APC and MUTYH Analysis in FAP Patients: A Novel Mutation in APC Gene and Genotype-Phenotype Correlation.

Giovanna D’Elia,Amelia Casamassimi,Maria Vietri,Anna Molinari,Michele Cioffi,Gemma Caliendo

doi:10.3390/genes9070322

Abstract

APC and MUTYH genes are mutated in 70–90% and 10–30% of familial adenomatous polyposis cases (FAP) respectively. An association between mutation localization and FAP clinical phenotype is reported. The aims of this study were to determine APC and MUTYH mutational status in a small cohort of FAP patients and to evaluate the genotype-phenotype correlation in mutated patients. Here, we report the identification of a novel APC germline mutation, c.510_511insA. Overall, mutational analysis showed pathogenic mutations in 6/10 patients: 5/10 in APC and 1/10 in MUTYH. Additionally, we found three variants of unknown significance in MUTYH gene that showed no evidence of possible splicing defects by in silico analysis. Molecular analysis was also extended to family members of mutated patients. A genotype-phenotype correlation was observed for colonic signs whereas a variation of disease onset age was revealed for the same mutation. Moreover, we found an intrafamilial variability of FAP onset age. Regarding extracolonic manifestations, the development of desmoid tumors was related to surgery and not to mutation position, while a genotype-phenotype correspondence was observed for the onset of thyroid or gastric cancer. These findings can be useful in association to clinical data for early surveillance and suitable treatment of FAP patients.

Highlights

Familial adenomatous polyposis (FAP) is a hereditary disorder characterized by a large number of precancerous polyps initiating to grow in childhood and adolescence
The novel mutation c.510_511insA (p.Ser171LysfsX6) has not been previously reported in published literature or in any database. This frameshift mutation, localized in exon 4, consists of an adenine insertion between nucleotide 510 and 511, which results in the introduction of a stop codon at amino acid position 176 (Figure 1a)
Despite the small group of patients analyzed for mutations in adenomatous polyposis coli (APC) and mutY homolog (MUTYH) genes, we report the identification of a novel germline mutation in APC gene, c.510_511insA (p.Ser171LysfsX6)

Summary

Introduction

Familial adenomatous polyposis (FAP) is a hereditary disorder characterized by a large number of precancerous polyps initiating to grow in childhood and adolescence. These polyps transform into colorectal carcinoma during the fourth and fifth decades of life [1]. Several clinical variants of the FAP phenotype have been described, based on the number of colorectal polyps and onset age [2]. Profuse or aggressive FAP is characterized by the presence of hundreds to thousands of adenomatous polyps throughout the colon and the rectum; about half patients develop adenomas by the age of 15 years. Intermediate FAP is characterized by the presence of hundreds of polyps that develop around the second-third decade of life.

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