The role of MYH and microsatellite instability in the development of sporadic colorectal cancer

A Colebatch, M Hitchins, R Williams, A Meagher, N J Hawkins, R L Ward, A Colebatch, M Hitchins, R Williams, A Meagher, N J Hawkins, R L Ward

Abstract

Biallelic germline mutations in MYH are associated with colorectal neoplasms, which develop through a pathway involving somatic inactivation of APC. In this study, we investigated the incidence of the common MYH mutations in an Australian cohort of sporadic colorectal cancers, the clinicopathological features of MYH cancers, and determined whether inactivation of mismatch repair and base excision repair (BER) were mutually exclusive. The MYH gene was sequenced from lymphocyte DNA of 872 colorectal cancer patients and 478 controls. Two compound heterozygotes were identified in the cancer population and all three cancers from these individuals displayed a prominent infiltration of intraepithelial lymphocytes. In total, 11 heterozygotes were found in the cancer group and five in the control group. One tumour from an individual with biallelic germline mutation of MYH also demonstrated microsatellite instability (MSI) as a result of biallelic hypermethylation of the MLH1 promoter. Although MYH-associated cancers are rare in a sporadic colorectal population, this study shows that these tumours can develop through either a chromosomal or MSI pathway. Tumours arising in the setting of BER or mismatch repair deficiency may share a biological characteristic, which promotes lymphocytic infiltration.

Figures

Figure 1
Figure 1
(A) Pedigree showing the family of the proband (case 9033, marked with black arrow) and their respective disease and mutation status. WT, wild type; left half shaded black, polyps; right half shaded black, cancer. (B) Schematic of promoter region of MLH1 from the caecal tumour from case 9033 demonstrating biallelic methylation. Each allele is distinguished by the presence of an SNP (coloured square). Circles represent CpG islands, filled circles represent methylation, the blue square represents guanine and the red square represents adenine. (C) Sequence traces obtained from the caecal tumour of case 9033 demonstrate the presence of biallelic MYH mutations. The patient was compound heterozygote for the Y165C and G382D mutations.

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Source: PubMed

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