{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:34:57Z","timestamp":1761093297922,"version":"build-2065373602"},"reference-count":46,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2006,5,12]],"date-time":"2006-05-12T00:00:00Z","timestamp":1147392000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2006,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Birt\u2013Hogg\u2013Dub\u00e9 (BHD) syndrome is a rare form of autosomal dominantly inherited genodermatosis characterized by benign hamartomatous skin lesions named fibrofolliculomas, and an increased risk for developing pulmonary cyst\/pneumothorax and various forms of renal cell carcinoma. Many of the patients harbour insertion\/deletion mutations in the hypermutable poly(C)<jats:sub>8<\/jats:sub> tract in exon 11 of the <jats:italic>BHD<\/jats:italic> gene. This mutational hot spot is also reported to be a target of mutation in microsatellite instability (MSI) sporadic colorectal cancer. To test the hypothesis that the <jats:italic>BHD<\/jats:italic> gene is also a mutational target in sporadic endometrial carcinoma with microsatellite instability, 139 cases of sporadic endometrial carcinoma were screened for MSI status, and mutations of the poly(C)<jats:sub>8<\/jats:sub> tract in exon 11 as well as other coding exons of the <jats:italic>BHD<\/jats:italic> gene. The poly(G)<jats:sub>8<\/jats:sub> tract of the <jats:italic>BAX<\/jats:italic> gene, the poly(C)<jats:sub>8<\/jats:sub> tract of <jats:italic>MSH6<\/jats:italic>, and methylation status of <jats:italic>hMLH1<\/jats:italic> were also assessed. Thirty\u2010nine of 139 cases (28%) showed MSI. Mutations in the poly(C)<jats:sub>8<\/jats:sub> tract of <jats:italic>BHD<\/jats:italic> were detected in five of the 39 MSI cases (12.8%). Of these, one showed additional mutation in exon 4, possibly satisfying the two\u2010hit hypothesis of tumour suppressor genes. <jats:italic>BAX<\/jats:italic> gene mutation was detected in ten of the 39 MSI cases (25.6%). Four tumours showed both <jats:italic>BAX<\/jats:italic> and <jats:italic>BHD<\/jats:italic> mutations, and a significant positive association was found between mutations of the two genes. No association was found between <jats:italic>BHD<\/jats:italic> status and <jats:italic>MSH6<\/jats:italic> mutation or <jats:italic>hMLH1<\/jats:italic> methylation. When multiple foci were microdissected and individually screened for mutation, <jats:italic>BHD<\/jats:italic> mutations were shown to have been acquired during tumour progression, after mutation of the <jats:italic>BAX<\/jats:italic> gene, in three of five cases. Taken together, these findings show that the <jats:italic>BHD<\/jats:italic> gene is a target gene in MSI endometrial carcinoma. However, its mutational frequency is lower than that of <jats:italic>BAX<\/jats:italic>, and <jats:italic>BHD<\/jats:italic> mutation tends to occur during neoplastic progression after the acquisition of mutations in another MSI target gene, <jats:italic>BAX<\/jats:italic>. Copyright \u00a9 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.1992","type":"journal-article","created":{"date-parts":[[2006,5,12]],"date-time":"2006-05-12T08:32:45Z","timestamp":1147422765000},"page":"328-335","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Birt\u2013Hogg\u2013Dub\u00e9 gene mutations in human endometrial carcinomas with microsatellite 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