18 May 2005
Colorectal cancer is a common disease, with around 35,000 new cases in the UK each year. A high proportion of colorectal cancer patients have a family history of the disease, but autosomal dominant familial cancer syndromes associated with very high risk of colorectal cancer (familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer) account for less than 5% of cases. Most cases of familial colorectal cancer are therefore thought to be the result of genetic variants with lower penetrance.
A paper in the latest edition of the Journal of the National Cancer Institute (JNCI) reports an association between mutations in the MYH gene and increased colorectal cancer risk [Croitoru ME et al. (2004) J Natl Cancer Inst. 96, 1631-1634]. The MYH gene on chromosome 1p encodes a protein involved in the DNA base excision repair pathway. Previous reports have linked two MYH gene mutations, Y165C and G382D, with impaired DNA repair and colorectal polyposis and cancer in individuals found to be compound heterozygotes for these two mutations (carriers of biallelic MYH gene mutations). The report by Croitoru et al examines the prevalence of germline MYH gene mutations in a Canadian population and the risk of colorectal cancer among monoallelic MYH mutation carriers, using the Ontario Familial Colorectal Cancer Registry. A total of 1238 patients diagnosed with colorectal cancer between 1997 and 2000 and 1255 matched controls were recruited. DNA was analysed by PCR to identify the presence of the Y165C and G382D mutations. Pathogenic biallelic MYH mutations were detected in 12 (1.0%) of the case patients, but none of the control subjects. Monoallelic Y165C or G382D mutations were found in 29 (2.34%) of the case patients and 21 (1.67%) of the control subjects. The presence of a germline MYH Y165C and/or G382D mutation was associated with a two-fold increase in colorectal cancer risk compared with individuals lacking such mutations.
The researchers then assessed the clinicopathologic features of the MYH mutation carriers. It was found that the mean age at diagnosis of colorectal cancer for patients with germline MYH Y165C and/or G382D mutations was significantly younger than that for patients without the mutations (56.3 years versus 59.8 years). Next, the association between MYH gene mutations and a family history of colorectal cancer were analysed. Case patients with MYH Y165C and/or G382D mutations were found to be slightly more likely to have a first- or second-degree relative affected with colorectal cancer than case patients without the mutations. Finally, the team tested colorectal tumour specimens from 16 monoallelic and 10 biallelic MYH gene mutation carriers for loss of heterozygosity (LOH) of the MYH gene. LOH refers to the deletion or mutation of the normal allele at a heterozygous locus, such that the cell becomes either hemizygous (having one mutant allele and one deleted allele) or homozygous for the mutant allele. Loss of heterozygosity was reportedly identified in 47% of the tumors from monoallelic MYH mutation carriers but only 20% of those from biallelic carriers. The authors propose that since allelic loss of chromosome 1p is an early event in colorectal tumorigenesis, LOH in some monoallelic carriers may cause an increased risk of colorectal cancer.
The paper concludes that