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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 .

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