Germline mutations in the base-excision-repair gene MYH have been associated with recessive inheritance of multiple colorectal adenomas.
Tumors from affected individuals display excess somatic transversions of a guanine-cytosine pair to a thymine-adenine pair in the APC gene.
In this study, researchers screened for germline MYH mutations in 152 patients with multiple (3 to 100) colorectal adenomas. They also screened 107 APC-mutation-negative probands with classic familial adenomatous polyposis (>100 adenomas).
The team's results are published in this week's New England Journal of Medicine.
The researchers also analyzed subgroups for changes in the related genes MTH1 and OGG1.
In addition, adenomas were tested for somatic APC mutations.
|6 patients with multiple adenomas and 8 with polyposis had biallelic germline MYH variants.|
|New England Journal of Medicine|
The research team found that 6 patients with multiple adenomas and 8 with polyposis had biallelic germline MYH variants.
The team also identified missense and protein-truncating mutations. The spectrum of mutations was very similar in the 2 groups of patients.
In the tumors of carriers of biallelic mutations, all somatic APC mutations were guanine-cytosine to thymine-adenine transversions.
Furthermore, in the group with multiple adenomas, about 1 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), however 3 had extracolonic disease.
The team did not identify any clearly pathogenic MTH1 or OGG1 mutations.
Dr Oliver Sieber's team concluded, "Germline 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."