Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Methylation profiling of human colon cancer specimens with or without methylation of the MLH1 promoter.

ABSTRACT: Expression profile was obtained for GeneChip probe sets among colon cancer specimens with or without the methylation of MLH1 promoter.

ORGANISM(S): Homo sapiens

SUBMITTER: Hiroyuki Mano

PROVIDER: E-GEOD-2138 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Epigenetic silencing of AXIN2 in colorectal carcinoma with microsatellite instability.

Koinuma K K Yamashita Y Y Liu W W Hatanaka H H Kurashina K K Wada T T Takada S S Kaneda R R Choi Y L YL Fujiwara S-I SI Miyakura Y Y Nagai H H Mano H H

Oncogene 20060101 1

Mutation or epigenetic silencing of mismatch repair genes, such as MLH1 and MSH2, results in microsatellite instability (MSI) in the genome of a subset of colorectal carcinomas (CRCs). However, little is yet known of genes that directly contribute to tumor formation in such cancers. To characterize MSI-dependent changes in gene expression, we have now compared transcriptomes between fresh CRC specimens positive or negative for MSI (n=10 for each) with the use of high-density oligonucleotide micr ...[more]

PMID: 16247484

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Project description:BackgroundTo investigate the etiology of MLH1 promoter methylation in mismatch repair (MMR) mutation-negative early onset MSI-H colon cancer. As this type of colon cancer is associated with high ages, young patients bearing this type of malignancy are rare and could provide additional insight into the etiology of sporadic MSI-H colon cancer.MethodsWe studied a set of 46 MSI-H colon tumors cases with MLH1 promoter methylation which was enriched for patients with an age of onset below 50 years (n=13). Tumors were tested for CIMP marker methylation and mutations linked to methylation: BRAF, KRAS, GADD45A and the MLH1 -93G>A polymorphism. When available, normal colon and leukocyte DNA was tested for GADD45A mutations and germline MLH1 methylation. SNP array analysis was performed on a subset of tumors.ResultsWe identified two cases (33 and 60 years) with MLH1 germline promoter methylation. BRAF mutations were less frequent in colon cancer patients below 50 years relative to patients above 50 years (p-value: 0.044). CIMP-high was infrequent and related to BRAF mutations in patients below 50 years. In comparison with published controls the G>A polymorphism was associated with our cohort. Although similar distribution of the pathogenic A allele was observed in the patients with an age of onset above and below 50 years, the significance for the association was lost for the group under 50 years. GADD45A sequencing yielded an unclassified variant. Tumors from both age groups showed infrequent copy number changes and loss-of-heterozygosity.ConclusionSomatic or germline GADD45A mutations did not explain sporadic MSI-H colon cancer. Although germline MLH1 methylation was found in two individuals, locus-specific somatic MLH1 hypermethylation explained the majority of sporadic early onset MSI-H colon cancer cases. Our data do not suggest an intrinsic tendency for CpG island hypermethylation in these early onset MSI-H tumors other than through somatic mutation of BRAF.

Dataset Information

Methylation profiling of human colon cancer specimens with or without methylation of the MLH1 promoter.

Publications

Epigenetic silencing of AXIN2 in colorectal carcinoma with microsatellite instability.

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