Dataset Information

Hypermethylation of the WT1 and calcitonin gene promoter regions at chromosome 11p in human colorectal cancer.

ABSTRACT: The short arm of the chromosome 11, known to harbour a number of putative and established tumour-suppressor genes, is frequently hypermethylated in various human neoplasms. We subjected the promoter regions of two genes residing at 11p, namely the tumour-suppressor gene WT1 (Wilms' tumour gene) (11p13) and the calcitonin gene (11p15.5), to methylation analysis in human sporadic colorectal cancer using genomic sequencing. Both genes showed significant hypermethylation of CpG sites within their promoter regions in adenomas and carcinomas compared with normal colonic mucosa. Although the WT1 promoter region was significantly hypermethylated, two CpG sites located in Sp1 motifs were unmethylated in the majority of cases (68-74% of carcinomas). The expression of WT1 gene, as revealed by in situ hybridization, showed no differences between normal colonic mucosa and malignant carcinoma. Together with earlier observations, our present results support the view that the short arm of human chromosome 11 is subjected to widespread regional hypermethylation in various human malignancies.

SUBMITTER: Hiltunen MO

PROVIDER: S-EPMC2228127 | biostudies-other | 1997

REPOSITORIES: biostudies-other

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Hypermethylation of the WT1 and calcitonin gene promoter regions at chromosome 11p in human colorectal cancer.

Hiltunen M O MO Koistinaho J J Alhonen L L Myöhänen S S Marin S S Kosma V M VM Pääkkönen M M Jänne J J

British journal of cancer 19970101 9

The short arm of the chromosome 11, known to harbour a number of putative and established tumour-suppressor genes, is frequently hypermethylated in various human neoplasms. We subjected the promoter regions of two genes residing at 11p, namely the tumour-suppressor gene WT1 (Wilms' tumour gene) (11p13) and the calcitonin gene (11p15.5), to methylation analysis in human sporadic colorectal cancer using genomic sequencing. Both genes showed significant hypermethylation of CpG sites within their pr ...[more]

PMID: 9365158

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Project description:BackgroundColorectal cancers (CRCs) that have microsatellite instability (MSI) and mutL homolog 1 (MLH1) immunoloss are observed in 3 clinical scenarios: Lynch syndrome (LS), sporadic MSI CRC, and Lynch-like syndrome (LLS). v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutational analysis is used to differentiate LS from sporadic MSI CRC. The role of MLH1 promoter methylation status for the differential diagnosis of these clinical forms is not well established. The objectives of this study were: 1) to analyze MLH1 promoter methylation in MLH1-deficient CRCs by pyrosequencing, and 2) to assess its role in the differential diagnosis of MLH1-deficient CRCs.MethodsIn total, 165 CRCs were analyzed, including LS (n = 19), MSI BRAF-mutated CRC (n = 37), MSI BRAF wild-type CRC (n = 60), and a control group of CRCs without MSI (microsatellite stable [MSS] CRC; n = 49). MLH1 promoter methylation status was analyzed by pyrosequencing, and the ability of different strategies to identify LS was assessed.ResultsThe average ± standard deviation methylation in LS (9% ± 7%) was significantly lower than that in MSI BRAF-mutated CRC (42% ± 17%; P < .001) and in MSI BRAF wild-type CRC (25% ± 19%; P = .002). Somatic MLH1 hypermethylation was detected in 3 patients (15.8%) with LS, in 34 patients (91.9%) with MSI BRAF-mutated CRC, and in 37 patients (61.7%) with MSI BRAF wild-type tumors. Patients with MSI BRAF wild-type, unmethylated tumors (ie, LLS) had a stronger family history of CRC than those who had tumors with MLH1 methylation (P < .05). The sensitivity for ruling out LS was 100% for BRAF analysis, 84.2% for MLH1 methylation analysis, and 84.2% for the combination of both analyses.ConclusionsSomatic MLH1 promoter methylation occurs in up to 15% of LS CRCs. Somatic BRAF analysis is the most sensitive strategy for ruling out LS. Patients who have CRCs with loss of MLH1 protein expression and neither BRAF mutation nor MLH1 methylation resemble patients with LS.

Dataset Information

Hypermethylation of the WT1 and calcitonin gene promoter regions at chromosome 11p in human colorectal cancer.

Publications

Hypermethylation of the WT1 and calcitonin gene promoter regions at chromosome 11p in human colorectal cancer.

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