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Therapeutic strategies that promote read-through of a mutant gene have proved effective for certain non-neoplastic diseases. However, the efficacy of this approach is unproven regarding neoplastic diseases with germline nonsense mutations, including familial adenomatous polyposis. Here we examined the cancer-preventive efficacy of the macrolide antibiotic azithromycin, with a reported read-through effect, on intestinal tumorigenesis in C3B6F1 Apc Min/+ mice harboring a nonsense Apc mutation resulting in a truncated Apc protein. Mice were given drinking water lacking azithromycin or containing 0.0125-0.2 mg/mL azithromycin from 3 weeks of age. The small intestine and cecum were analyzed for pathological changes and alterations of intestinal flora. Azithromycin suppressed the number of tumors and the proportion of adenocarcinomas, with the most effective drinking-water concentration being 0.0125 mg/mL. Furthermore, azithromycin recovered the cellular level of full-length Apc, resulting in downregulation of β-catenin and cyclin D1. Conversely, the effect of azithromycin on the diversity of the intestinal microbiota depended on the drinking-water concentration. These results suggest that the balance between azithromycin-mediate read-through of mutant Apc mRNA and antibacterial effects influences intestinal tumorigenesis. Thus, azithromycin is a potential anticancer agent for familial adenomatous polyposis patients harboring nonsense mutations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background and Aim: Gastric neoplasms (GN), including gastric adenoma and carcinoma, are well known as extracolonic manifestations of familial adenomatous polyposis (FAP). We aimed to investigate the clinicopathological features of GN in FAP patients and to clarify their relationship with the endoscopic status of the background mucosa., Methods: We analyzed the records of 39 patients who were diagnosed with FAP and underwent esophagogastroduodenoscopy between April 2005 and July 2016. Patients were divided into two groups according to atrophic gastritis (AG) status. Endoscopic findings of GN and background mucosa, and histopathological findings, including phenotypic expression of GN and mutation locus of adenomatous polyposis coli (APC) gene, were evaluated., Results: Gastric neoplasms were more predominant in the AG-positive group than in the AG-negative group (6/9, 66.7% vs 7/30, 23.3%; P = 0.039). Of 36 GN detected in 13 patients, six GN in five patients were followed and 30 GN in eight patients were endoscopically resected and analyzed. GN in the AG-negative group frequently showed whitish color, were located in the proximal stomach, and presented the gastric immunophenotype compared to GN in the AG-positive group. All GN were intramucosal lesions and were curatively resected regardless of AG status. APC germline mutations were identified in 32 patients. In patients with GN, a significantly higher number of mutation loci were among exons 10-15 (codons 564-1465)., Conclusion: Clinicopathological characteristics and phenotypic expressions of GN in FAP patients depend on background mucosa status with or without AG. These findings are useful for detecting GN in FAP patients., (© 2019 Japan Gastroenterological Endoscopy Society.)

Germline mutations in the tumor suppressor gene APC are associated with familial adenomatous polyposis (FAP). Here we applied whole-genome sequencing (WGS) to the DNA of a sporadic FAP patient in which we did not find any pathological APC mutations by direct sequencing. WGS identified a promoter deletion of approximately 10 kb encompassing promoter 1B and exon1B of APC. Additional allele-specific expression analysis by deep cDNA sequencing revealed that the deletion reduced the expression of the mutated APC allele to as low as 11.2% in the total APC transcripts, suggesting that the residual mutant transcripts were driven by other promoter(s). Furthermore, cap analysis of gene expression (CAGE) demonstrated that the deleted promoter 1B region is responsible for the great majority of APC transcription in many tissues except the brain. The deletion decreased the transcripts of APC-1B to 39-45% in the patient compared to the healthy controls, but it did not decrease those of APC-1A. Different deletions including promoter 1B have been reported in FAP patients. Taken together, our results strengthen the evidence that analysis of structural variations in promoter 1B should be considered for the FAP patients whose pathological mutations are not identified by conventional direct sequencing.

Germline MUTYH mutations were investigated in 14 Japanese colorectal polyposis patients without germ line adenomatous polyposis coli (APC) gene mutations. Three patients had a heterozygous IVS10-2A>G MUTYH mutation. The onset of MUTYH-associated polyposis (MAP) occurs later than that of familial adenomatous polyposis with germline APC mutation. Thus, we compared the carrier frequency of MUTYH IVS10-2A>G heterozygote in the APC mutation negative cases with that in 115 controls over 70 years of age who showed no apparent clinical manifestations of cancer and claimed that they had no history of cancer at the time of enrollment. The frequency of IVS10-2A>G heterozygote in APC germline mutation negative polyposis patients was significantly higher than control subject (p = 0.012, Chi square test). Although the sample size is still too small to conclude, the IVS10-2A>G MUTYH heterozygote might add to the risk of developing germline APC mutation negative polyposis.

The proband was a 32-year-old man with sparse type of familial adenomatous polyposis with fundic gland and duodenal polyps and congenital hypertrophy of the retinal pigment epithelium without osteoma, dental abnormalities and desmoid tumors. Direct DNA sequencing did not detect germline mutations in any APC exon. However, using the multiplex ligation-dependent probe amplification method, we detected germline deletions of all APC exons. Using dual-color fluorescence in situ hybridization, we identified germline deletion of locus 5q22.1-22.2 that includes APC. Analysis of colorectal tumors identified somatic APC mutations in the cluster region in all polyps, but no loss of heterozygosity was detected in any polyp., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Familial adenomatous polyposis is an autosomal dominant hereditary disease characterized by the appearance of hundreds to thousands of colorectal adenomatous polyps; if left untreated, there is nearly a 100% lifetime risk of colorectal cancer. In the present case, adenomatous polyps were observed at 6 years of age. Unlike our previous assumption, adenomatous polyps were detected by colonoscopy at <10 years of age. Considering the clinical importance of early diagnosis, we report this case involving germline adenomatous polyposis coli mutation (c.1958G > C, GenBank: M74088.1) that caused an increase in the isoform without exon 15. Although this isoform has been reported previously, it remains controversial whether the variant is pathogenic or not because it was observed both in patients with familial adenomatous polyposis and in normal controls. Nonetheless, due to quantitative distortion of splice variants in adenomatous polyposis coli transcripts and the early development of adenomatous polyps, we believe that this variant may be pathogenic., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

We describe a sporadic case with familial adenomatous polyposis, multiple endocrine neoplasia type 1 (MEN1)-related tumors (an endocrine cell tumor of the pancreas and bilateral parathyroid tumors), and a papillary thyroid carcinoma. To clarify how mutations of the adenomatous polyposis coli ( APC ) gene and the MEN1 gene, responsible for familial adenomatous polyposis and MEN1, respectively, might have contributed to tumorigenesis in this case, we studied germline mutations in both genes and loss of heterozygosity at their genetic loci in multiple lesions. In addition, we performed immunohistochemistry for beta-catenin, associated with the function of the APC gene. A germline mutation was found in the APC gene but not in the MEN1 gene. Normal allelic loss at the APC gene locus was observed in bilateral parathyroid tumors. Immunohistochemical staining of beta-catenin demonstrated accumulation in the cytoplasm in addition to membrane staining in all analyzed tumors and a strong nuclear reaction in the endocrine cell tumor of the pancreas. The presence of normal allelic deletions of the APC gene in bilateral parathyroid tumors and nuclear staining of beta-catenin in the pancreatic tumor in addition to the germline mutations suggests that functional loss of the APC gene played an important role not only in familial adenomatous polyposis but also in the MEN1-related tumors in this case.