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

BMC Research Notes, Nov 2010

Background Familial 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. Findings Nine 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. Conclusions Nine 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.

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

BMC Research Notes Identification of 5 novel germline APC mutations and characterization of clinical phenotypes in Japanese patients with classical and attenuated familial adenomatous polyposis Hong Tao 0 Kazuya Shinmura 0 Hidetaka Yamada 0 Masato Maekawa 2 Satoshi Osawa 1 Yasuhiro Takayanagi 1 Kazuya Okamoto 4 Tomohiro Terai 1 Hiroki Mori 0 Toshio Nakamura 3 Haruhiko Sugimura 0 0 First Department of Pathology, Hamamatsu University School of Medicine , 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka 431-3192 , Japan 1 First Department of Medicine, Hamamatsu University School of Medicine , 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka 431-3192 , Japan 2 Department of Laboratory Medicine, Hamamatsu University School of Medicine , 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka 431-3192 , Japan 3 Second Department of Surgery, Hamamatsu University School of Medicine , 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka 431-3192 , Japan 4 Department of Surgery, Fujinomiya City General Hospital , 3-1 Nishiki- cho, Fujinomiya, Shizuoka 418-0076 , Japan Background: Familial 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. Findings: Nine 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. Conclusions: Nine 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. Background Familial adenomatous polyposis (FAP) is an autosomal dominant familial cancer syndrome characterized by the early onset of large numbers of adenomatous polyps throughout the entire colon and a nearly 100% lifetime risk of colorectal cancer (CRC) if the colon is not removed [ 1 ]. A small proportion of familial colorectal polyposis cases were recently found to be associated with biallelic germline mutations of the MutYH gene [ 2 ]. However most FAP cases are caused by germline mutations of the tumor suppressor gene adenomatous polyposis coli (APC), which encodes a 2843-amino-acid protein that contains a variety of functional domains involved in cell cycle control, differentiation, transcription, migration, and apoptosis [ 3 ]. More than 1000 pathogenetic mutations have been detected throughout the APC gene, and the lifetime penetrance of the disease is close to 100% [ 3-5 ]. Some FAP cases have been classified as ‘attenuated FAP (AFAP)’ because of their attenuated phenotypes. Although there is still no consensus as to the precise definition of AFAP, some papers have summarized the characteristics of AFAP as follows: development of far fewer colorectal adenomatous polyps in AFAP patients than in classical FAP and the onset of adenomatous polyps and colorectal cancer 10~15 years later in AFAP patients than in classical FAP [ 6-8 ]. The germline APC mutations in AFAP patients have been found to occur at the 5’ end and 3’ end and in a specific region of exon 9 of the APC gene, in contrast to the germline APC mutations in classical FAP patients, which are found in other locations [ 3,8-10 ]. Thus, the analysis of the sites and spectrum of germline APC mutations in patients with multiple colorectal polyps is very important to the proper management of (A)FAP. A number of ex (...truncated)


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Hong Tao, Kazuya Shinmura, Hidetaka Yamada, Masato Maekawa, Satoshi Osawa, Yasuhiro Takayanagi, Kazuya Okamoto, Tomohiro Terai, Hiroki Mori, Toshio Nakamura, Haruhiko Sugimura. Identification of 5 novel germline APC mutations and characterization of clinical phenotypes in Japanese patients with classical and attenuated familial adenomatous polyposis, BMC Research Notes, 2010, pp. 305, Volume 3, Issue 1, DOI: 10.1186/1756-0500-3-305