Article

Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH.

Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, London, United Kingdom.
New England Journal of Medicine (impact factor: 53.3). 02/2003; 348(9):791-9. DOI:10.1056/NEJMoa025283 pp.791-9
Source: PubMed

ABSTRACT Germ-line mutations in the base-excision-repair gene MYH have been associated with recessive inheritance of multiple colorectal adenomas. Tumors from affected persons displayed excess somatic transversions of a guanine-cytosine pair to a thymine-adenine pair (G:C-->T:A) in the APC gene.
We screened for germ-line MYH mutations in 152 patients with multiple (3 to 100) colorectal adenomas and 107 APC-mutation-negative probands with classic familial adenomatous polyposis (>100 adenomas). Subgroups were analyzed for changes in the related genes MTH1 and OGG1. Adenomas were tested for somatic APC mutations.
Six patients with multiple adenomas and eight patients with polyposis had biallelic germline MYH variants. Missense and protein-truncating mutations were found, and the spectrums of mutations were very similar in the two groups of patients. In the tumors of carriers of biallelic mutations, all somatic APC mutations were G:C-->T:A transversions. In the group with multiple adenomas, about one third of patients with more than 15 adenomas had biallelic MYH mutations. In the polyposis group, no patient with biallelic MYH mutations had severe disease (>1000 adenomas), but three had extracolonic disease. No clearly pathogenic MTH1 or OGG1 mutations were identified.
Germ-line MYH mutations predispose persons to a recessive phenotype, multiple adenomas, or polyposis coli. For patients with about 15 or more colorectal adenomas--especially if no germ-line APC mutation has been identified and the family history is compatible with recessive inheritance--genetic testing of MYH is indicated for diagnosis and calculation of the level of risk in relatives. Clinical care of patients with biallelic MYH mutations should be similar to that of patients with classic or attenuated familial adenomatous polyposis.

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Keywords

15 adenomas
 
APC gene
 
attenuated familial adenomatous polyposis
 
base-excision-repair gene MYH
 
biallelic mutations
 
biallelic MYH mutations
 
classic familial adenomatous polyposis
 
excess somatic transversions
 
germ-line APC mutation
 
Germ-line mutations
 
germ-line MYH mutations
 
multiple adenomas
 
multiple colorectal adenomas
 
OGG1 mutations
 
pathogenic MTH1
 
polyposis coli
 
protein-truncating mutations
 
recessive inheritance
 
related genes MTH1
 
somatic APC mutations