Abstract
Background and Aim. Germline mutations of the adenomatous polyposis coli (APC) gene cause familial adenomatous polyposis (FAP), an autosomal dominant inherited disease mainly characterized by colorectal adenomatous polyposis. Genetic studies of FAP have shown that somatic APC mutations are dependent on the position of the germline APC mutation. However, the molecular mechanism underlying these genotype-phenotype associations for APC in Chinese remain largely unknown. Patients and Methods. In this study, we investigated the APC gene mutation in a Chinese FAP family by systematic screening with multiplex ligation-dependent probe amplification (MLPA), denaturing high-performance liquid chromatography (dHPLC), and DNA sequencing. Promoter methylation was detected by methylation-specific PCR. Results. The identical germline mutation c.1999 C>T (Q667X) of APC was identified in 5 affected members, among which 2 members carried somatic mutations of APC, one with promoter hypermethylation and the other with loss of wild-type allele in their adenomas. The somatic mutations were shown connected with the disease severity, demonstrating a unique genotype-phenotype association in this FAP pedigree. Conclusion. The study revealed the existence of novel pathogenic mutations in Chinese patients with FAP. Somatic mutations are of particular interest because of the unusual phenotypic features shown by patients.
Highlights
Familial adenomatous polyposis (FAP; MIM #175100) is a common hereditary syndrome characterized by early onset form of colorectal cancer based on multiple adenomas in the colon and rectum [1]
By multiplex ligationdependent probe amplification (MLPA), large deletion or duplication of adenomatous polyposis coli (APC) gene was not found in constitutional DNA
Examination of APC germline mutations in familial adenomatous polyposis (FAP) families is being used as an efficient tool for predictive testing of subjects at risk
Summary
Familial adenomatous polyposis (FAP; MIM #175100) is a common hereditary syndrome characterized by early onset form of colorectal cancer based on multiple adenomas in the colon and rectum [1]. Several studies revealed that the exon-spanning fragment variations in APC gene may be a frequent cause of FAP [6, 7]. An association between the location of the APC mutation and the phenotype in FAP patients has been described [8]. Identification of the APC mutation in one affected individual of a family opens the possibility of testing the at-risk members for the same mutation, preventing the development of colorectal cancer by the prophylactic removal of the bowel. We screened the whole coding region of APC gene by MLPA, dHPLC, and DNA sequencing to identify the germline and somatic mutations in all of the affected members of a suspicious FAP family and discussed the genotype-phenotype association
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