What is loss of imprinting (LOI)?

What is Loss of Imprinting (LOI)?

Loss of imprinting (LOI) is an epigenetic alteration where a gene that should normally be expressed from only one parent's chromosome (either maternal or paternal) becomes abnormally expressed from both parental chromosomes, or conversely, becomes silenced on both copies. 1

Core Mechanism

Genomic imprinting is the normal process where approximately 50-80 genes in the human genome are expressed from only one parental allele (either maternal or paternal), with the other allele being epigenetically silenced through DNA methylation. 1 This monoallelic expression ensures precise control of protein levels for genes critical to embryonic growth, placental development, and adult metabolism. 1

How Imprinting Normally Works

• Imprinting Control Regions (ICRs) are specific chromosomal regions that receive methylation marks during germ cell development. 1
• These methylation marks are maintained through cellular replication by the Dnmt1 methylation enzyme complex. 1
• The methylation status is "read" by two primary mechanisms: chromatin barrier formation (via CTCF protein) or untranslated RNAs. 1
• A short DNA sequence called the "imprinting center" controls switching and maintenance of the imprinting pattern, which is critical when chromosomes are passed from one generation to the next. 2

What Happens in Loss of Imprinting

LOI represents a failure of this normal regulatory mechanism, resulting in:

• Biallelic expression: The normally silent allele becomes activated, leading to expression from both parental chromosomes. 3
• Complete silencing: Both alleles become methylated and silenced (as seen in imprinting errors causing Prader-Willi syndrome). 2

Clinical Example: Prader-Willi Syndrome

The American Academy of Pediatrics describes imprinting errors in Prader-Willi syndrome (occurring in ≤5% of cases) where the father passes on a chromosome 15 that he inherited from his mother, but the imprinted (silenced) genes cannot be reactivated. 2 The infant inherits one copy of chromosome 15 from each parent, but the PWS region is fully methylated on both copies and thus silenced in both, resulting in no functional gene expression. 2

Clinical Significance

Cancer Association

LOI is currently considered the most abundant and most precocious alteration in cancer. 1

• LOI of the IGF2 gene (insulin-like growth factor II) is particularly common, occurring in 44% of colorectal cancer patients and representing the most common genetic or epigenetic alteration in Wilms tumor. 4, 5
• Importantly, LOI is found not only in tumor tissue but also in histologically normal tissues surrounding tumors, suggesting a widespread epigenetic field defect. 6, 4
• In colorectal cancer, 91% of tumors with microsatellite instability showed LOI, compared with only 12% without microsatellite instability. 4

Developmental Disorders

Without precise control of imprinted gene expression, developmental abnormalities result, including:

• Beckwith-Wiedemann syndrome (overgrowth syndrome). 1
• Prader-Willi syndrome (absence of paternal contribution to chromosome 15q11-q13). 2
• Angelman syndrome (absence of maternal contribution to the same region, but affecting different genes). 2, 7

Placental Abnormalities

LOI is remarkably common in human placentas, with 25% of examined heterozygosities showing LOI >3% in one study of 27 placental samples. 3 This suggests LOI may be an important biomarker for influences on prenatal epigenetics. 3

Key Distinguishing Features

LOI differs from genetic mutations because it does not involve changes in DNA sequence but rather changes to genomic structure that affect regulation of gene expression. 2 The DNA sequence remains intact, but the epigenetic "marks" (primarily methylation patterns) that control gene expression are altered. 1

Diagnostic and Prognostic Value

• LOI can be detected in normal tissues (such as colonic mucosa and peripheral blood) of cancer patients, potentially identifying individuals at risk before cancer develops. 4
• LOI in prostate tissues occurs not only adjacent to tumor foci but is widely prevalent even in distant areas within the peripheral zone, providing evidence for a widespread epigenetic field defect. 6
• The frequency and early occurrence of LOI in various cancers makes it a potentially valuable tool for both diagnosis and treatment. 1