Misato Takao1,2, Tatsuro Yamaguchi3,4,5, Hidetaka Eguchi6, Takeshi Yamada7, Yasushi Okazaki6, Naohiro Tomita8, Tadashi Nomizu9, Tomoyuki Momma10, Tetsuji Takayama11, Kohji Tanakaya12, Kiwamu Akagi13, Hideyuki Ishida2. 1. Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-8677, Japan. 2. Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan. 3. Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-8677, Japan. tatsuro@yamaguchi.email.ne.jp. 4. Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan. tatsuro@yamaguchi.email.ne.jp. 5. Department of Clinical Genetics, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan. tatsuro@yamaguchi.email.ne.jp. 6. Diagnostics and Therapeutics of Intractable Diseases and Intractable Disease Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan. 7. Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan. 8. Division of Lower GI Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan. 9. Department of Surgery, Hoshi General Hospital, Koriyama, Japan. 10. Department of Gastrointestinal Tract Surgery, Fukushima Medical University, Fukushima, Japan. 11. Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. 12. Department of Surgery, Iwakuni Clinical Center, Iwakuni, Japan. 13. Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan.
Abstract
BACKGROUND: Familial adenomatous polyposis (FAP), an autosomal dominant disorder characterized by multiple colonic polyps, is caused by a germline pathogenic variant of the APC gene. However, this variant is not detected in up to 30% of patients with the adenomatous polyposis phenotype. METHODS: We performed next-generation sequencing (NGS) to identify the causative genes in FAP patients with 10 or more polyps. For patients in whom the APC germline variant was not able to be identified, we screened for APC mosaicism using high-coverage NGS of APC with DNA from leucocytes and/or frozen tissue. RESULTS: The pathogenic APC germline variant was found in 93.3%, 71.6%, and 17.1% of patients with profuse-type polyposis, sparse-type polyposis, and oligo-polyposis, respectively. The APC germline variant detection rate in patients with FAP-related diseases was 69.7% for fundic gland polyposis, 79.7% for duodenal adenoma, 94.7% for desmoid tumor, and 71.4% for thyroid cancer, with increasing numbers of extracolonic lesions associated with an increasing APC germline variant detection rate. A mosaic test detected nine patients with APC mosaicism. A comparison of APC-associated polyposis with APC mosaicism showed that patients with APC mosaicism had a low frequency of duodenal adenoma and a family history of colonic polyposis. CONCLUSIONS: We determined the detection rate of the APC germline variant by phenotype and identified APC mosaicism. Genetic testing of FAP patients is important because it can help with surgical decision-making, monitoring, and genetic counseling. Furthermore, genetic testing by NGS proved to be an effective method of detecting APC germline variants.
BACKGROUND: Familial adenomatous polyposis (FAP), an autosomal dominant disorder characterized by multiple colonic polyps, is caused by a germline pathogenic variant of the APC gene. However, this variant is not detected in up to 30% of patients with the adenomatous polyposis phenotype. METHODS: We performed next-generation sequencing (NGS) to identify the causative genes in FAP patients with 10 or more polyps. For patients in whom the APC germline variant was not able to be identified, we screened for APC mosaicism using high-coverage NGS of APC with DNA from leucocytes and/or frozen tissue. RESULTS: The pathogenic APC germline variant was found in 93.3%, 71.6%, and 17.1% of patients with profuse-type polyposis, sparse-type polyposis, and oligo-polyposis, respectively. The APC germline variant detection rate in patients with FAP-related diseases was 69.7% for fundic gland polyposis, 79.7% for duodenal adenoma, 94.7% for desmoid tumor, and 71.4% for thyroid cancer, with increasing numbers of extracolonic lesions associated with an increasing APC germline variant detection rate. A mosaic test detected nine patients with APC mosaicism. A comparison of APC-associated polyposis with APC mosaicism showed that patients with APC mosaicism had a low frequency of duodenal adenoma and a family history of colonic polyposis. CONCLUSIONS: We determined the detection rate of the APC germline variant by phenotype and identified APC mosaicism. Genetic testing of FAP patients is important because it can help with surgical decision-making, monitoring, and genetic counseling. Furthermore, genetic testing by NGS proved to be an effective method of detecting APC germline variants.