Frequency of the Common MYH Mutations (G382D and Y165C) in MMR Mutation Positive and Negative HNPCC Patients

Katie A Ashton,Cliff J Meldrum,Rodney J Scott,Carla F Kairupan,Mary L Mcphillips

doi:10.1186/1897-4287-3-2-65

Katie A Ashton, Cliff J Meldrum + Show 3 more

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https://doi.org/10.1186/1897-4287-3-2-65

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Abstract

Recently mutations in the MYH gene have been associated with a milder form of adenomatous polyposis which is characterized by a variable level of colonic polyps ranging from a few to several hundred. In the context of HNPCC it is not unusual to identify patients with a smattering of polyps. The MYH gene product is involved in DNA repair and indeed the hMSH2/hMSH6 complex (both genes being essential elements of the DNA mismatch repair pathway) is required to stimulate MYH activity. We reasoned that because of the clinical similarity of a subset of HNPCC patients to those described with MYH mutations and the role of the hMSH2/hMSH6 complex in the activation of MYH protein that MYH mutations may account for a small proportion of HNPCC patients. In a study of 442 HNPCC patients we identified MYH mutations at the same frequency as that expected in the general population. Nevertheless, two HNPCC families were identified harbouring biallelic changes in MYH.

Highlights

Hereditary Non Polyposis Colorectal Cancer (HNPCC) is an autosomal dominant inherited disorder associated with a familial predisposition to colorectal cancer (CRC)
mismatch repair (MMR) gene mutations do not account for all CRC cases in HNPCC since some patients fit the clinical criteria for HNPCC yet they do not harbour a MMR gene mutation
We have investigated a series of patients that have been extensively screened for hMLH1 and hMSH2 germline mutations by denaturing high performance liquid chromatography analysis, denaturing gradient gel electrophoresis (DGGE), direct sequencing and multiplex ligation probe amplification (MLPA) analysis

Summary

Introduction

Hereditary Non Polyposis Colorectal Cancer (HNPCC) is an autosomal dominant inherited disorder associated with a familial predisposition to colorectal cancer (CRC). The results obtained in these studies suggest that colorectal cancer and in particular HNPCC might be confined to mutations in MMR genes and to other genes involved in DNA repair such as MYH. A study by Jones et al [15] showed that biallelic nonsense and missense mutations in MYH were found in colorectal cancer patients that were unrelated and in addition they identified that sequence variants are found in different ethnic groups that include the Caucasian (Y165C, G382D), Indian (E466X), Pakistani (Y90X) and the Italian (1395delGGA).

Results

Conclusion