What is loss of imprinting (LOI)?

Loss of Imprinting (LOI): Definition and Mechanisms

Loss of imprinting (LOI) is an epigenetic alteration in which a gene that should normally be expressed from only one parental allele (either maternal or paternal) becomes abnormally expressed from both alleles, or conversely, becomes silenced on both alleles, disrupting the normal monoallelic expression pattern. 1

Molecular Basis

LOI does not involve changes in the DNA sequence itself—it reflects abnormal epigenetic marks, primarily DNA methylation patterns, that affect gene regulation. 1 This distinguishes LOI fundamentally from classic genetic mutations. 1

Normal Imprinting Mechanism

• Genomic imprinting is an epigenetic form of gene silencing that occurs during gametogenesis and results in parent-of-origin-specific gene expression. 2
• A short DNA sequence called the "imprinting center" governs the switching and maintenance of parental-specific methylation patterns that ensure monoallelic expression of approximately 50-80 imprinted genes. 1, 3
• These methylation marks are laid down during embryological development of germ cells at specific chromosomal regions called Imprinting Control Regions (ICRs). 3
• The methylation status is maintained through cellular replication by a methylation enzyme complex containing Dnmt1. 3

When Imprinting Fails

• LOI represents a gain of expression from the normally silent allele, or conversely, complete silencing when both copies become methylated. 3, 4
• This mis-regulation disrupts the precise control of protein levels encoded by imprinted genes, which are important factors in embryonic growth, placental growth, and adult metabolism. 3

Clinical Manifestations

Prader-Willi Syndrome (PWS)

• In ≤5% of PWS cases, an imprinting error occurs where the paternal chromosome 15 inherited from the father's mother is fully methylated, preventing re-activation of silenced genes and leading to loss of paternal gene expression. 1
• The infant receives one copy of chromosome 15 from each parent, but the PWS region (15q11-q13) is methylated on both copies, resulting in complete silencing and absence of functional gene products. 1
• This represents <2% of all PWS cases, with the majority (>70%) caused by deletion and ~28% by maternal uniparental disomy. 2, 5

Angelman Syndrome (AS)

• Angelman syndrome arises from loss of the maternal contribution to the same 15q11-q13 region, reflecting an imprinting error that silences maternal alleles while paternal alleles remain inactive. 1
• When biparental inheritance is identified but an imprinting mutation is present, this represents the LOI mechanism. 2

Role in Cancer

LOI is presently considered the most abundant and most precocious alteration in cancer. 3

Colorectal Cancer

• LOI of the insulin-like growth factor-II (IGF2) gene occurred in 44% of informative colorectal cancer patients, and importantly, was also present in matched normal colonic mucosa and peripheral blood samples. 6
• 91% of cancers with microsatellite instability showed LOI, compared with only 12% without microsatellite instability. 6
• Control patients without cancer showed LOI in only 12% of colonic mucosa samples and 13% of blood samples. 6
• Hypermethylation of promoters of tumor suppressor genes (including MLH1, p16) results in inhibition of their expression and potential for tumor progression. 2

Temporal Stability

• LOI of IGF2 in peripheral blood lymphocytes appears to be a stable epigenetic phenomenon, with 94% agreement on repeat testing at mean follow-up of 38 months. 7
• LOI was present across all age strata with no significant association with age, suggesting an inherited or congenital epigenetic event rather than an acquired age-related change. 7

Field Defect in Prostate Cancer

• Marked IGF2 LOI was found not only adjacent to prostate tumor foci (39%) but also in tissues distant (38%) from tumors, indicating a widespread epigenetic field defect. 8
• This provides evidence that LOI may identify individuals at risk before cancer develops. 8

Diagnostic and Prognostic Implications

• LOI may be a valuable tool for both cancer diagnosis and treatment, as it occurs frequently and precociously in a large variety of human tumors. 3
• LOI of IGF2 may serve as a useful risk factor for colorectal cancer predisposition given its stability and presence in normal tissues of cancer patients. 7
• LOI is common in human placentas (25% showed LOI >3% among 93 heterozygosities examined), suggesting it may be an important biomarker for influences on prenatal epigenetics. 4