An APC Mutation in a Large Chinese Kindred With Familial Adenomatous Polyposis Was Identified Using Both Next Generation Sequencing and Simple STR Marker Haplotypes

Abstract

Background: Familial adenomatous polyposis (FAP) is an autosomal dominant disorder characterized primarily by the development of numerous adenomatous polyps in the colon and a high risk for colorectal cancer. FAP is caused by germline mutations of the adenomatous polyposis coli (APC) gene. The proband in this family was a 39year-old female patient with the pathologic diagnosis of adenomatous polyps, and then a five-generation kindred with FAP was characterized in the following years. This article identified an APC mutation, and demonstrated the practical use of APC-linked STR markers, which could be used to reduce misdiagnosis of prenatal diagnosis or preimplantation genetic diagnosis resulted from contamination or allele drop-out. Methods: Next-generation sequencing (NGS) was used to identify the possible APC mutations in an affected individual from a family with autosomal dominant colon cancer. Targeted sequencing then used to identify additional related individuals with the mutation. Three short tandem repeat (STR) loci, D5S299, D5S134, and D5S346, were used for PCR-based microsatellite analysis of the APC gene in the extended family. Results: We identified an APC: p.W553X mutation. The STR haplotype at the APC locus, A1B4C1, was shared by all clinically affected individuals with the APC: p.W553X mutation. In addition, the APC: p.D1822V variant was observed in 40% affected individuals and in two unaffected individuals. Conclusion: We described a protein truncation mutation, APC: p.W553X; demonstrated the value of APC-linked STR markers (D5S299, D5S134, and D5S346) haplotypes; and suggested the potential role of these haplotypes in detecting loss of heterozygosity of the APC gene.

Hsa_circ_0036740 in familial adenomatous polyposis: Immune regulation and neutrophil effects in CRC based on high-throughput assay

“…The main causes of death among FAP patients are CRC, duodenal cancer, and fibroma durum (Martin et al, 2021). The mean age for developing CRC is 39 years, and 7% of FAP patients are diagnosed with CRC before the age of 21 years (Zhan et al, 2020). Currently, sulforaphane combined with erlotinib and endoscopic resection combined with low-dose aspirin have been identified as potentially effective treatment options for FAP (Ulusan et al, 2021).…”

APC Splicing Mutations Leading to In-Frame Exon 12 or Exon 13 Skipping Are Rare Events in FAP Pathogenesis and Define the Clinical Outcome

“…The remaining molecularly characterized splicing mutations leading to an in-frame protein (5/9) result in skipping of exon 5, 7, 8, or (partially) 9 with loss of APC regions not encompassing known functional sites/domains [45,54,67] (Table S3). In order to provide further insight into the relationship between APC exon 12 or exon 13 splicing mutations leading to an in-frame protein, the clinical phenotype, and the potential underlying molecular mechanisms in FAP disease, we retrieved clinical and molecular data of FAP patients bearing truncating mutations that lead to partial or total removal of ARM2 and/or ARM3 and disrupt all downstream APC protein domains [50,53,71,[89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105] (Table S4). Then, we sought to compare the phenotypic consequences of splicing mutations leading to in-frame amino acid deletions within the ARM2 or ARM3 motifs of the APC protein N-terminal armadillo repeat domain with those of truncating mutations located in the ARM2 (aa 505-547) or ARM3 (aa 548-591) domains leading to partial or total removal of ARM2 and/or ARM3 and disrupting all APC downstream regions (aa 505-2843), including the β-catenin-regulating domains (Figure 4).…”