Table 1.
Summary of the main genetic and epigenetic changes of IGF2 and IGF2-associated biomarkers in CRC.
| Biomarker | Type of Change | Summary of the Findings | Potential Clinical Significance |
|---|---|---|---|
| IGF2 gene | LOI | The adjusted OR for IGF2 LOI in lymphocytes was 5.15 for patients with a positive family history, 3.46 for patients with adenomas, and 21.7 for patients with CRC [67]. | Diagnosis |
| IGF2 LOI occurs not only in colon cancer tissues but also in matched normal tissues and peripheral blood cells [68]. | Screening and diagnosis | ||
| IGF2 LOI were associated with increased risk of mortality in patients with stage IV disease; higher plasma IGF2 levels were associated with reduced risk of mortality [80]. | Diagnosis and prognosis | ||
| IGF2 LOI was in 63% of CRC and in 21.7% of the normal control group (p < 0.01) [69]. | Screening and diagnosis | ||
| IGF2 LOI with IGF2 overexpression [63] | Screening and diagnosis | ||
| IGF2 LOI was a common feature in CSCs; increased IGF2 was found in CSCs isolated from CRC cell lines (HT29, HRT18, and HCT116); higher rate of colony formation and greater resistance to chemotherapy and radiotherapy were found in vitro [142]. | Diagnosis, mechanisms, and therapeutics | ||
| IGF2 LOI leads to rebalancing of activities of canonical AKT and ERK pathways; altered signaling balance leads to rebalancing of pro- and antiapoptotic control [28]. | Diagnosis, mechanisms, and therapeutics | ||
| Amplification | Colorectal intrinsic D (CRIS-D) subtype was specifically enriched for amplification of chromosome 11p15.5 and IGF2 high-level overexpression in CRC [17]. | Diagnosis and mechanisms | |
| DNA methylation | Biallelic hypermethylation of a core of five CpG sites in the insulator region of IGF2/H19 correlated strongly with IGF2 LOI [171]. | Diagnosis and mechanisms | |
| Hypomethylation of the H19 differentially methylated region (DMR) and DMR upstream of exon 3 of IGF2 was found in CRC and normal colon mucosa; normal imprinting in the colon and LOI in CRC is specifically linked to the methylation status of a DMR within IGF2 and not H19 [172]. | Diagnosis and mechanisms | ||
| DMR IGF2/H19 hypomethylation correlated with IGF2 LOI; IGF2 overexpression did not correlate with IGF2/H19 hypomethylation but negatively correlated with MSI [140]. | Diagnosis and mechanisms | ||
| Lower levels of IGF2 DMR0 methylation were found in CRC than in control mucosa; IGF2 DMR0 hypomethylation associated with male sex, low tumor grade, microsatellite instability (MSI)-low/microsatellite stable (MSS), CpG island methylator phenotype (CIMP)-low/0, wild-type proto-oncogene B-Raf (wt BRAF), and proto-oncogene K-ras (KRAS) mutation and higher overall mortality [162]. | Diagnosis and prognosis | ||
| Hypomethylation of the six CTCF-binding sites in IGF2/H19 DMR were linked to IGF2 LOI (two forms of aberrant IGF2 expression) and promotes MSI and oncogenesis. [69] | Diagnosis and mechanisms | ||
| IGF2 was between the five genes with the highest average hypermethylated percentages (50.4%) of CRC patients [56]. | Diagnosis | ||
| Lower levels of IGF2 DMR0 methylation and ≥15 g/day alcohol consumption were associated with elevated risk of CRC [71]. | Diagnosis and mechanisms | ||
| IGF2 DMR0 hypomethylation and aberrant methylation of other iDMRs within the IGF2/H19 domain with no association with IGF2 LOI [174] | Diagnosis and mechanisms | ||
| The “insular” genomic aberrations in IGF2; mosaic distribution of methylation in 1 region of the primaries or the metastases [10] | Diagnosis and prognosis | ||
| Chromosomal gains | IGF2 overexpression in primary CRC and liver metastases was accompanied by chromosomal gains at 11p15.5 in a subset of CRC patients [6,141]. | Diagnosis and prognosis | |
| LOH | LOH of IGF2 was present in 13% of CRC patients with 33% with LOI of the IGF2 gene [70]. | Diagnosis | |
| Others | A tumor type-specific analysis uncovered that enhancer hijacking mediates gene dysregulation at the IGF2 locus in CRC [24]. | Mechanisms | |
| IGF2R gene | Genetic variants | Women homozygous for the IGF2R c.5002 G > A allele had higher mean levels of sIGF2; Whites homozygous for IGF2R c.901 C > G variant had a higher risk of CRC [59]. | Diagnosis and prognosis |
| lncRNAs | IGF2-AS | This key type of lncRNAs has correlation with certain clinical features (e.g., negative correlation between upregulation of IGF2-AS and distant metastasis) [15]. | Diagnosis and prognosis |
| This type of differentially expressed genes (DEG) was negatively correlated with overall survival (OS) [34]. | Prognosis | ||
| H19 | This type of lncRNA was increased significantly in immunodeficient mice induced with human colon cancer cells when compared with controls [163]. | Prognosis and therapeutics | |
| H19 upregulated a series of cell-cycle genes; eIF4A3 binds to H19. Higher expression of H19 was correlated with tumor differentiation and advanced Tumor-Node-Metastasis (TNM) stage [175]. | Prognosis, mechanisms, and therapeutics | ||
| H19 overexpressed in CRC tissues and cell lines; the interference of H19 by shRNA effectively decreased the migration and invasion of CRC cells. H19 shRNA strongly reduced the tumor growth and tumor volume in vivo [165]. | Mechanisms and therapeutics | ||
| Elevated expression of H19 lncRNA due to promoter demethylation was observed in cells isolated from metastases and was associated with poor survival of CRC patients [15]. | Diagnosis and prognosis | ||
| H19 was significantly upregulated in CRC tissues compared with normal control, which might regulate FSCN1 expression by competitively sponging miR-29b-3p [40]. | Diagnosis and mechanisms | ||
| H19 was upregulated in colon tumors and correlated with poor prognosis [46]. | Diagnosis, mechanisms, and prognosis | ||
| CRNDE | Regulates cellular metabolism, which may correlate with their upregulation in CRC; can promote the metabolic changes in cancer cells (switch to aerobic glycolysis) [37]. | Diagnosis and mechanisms | |
| miRNAs | miR-675 | H19-derived miRNA was upregulated in cell lines and primary CRC as compared to noncancerous tissues through downregulation of RB, increased tumor cells growth, and regulation of the CRC development [176]. | Mechanisms and therapeutics |
| miR-483 | miR-483 was a dominant driver oncogene at the IGF2 11p15.5 CRC amplicon, inducing dysplasia in vitro and tumorigenicity in vivo [109]. | Mechanisms and therapeutics |
|
| miR-483-3p, miR-483-5p | The levels of IGF2, miR-483-3p, and -5p were synchronously increased in CRC tissues; IGF2 correlated with both types of miRNAs; and higher smiR-483-5p levels were found compared to controls [143]. | Diagnosis, mechanisms, and therapeutics | |
| miR-486-5p | Plasma miR-486-5p expression was upregulated in CRC; decreased levels were associated with TNM stage, larger tumor size, lymphatic metastasis, and poor prognosis [101]. | Diagnosis, mechanisms, prognosis, and therapeutics | |
| miR-491-5p | The overexpression of IGF2 rescued the miR-491-5p-induced suppression of proliferation in CRC cells; decreased plasma miR-491-5p expression in CRC was found compared to controls [177]. | Mechanisms, prognosis, and therapeutics | |
| miR-181a/135a/302c | DNA methylation mediated repression via repressing PLAG1/IGF2 signaling; promotes the microsatellite-unstable CRC development and 5-FU resistance [178]. | Mechanisms, prognosis, and therapeutics |
AS: antisense; CRC: colorectal cancer; CRIS: CRC intrinsic subtype; CRNDE: Colorectal neoplasia differentially expressed; CSCs: cancer stem cells; CTCF: CCCTC-Binding Factor; eIF4A3: Eukaryotic initiation factor 4A-III; FSCN1: Fascin Actin-Bundling Protein 1; iDEGs: imprinting-associated Differentially Expressed Genes; lncRNAs: long non-coding RNAs; LOH: loss of heterozygosity; LOI: loss of imprinting; miRNAs: mikroRNAs; MSI: Microsatellite instability; OR: odds ratio; RB: retinoblastoma; shRNA: short hairpin RNA; s: serum; TADs: topologically associating domains; wt: wild type.