Identification of 5 novel germline APC mutations and characterization of clinical phenotypes in Japanese patients with classical and attenuated familial adenomatous polyposis

Abstract

BackgroundFamilial adenomatous polyposis (FAP) is an autosomal dominant hereditary disease characterized by multiple colorectal adenomatous polyps and frequent extracolonic manifestations. An attenuated form of FAP (AFAP) is diagnosed based on a milder colorectal phenotype, and the colorectal phenotype of (A)FAP has been linked to germline APC mutations. The relationships between the spectrum of mutations and extracolonic manifestations are quite well known, but they need to be further defined.FindingsNine germline APC mutations, but no large deletions, were identified in the APC locus of 8 (A)FAP patients, and 5 of the mutations, c.446A > T (p.Asp149Val), c.448A > T (p.Lys150X), c.454_457insAGAA (p.Glu152ArgfsX17), c.497insA (p.Thr166AsnfsX2), and c.1958G > C (p.Arg653Ser), were novel mutations. In one patient the p.Asp149Val mutation and p.Lys150X mutation were detected in the same APC allele. The c.1958G > C mutation was located in the last nucleotide of exon 14, and RT-PCR analysis revealed that the mutation resulted in abnormal splicing. The above findings meant that a nonsense mutation, a frameshift mutation, or an exonic mutation leading to abnormal splicing was found in every patient. The following phenotypes, especially extracolonic manifestations, were observed in our (A)FAP patients: (1) multiple gastroduodenal adenomas and early-onset gastric carcinoma in AFAP patients with an exon 4 mutation; (2) a desmoid tumor in two FAP patients with a germline APC mutation outside the region between codons 1403 and 1578, which was previously reported to be associated with the development of desmoid tumors in FAP patients; (3) multiple myeloma in an AFAP patient with an exon 4 mutation.ConclusionsNine germline APC mutations, 5 of them were novel, were identified in 8 Japanese (A)FAP patients, and some associations between germline APC mutations and extracolonic manifestations were demonstrated. These findings should contribute to establishing relationships between germline APC mutations and the extracolonic manifestations of (A)FAP patients in the future.

A Case of a Child with an APC Pathogenic Mutation, Aberrant Expression of Splice Variants and Positive Family History of FAP

“…The variant lacking exon 15 has been reported to cause quantitative distortion of mRNA isoforms both in the splice acceptor site mutant and in a germline mutation at the last nucleotide of exon 15 (6). The latter diagnosed case revealed over 300 colorectal polyps at 32 years of age, including colorectal cancer, multiple gastroduodenal adenomas and duodenal adenocarcinoma (6). Quantitative distortions of mRNA isoforms were also observed in the present case.…”

“…Varesco et al (7) indicated that a splice donor site mutation on exon 10 was associated with late-onset FAP, which is a milder form of the disease. The variant lacking exon 15 has been reported to cause quantitative distortion of mRNA isoforms both in the splice acceptor site mutant and in a germline mutation at the last nucleotide of exon 15 (6). The latter diagnosed case revealed over 300 colorectal polyps at 32 years of age, including colorectal cancer, multiple gastroduodenal adenomas and duodenal adenocarcinoma (6).…”

“…Colonoscopic diagnosis showed internal hemorrhoids, Jpn J Clin Oncol 2014;44 (6) 603 and the cause of melena was assessed as a hemorrhoid. However, three flat polyps were incidentally identified and were diagnosed as tubular adenomas according to endoscopic findings.…”

Familial Gastric Cancers

“…However, no difference has been observed between gastric or duodenal location of the polyps and mutation sites [19]. With regard to the subtype, mutations in exons 10-15H (codon 564-1,465) have been seen with a significantly higher frequency in GAs yet are undetected in FGPs [20].Finally,afewstudieshavereportedmutationalvariation in dysplastic and malignant FAP-associated gastric polyps, with rare KRAS mutations in codon 12 seen in FGPs harboring low grade [21] and mutations in exon 4 of the FAP gene reported in gastric polyposis and early-onset gastric carcinoma in AFAP patients [22].…”

Hepatocellular adenoma associated with familial adenomatous polyposis coli

“…esis of this patient, genetic alterations of the germ-line and somatic genes were examined [16] . Sequencing of the germline APC gene revealed a transition from ACG to ATG at codon 499 in exon 11.…”