Specific hypomethylated CpGs at the IGF2 locus act as an epigenetic biomarker for familial adenomatous polyposis colorectal cancer.

AIMS: The identification of specific biomarkers for colorectal cancer is of primary importance for early diagnosis. The aim of this study was to evaluate if methylation changes at the IGF2/H19 locus could be predictive for individuals at high risk for developing sporadic or hereditary colorectal cancer. MATERIALS & METHODS: Quantitative methylation analysis using pyrosequencing was performed on three differentially methylated regions (DMRs): IGF2 DMR0 and DMR2 and the H19 DMR in DNA samples from sporadic colorectal cancer (n = 26), familial adenomatous polyposis (n = 35) and hereditary nonpolyposis colorectal cancer (n = 19) patients. RESULTS: We report in this article for the first time, that in sporadic colorectal cancer tumor DNA both the IGF2 DMR0 and DMR2 are hypomethylated, while the H19 DMR retains its monoallelic methylation pattern. In lymphocyte DNA, a striking hypomethylation of nine contiguous correlated CpGs was found in the IGF2 DMR2 but only in familial adenomatous polyposis patients. CONCLUSION: Methylation alterations at the IGF2 locus are more extensive than previously reported and DMR2 hypomethylation in lymphocyte DNA might be a specific epigenetic biomarker for familial adenomatous polyposis patients.

Liver insulin-like growth factor 2 methylation in hepatitis C virus cirrhosis and further occurrence of hepatocellular carcinoma.

AIM: To assess the predictive value of the insulin-like growth factor 2 (Igf2) methylation profile for the occurrence of Hepatocellular Carcinoma (HCC) in hepatitis C (HCV) cirrhosis. METHODS: Patients with: (1) biopsy-proven compensated HCV cirrhosis; (2) available baseline frozen liver sample; (3) absence of detectable HCC; (4) regular screening for HCC; (5) informed consent for genetic analysis were studied. After DNA extraction from liver samples and bisulfite treatment, unbiased PCR and DHPLC analysis were performed for methylation analysis at the Igf2 locus. The predictive value of the Igf2 methylation profile for HCC was assessed by Kaplan-Meier and Cox methods. RESULTS: Among 94 included patients, 20 developed an HCC during follow-up (6.9 +/- 3.2 years). The methylation profile was hypomethylated, intermediate and hypermethylated in 13, 64 and 17 cases, respectively. In univariate analysis, two baseline parameters were associated with the occurrence of HCC: age (P = 0.01) and prothrombin (P = 0.04). The test of linear tendency between the three ordered levels of Igf2 methylation and probability of HCC occurrence was significant (Log Rank, P = 0.043; Breslow, P = 0.037; Tarone-Ware, P = 0.039). CONCLUSION: These results suggest that hypomethylation at the Igf2 locus in the liver could be predictive for HCC occurrence in HCV cirrhosis.

The H19 locus acts in vivo as a tumor suppressor.

The H19 locus belongs to a cluster of imprinted genes that is linked to the human Beckwith-Wiedemann syndrome. The expression of H19 and its closely associated IGF2 gene is frequently deregulated in some human tumors, such as Wilms' tumors. In these cases, biallelic IGF2 expression and lack of expression of H19 are associated with hypermethylation of the imprinting center of this locus. These observations and others have suggested a potential tumor suppressor effect of the H19 locus. Some studies have also suggested that H19 is an oncogene, based on tissue culture systems. We show, using in vivo murine models of tumorigenesis, that the H19 locus controls the size of experimental teratocarcinomas, the number of polyps in the Apc murine model of colorectal cancer and the timing of appearance of SV40-induced hepatocarcinomas. The H19 locus thus clearly displays a tumor suppressor effect in mice.

Riluzole attenuates spinal muscular atrophy disease progression in a mouse model.

Spinal muscular atrophy (SMA) is a motor neuron disease caused by mutations of the survival motor neuron 1 gene (SMN1). No curative treatment is available. Mutant mice carrying homozygous deletion of Smn exon 7 directed to neurons display a degenerative process of motor neurons similar to that found in human SMA. To test whether riluzole, which exhibits neurotrophic properties, might have a protective role in SMA, mutant mice were treated with it after the onset of the degenerative process. Riluzole improved median survival and exerted a protective effect against aberrant cytoskeletal organization of motor synaptic terminals but not against loss of proximal axons. These results demonstrate that the disease course of SMA can be attenuated after the onset of neuromuscular defects and may warrant further investigation in a therapeutic trial in SMA.

Therapeutic benefits of cardiotrophin-1 gene transfer in a mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a recessive autosomal disorder characterized by degeneration of lower motor neurons caused by mutations of the survival motor neuron gene (SMN1). No curative treatment is known so far. Mutant mice carrying homozygous deletion of Smn exon 7 directed to neurons display skeletal muscle denervation, moderate loss of motor neuron cell bodies and severe axonal degeneration. These features, similar to those found in human SMA, strongly suggest the involvement of a dying back process of motor neurons and led us to test whether neurotrophic factors might have a protective role in SMA. We report here the therapeutic benefits of systemic delivery of cardiotrophin-1 (CT-1), a neurotrophic factor belonging to the IL-6 cytokine family. Intra-muscular injection of adenoviral vector expressing CT-1, even at very low dose, improves median survival, delays motor defect of mutant mice and exerts protective effect against loss of proximal motor axons and aberrant cytoskeletal organization of motor synaptic terminals. In spite of the severity of SMA phenotype in mutant mice, CT-1 is able to slow down disease progression. Neuroprotection could be regarded as valuable therapeutic approach in SMA.