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Open Access Highly Accessed Research article

Early onset MSI-H colon cancer with MLH1 promoter methylation, is there a genetic predisposition?

Eddy HJ van Roon12, Marjo van Puijenbroek1, Anneke Middeldorp1, Ronald van Eijk1, Emile J de Meijer2, Dianhdra Erasmus1, Kim AD Wouters3, Manon van Engeland3, Jan Oosting1, Frederik J Hes2, Carli MJ Tops2, Tom van Wezel1, Judith M Boer2* and Hans Morreau1*

Author Affiliations

1 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands

2 Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands

3 Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands

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BMC Cancer 2010, 10:180  doi:10.1186/1471-2407-10-180

Published: 5 May 2010

Abstract

Background

To 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.

Methods

We 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.

Results

We 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.

Conclusion

Somatic 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.