Three novel mutations of APC gene in Chinese patients with familial adenomatous polyposis.

Qi Liu,Yang Luo,Xiaoxia Li,Hongwei Ma,Sen Li,Qingzhu Tang,Yu Wang,Shengqiang Qu

doi:10.1007/s13277-016-4986-1

Abstract

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder characterized by the development of hundreds to thousands of colonic adenomas and an increased risk of colorectal cancer. Adenomatous polyposis coli (APC), encoding a large multidomain protein involved in antagonizing the Wnt signaling pathway, has been identified as the main causative gene responsible for FAP. In this study, we identified three novel mutations as well as two recurrent mutations in the APC in five Chinese FAP families by sequencing. Immunohistochemical analysis revealed that among these mutations, a nonsense mutation (c.2510C>G) and two small deletions (c.2016_2047del, c.3180_3184del) led to the truncation of the APC protein and the cytoplasmic and nuclear accumulation of β-catenin in the colorectal samples from affected individuals, respectively. Our study expands the database on mutations of APC and provides evidence to understand the function of APC in FAP.

Highlights

Familial adenomatous polyposis (FAP; OMIM#175100) is an autosomal dominant disorder characterized by hundreds to thousands of adenomatous polyposis throughout the colon and rectum that evolve into fatal aggressive tumors when left untreated [1]
This mutation was predicted to lead to a premature termination codon (PTC) at codon 589 and to result in truncated adenomatous polyposis coli (APC) protein lacking 2254 amino acid residues (Fig. 2b)
As a large protein with multiple domains, the human APC contains an oligomerization domain, an armadillo region, three 15-amino acid repeats, seven 20-amino acid repeats, a basic domain, an EB1-binding domain, and a human disc large binding site, which is comprised by amino acids 6-57, 453-767, 1020-1070, 1265-2035, 2200-2400, 2559-2771, and 2771-2843, respectively [2, 16]

Summary

Introduction

Familial adenomatous polyposis (FAP; OMIM#175100) is an autosomal dominant disorder characterized by hundreds to thousands of adenomatous polyposis throughout the colon and rectum that evolve into fatal aggressive tumors when left untreated [1]. The penetrance is approximately 100 %, with the appearance of polyps by adolescence or the third decade of life. The incidence of FAP in the population is approximately 1 in 8000. FAP has a relatively equal worldwide distribution and occurs almost among males and females. Patients with FAP may have extracolonic manifestation, such as congenital hypertrophy of the retinal pigment epithelium, dental abnormalities, and upper gastrointestinal polyps [2, 3]. In 1991, the adenomatous polyposis coli (APC) gene was identified as responsible for FAP [4]

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Results

Conclusion