MUTYH Mutations Do Not Cause HNPCC or Late Onset Familial Colorectal Cancer

Astrid Stormorken,Pål Møller,Karen-Marie Heintz,Eivind Hovig,Per Andresen

doi:10.1186/1897-4287-4-2-90

Abstract

Recently, carriers of biallelic mutations in the base excision repair gene MUTYH, have been demonstrated to have a predisposition for multiple adenomas and colorectal cancer. Still, many questions remain unanswered concerning MUTYH. We have addressed the following: Do biallelic MUTYH mutation carriers invariably demonstrate FAP, and may MUTYH be a gene causing HNPCC, HNPCC-like or dominantly inherited late onset colorectal cancer? We examined affecteds from our total series of HNPCC, HNPCC-like and dominantly inherited late onset colorectal cancer kindreds not demonstrated to have any MMR mutations. Bloodsamples from 96 patients were subjected to sequencing of exon 7 and exon 13 in the MUTYH gene. Two heterozygotes and one homozygote for the European founder mutations were found. The homozygous carrier did not meet criteria for FAP/AFAP. We conclude that MUTYH, when mutated, causes a rare recessively inherited disorder including colorectal- and duodenal cancers. It is not verified that heterozygous carriers of MUTYH mutations have an increased risk of cancer, and they do not explain the occurrence of familial colorectal cancer in the population.

Highlights

Carriers of biallelic mutations in the base excision repair gene, MUTYH at 1p34.1, have been demonstrated to have a predisposition for multiple adenomas and colorectal cancer (CRC) causing autosomal recessive inherited disease [1]
Families classified as Familial Adenomatous Polyposis (FAP) or Attenuated FAP (AFAP), but without a detected mutation in the Adenomatous Polyposis Coli (APC) gene, may be caused by biallelic MUTYH mutations [9]
We have addressed the following: 1) Do biallelic MUTYH mutation carriers invariably demonstrate FAP? 2) May MUTYH be a gene causing HNPCC, HNPCC-like or dominantly inherited late onset colorectal cancer (LOCRC)?

Summary

Introduction

Carriers of biallelic mutations in the base excision repair gene, MUTYH at 1p34.1, have been demonstrated to have a predisposition for multiple adenomas and colorectal cancer (CRC) causing autosomal recessive inherited disease [1]. The gene encodes a glycolase which is involved in repair of DNA damage caused by reactive oxygen species generated during aerobic metabolism [2, 3]. In variant forms this ability is reduced [4]. Combined data from previous studies suggest that about 1% of colorectal cancer cases can be attributed to biallelic MUTYH mutations [3, 6,7,8]. Families classified as Familial Adenomatous Polyposis (FAP) or Attenuated FAP (AFAP), but without a detected mutation in the Adenomatous Polyposis Coli (APC) gene, may be caused by biallelic MUTYH mutations [9]

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Results

Conclusion