Abstract
Background: The Adenomatous Polyposis Coli (APC) gene is considered as a gatekeeper in colorectal tumorigenesis. 60% of somatic mutations in the APC gene are concentrated in a region called the Mutation Cluster Region (MCR). In this study, our objective was to perform the genetic analysis of two patients (index patients) who had been selected by colorectal cancer features, and to identify the genetic changes in the MCR region of the APC gene. Following discussions about the disease, the patients (index persons) agreed to a further genetic evaluation. Materials and methods: Mutation analysis of the MCR, which spans codons 1286-1513, was performed on the paraffin-embedded cancerous tissue samples using macro dissection, nested PCR and direct sequencing of purified PCR fragments. Results: In our study, two new somatic mutations detected in these patients. In one patient, we have detected a CGA to TGA as a Nonsense mutation that lead to Arg to premature Stop codon at the 4507 nucleotide position (Codon 1503) and in another patient, we describe a G→A Transition (ACG to ACA) at nucleotide position 4638 in exon 15 (MCR) which causes a silent mutation since both normal and mutated alleles encode a Thr residue at codon 1546. These mutations have not been described previously. Conclusion: This observation could suggest differences in the frequency of pathological mutations in APC among different populations; however, epidemiological studies must be performed to confirm this theory which it is not the aim of our present work.
Highlights
Familial Adenomatous Polyposis (FAP) is a rare autosomal dominant genetic disease, with an approximate incidence rate of 1/8000 [1]
We have detected a CGA to TGA as a Nonsense mutation that lead to Arg to premature Stop codon at the 4507 nucleotide position (Codon 1503) and in another patient, we describe a G→A Transition (ACG to ACA) at nucleotide position 4638 in exon 15 (MCR) which causes a silent mutation since both normal and mutated alleles encode a Thr residue at codon 1546
Based on the model provided by the autosomal dominant condition, familial adenomatosis polyposis, it has long been assumed that Adenomatous Polyposis Coli (APC) mutation is the starting alteration is most colorectal cancers [6]
Summary
Familial Adenomatous Polyposis (FAP) is a rare autosomal dominant genetic disease, with an approximate incidence rate of 1/8000 [1]. Thereby, cancerization will occur before the age of 40 years in almost 100% of patients without treatment It was shown the occurrence of FAP was related to adenomatous polyposis coli gene mutations found at 5q21-q22 [2]. APC gene micro mutations were identified in about 60-70% of FAP patients [3], whereas large fragment deletion mutations of APC gene were identified in 10-15% [3,4] It is helpful for monitoring and in the clinical treatment of high-risk individuals with mutant genes and can effectively decrease the incidence and mortality of FAP [5]. Somatic mutations are clustered in the central region of the open reading frame, spanning codons 1286-1513 of exon 15 [13,14]. This MCR represents only 8% of the 8535 bp APC gene, 66-77% of somatic mutations in APC occur in this region [15]. Following discussions about the disease, the patients (index persons) agreed to a further genetic evaluation
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