genomic Imprinting

Loss of Genomic Imprinting is the disruption of the normal parent-of-origin-specific expression pattern maintained at imprinted genes, causing a gene that should normally be expressed from only the maternally or paternally inherited copy to instead be expressed from both copies, or to be silenced from both copies, in cancer cells.

Normal Genomic Imprinting

Parent-of-Origin Expression

Most genes in the human genome are expressed from both the maternally and paternally inherited copies equally, but a smaller subset of genes, known as imprinted genes, are normally expressed from only one parental copy, with the other copy kept transcriptionally silent regardless of its sequence.

Establishment Through Differential Methylation

Imprinting is established during germline development through parent-of-origin-specific patterns of DNA methylation at regulatory regions known as imprinting control regions, which are set differently depending on whether the chromosome passes through the maternal or paternal germline, and this differential methylation is subsequently maintained throughout the individual's life in somatic tissues.

Biological Role of Imprinting

Imprinted genes are particularly concentrated among genes involved in regulating fetal and early postnatal growth, and the normal balance between growth-promoting genes expressed from one parental allele and growth-restraining genes expressed from the other is thought to reflect an evolutionary balance between parental genetic interests.

Mechanisms of Imprinting Loss

Loss of Imprinting Through Biallelic Activation

The normally silent parental copy of an imprinted gene can become inappropriately activated, causing the gene to be expressed from both parental alleles simultaneously and effectively doubling its normal expression dosage.

Loss of Imprinting Through Biallelic Silencing

Conversely, the normally active parental copy can become inappropriately silenced, eliminating expression of the gene entirely, a pattern of particular significance when the affected gene functions as a tumor suppressor.

Disruption of Imprinting Control Regions

Aberrant DNA methylation at the imprinting control regions that normally establish and maintain parent-of-origin-specific expression can directly cause loss of imprinting, converting the differential methylation pattern that distinguishes the two parental alleles into either a uniformly methylated or uniformly unmethylated state.

Uniparental Disomy

In some cases, loss of normal imprinted expression arises not from a change in methylation but from the cell inheriting or generating two copies of a chromosome from a single parent, eliminating the presence of the alternate parental allele altogether.

Consequences for Cancer Development

Overexpression of Growth-Promoting Imprinted Genes

Loss of imprinting affecting growth-promoting imprinted genes can lead to their inappropriate biallelic expression, providing a growth advantage analogous to that produced by amplification or activating mutation of a conventional oncogene.

Silencing of Growth-Restraining Imprinted Genes

Loss of imprinting affecting growth-restraining imprinted genes can eliminate their protective function entirely, contributing to loss of normal growth control through a mechanism distinct from classical tumor suppressor mutation.

Association with Specific Tumor Types

Loss of imprinting at particular growth-regulatory loci has been documented as a recurrent and early event in several tumor types, including certain pediatric and embryonal tumors in which disrupted growth regulation during development plays a particularly prominent role.

Detection of Imprinting Loss

Allele-Specific Expression Analysis

Distinguishing which parental allele of an imprinted gene is being expressed requires methods capable of resolving expression at the level of individual sequence variants that differ between the maternal and paternal copies, allowing direct detection of inappropriate biallelic expression.

Methylation Analysis of Imprinting Control Regions

Measuring methylation status specifically at known imprinting control regions allows identification of the characteristic loss of the normal differential methylation pattern associated with imprinting disruption.

Clinical Significance

Loss of imprinting serves as both a biomarker and a potential contributing mechanism in specific cancer types, particularly those arising during early development when normal imprinted gene dosage plays an especially important regulatory role. Its detection can assist in tumor classification and contributes to a fuller understanding of how epigenetic dysregulation, beyond simple promoter hypermethylation or histone modification changes, contributes to abnormal gene dosage in cancer cells.