Risk factors for loss of genomic imprinting of insulin growth factor II gene in normal colonic tissue and blood.

摘要

Loss of genomic imprinting (LOI) of the insulin-like growth factor-II gene (IGF2) involves abnormal activation of the normally silent maternally inherited allele. LOI of IGF2 has been found in colorectal cancer (CRC) and in the matched normal colonic mucosa of patients with CRC, suggesting that this alteration precedes the development of malignancy. It is not known, whether LOI is present in the blood of patients with personal or familial history of CRC, which would be consistent with a predisposing role in CRC. We conducted a cross-sectional study to determine: (1) the colonic distribution of LOI of IGF2 in the colonic mucosa and its concordance with patients' match blood lymphocytes; (2) the prevalence of LOI of IGF2 in individuals with normal colons, with adenomas, and with CRC; and (3) those clinical and epidemiological characteristics that are associated with LOI of IGF2.; Imprinting was assayed using RT-PCR analysis of an Apa I and CA polymorphism in IGF2. Odds ratios (OR) and 95% CI were calculated. One hundred and ninety-one of 421 (45%) subjects were heterozygous for either Apa I or CA repeat polymorphism; 49.6% were male; the mean age was 59.1years; 7% of patients had CRC; and 26% had family history of CRC. There was a 100% concordance between the right and the left colon in regards to imprinting status (kappa 1.0, p 0.001). All the individuals who expressed LOI in the blood expressed LOI in their colonic mucosa. However, approximately 50% of individuals expressed LOI of IGF2 only in their colonic mucosa, and not in their blood. LOI of IGF2 was found in 7% of patients with normal colons, 22% of adenoma cases, and in 56% of CRC patients (p 0.0001). LOI of IGF2 in the blood, but not in the colonic mucosa only, was associated with personal history of adenomas (OR = 4.1, 95% CI 1.30–12.8) and CRC (OR = 34.4, 95% CI 6.10–193.9), and with family history of CRC (OR = 4.8, 95% CI 1.60–14.5). LOI of IGF2 is a molecular biomarker that may predict CRC risk and can be easily determined in blood and colonic mucosa. There was a lack of association between LOI of IGF2 and other known colorectal cancer risk factors.