The role of imprinting genes' loss of imprints in cancers and their clinical implications

Abstract

Genomic imprinting plays an important role in the growth and development of mammals. When the original imprint status of these genes is lost, known as loss of imprinting (LOI), it may affect growth, neurocognitive development, metabolism, and even tumor susceptibility. The LOI of imprint genes has gradually been found not only as an early event in tumorigenesis, but also to be involved in progression. More than 120 imprinted genes had been identified in humans. In this review, we summarized the most studied LOI of two gene clusters and 13 single genes in cancers. We focused on the roles they played, that is, as growth suppressors and anti-apoptosis agents, sustaining proliferative signaling or inducing angiogenesis; the molecular pathways they regulated; and especially their clinical significance. It is notable that 12 combined forms of multi-genes' LOI, 3 of which have already been used as diagnostic models, achieved good sensitivity, specificity, and accuracy. In addition, the methods used for LOI detection in existing research are classified into detection of biallelic expression (BAE), differentially methylated regions (DMRs), methylation, and single-nucleotide polymorphisms (SNPs). These all indicated that the detection of imprinting genes' LOI has potential clinical significance in cancer diagnosis, treatment, and prognosis.

Keywords: cancer; diagnosis; epigenetic control; gene imprint; methods; neoplastic gene regulation; prognosis; progression.

Figure 1

The molecular mechanism of LOI affecting cancers.

Figure 2

Schematic comparison of normal and loss of imprinting for human IGF2-H19 gene cluster. (A) Dark blue boxes: IGF2 exons, light blue boxes: IGF2 introns, P0–P4: IGF2 promoter regions, yellow rectangles: IGF2 DMRs, orange rectangle: ICR1, black circle: methylated, white circle: unmethylated, red polygons: insulator binding protein CTCF, black green rectangle: transcription element ZFP57, dark red boxes: H19 exon, light red box: H19 introns, grayish green squares: cis-remote control element enhancers. (B) Blue solid arrows: parent-specific transcripts of IGF2. (C) Red solid arrows: parent-specific transcripts of H19.

Figure 3

Schematic comparison of normal and loss of imprinting for human DLK1-MEG3 gene cluster. (A) Dark green boxes: DLK1 exons, light green boxes: DLK1 introns, dark blue rectangles: ICR (CpG Island CGI and TRE work independently on different alleles to restrict the activities of TETs and DNMTs), yellow quads in CGI: conserved tandem repeat array, black circle: methylated, white circle: unmethylated, orange trapezoid: demethylated enzyme TETs, blue cloud: methylated enzyme DNMTs, black green rectangle: transcription element ZFP57, dark yellow boxes: MEG3 exon, light yellow box: MEG3 introns. (B) Green solid arrows: parent-specific transcripts of DLK1, red letter x: absence. (C) Yellow solid arrows: parent-specific transcripts of MEG3.