Clonal Evolution

Loss of Imprinting (LOI)

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Loss of Imprinting (LOI)

Loss of imprinting (LOI) is an epigenetic alteration in which the normally silenced allele at an imprinted locus becomes transcriptionally active, resulting in biallelic expression. LOI is one of the most common and earliest detectable molecular alterations in several human cancers, functioning as an epigenetic driver mutation — it alters gene dosage without changing DNA sequence.

Mechanism

LOI occurs when the differential methylation that distinguishes the maternal and paternal alleles at a germline DMR is disrupted. The most well-characterized example is LOI at the IGF2/H19 locus on 11p15.5:

flowchart LR
    subgraph Normal["Normal: monoallelic expression"]
        N1[Maternal H19 allele: active]
        N2[Maternal IGF2 allele: silenced]
        N3[Paternal H19 allele: silenced]
        N4[Paternal IGF2 allele: active]
    end
    subgraph LOI["LOI at IGF2: biallelic expression"]
        L1[Maternal H19 allele: silenced by methylation]
        L2[Maternal IGF2 allele: active]
        L3[Paternal H19 allele: silenced]
        L4[Paternal IGF2 allele: active]
    end
    Normal -->|"IC1 hypermethylation"| LOI
    LOI --> Growth[Double IGF2 dosage → growth signal ×2]

At the IGF2/H19 locus, a shared enhancer competes for access to the two genes. CTCF binding at the unmethylated maternal IC1 (H19 DMR) blocks enhancer access to maternal IGF2, routing it to maternal H19 instead. On the paternal chromosome, IC1 is methylated, CTCF cannot bind, and the enhancer activates paternal IGF2. LOI typically involves hypermethylation of the maternal IC1, which silences maternal H19 and allows the enhancer to activate maternal IGF2 — producing biallelic IGF2 expression (Falls et al., 1999).

LOI as an epigenetic driver

LOI functions as a driver event through two distinct paths:

PathExampleEffect
Activation of growth promoterIGF2 LOI: biallelic expression doubles IGF2 dosageConstitutive growth signal
Silencing of growth restraintH19 silencing: loss of growth-inhibitory ncRNAReduced growth inhibition

From the perspective of clonal-evolution, LOI is a faster-than-mutation path to a fitness advantage. A somatic mutation in IGF2 coding sequence is a rare event (point mutation rate ~5 × 10^−10 per bp per division). In contrast, stochastic methylation changes at CpG-rich DMRs occur at substantially higher frequencies, and the methylation machinery (DNMT1, UHRF1) can propagate an aberrant methylation mark through cell divisions — making LOI both more likely to occur and heritable once established.

Cancer relevance

LOI of IGF2 is the most common molecular alteration in Beckwith-Wiedemann syndrome (BWS) patients without cytogenetic abnormalities and is found in approximately 70% of Wilms’ tumors (Falls et al., 1999). It has been documented in over 20 tumor types including:

  • Wilms’ tumor, rhabdomyosarcoma, hepatoblastoma (embryonal tumors)
  • Colorectal, breast, lung, prostate, bladder (adult carcinomas)
  • Testicular germ cell tumors

LOI at the 11p15.5 cluster can simultaneously dysregulate multiple growth-regulatory genes — activating IGF2 while silencing CDKN1C or H19 — because the imprinting centre controls expression of all genes in the domain. This makes LOI at an imprinting centre a compound epigenetic driver: a single methylation error produces multiple fitness-affecting expression changes (Falls et al., 1999).

LOI and intermediate clones

LOI of IGF2 has been detected in phenotypically normal tissue surrounding Wilms’ tumors (Okamoto et al., 1997, cited in Falls et al., 1999). This suggests that LOI can occur as an early, predisposing event — creating a field of epigenetically altered but phenotypically normal cells (an intermediate clone) within which a subsequent genetic event triggers frank neoplasia. This pattern mirrors the “first hit” in Knudson’s two-hit model, with the important difference that the first hit is epigenetic, not genetic.

  • LOI vs LOH: Loss of heterozygosity (LOH) deletes one allele entirely; LOI reactivates the silenced allele. Both can produce functional consequences at imprinted loci, but through different mechanisms.
  • LOI vs UPD: Uniparental disomy (UPD) replaces one parental chromosome region with a copy from the other parent. Paternal UPD at 11p15 produces biallelic IGF2 expression plus maternal loss of CDKN1C — a compound effect. LOI of IGF2 alone does not affect CDKN1C dosage.
  • LOI vs primary epimutation: Monk et al. (2019) distinguish primary epimutations (no detectable DNA sequence change) from secondary epimutations (driven by cis- or trans-acting mutations). Most cancer-associated LOI events are likely primary epimutations, though the distinction is rarely made in cancer studies.

Relevance to clonal evolution

LOI matters for somatic evolution because it represents a distinct class of heritable fitness-affecting change:

  1. Epigenetic heritability without genetic change. Unlike mutations, LOI can arise and be propagated without altering a single base pair. This expands the substrate of heritable variation available to somatic selection beyond DNA sequence.

  2. Higher rate than genetic drivers. The stochastic error rate of DNA methylation maintenance is higher than the point mutation rate. This means LOI-driven clonal expansions may initiate and progress on faster timescales than mutation-driven expansions.

  3. Reversibility. Unlike most mutations, epigenetic changes are potentially reversible — which is why Monk et al. (2019) discuss therapeutic approaches using antisense oligonucleotides and epigenetic drugs to re-silence aberrantly active alleles.

  4. Parallel to genetic instability. Just as mutator phenotypes accelerate genetic evolution, “epimutator” phenotypes (e.g., MLIDs from SCMC disruption) could accelerate epigenetic evolution, generating clonal heterogeneity at imprinted loci across the genome simultaneously.

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