Birt-Hogg-Dubé gene mutations in human endometrial carcinomas with microsatellite instability

Birt-Hogg-Dubé (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)8 tract in exon 11 of the BHD 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 BHD 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)8 tract in exon 11 as well as other coding exons of the BHD gene. The poly(G)8 tract of the BAX gene, the poly(C)8 tract of MSH6, and methylation status of hMLH1 were also assessed. Thirty-nine of 139 cases (28%) showed MSI. Mutations in the poly(C)8 tract of BHD were detected in five of the 39 MSI cases (12.8%). Of these, one showed additional mutation in exon 4, possibly satisfying the two-hit hypothesis of tumour suppressor genes. BAX gene mutation was detected in ten of the 39 MSI cases (25.6%). Four tumours showed both BAX and BHD mutations, and a significant positive association was found between mutations of the two genes. No association was found between BHD status and MSH6 mutation or hMLH1 methylation. When multiple foci were microdissected and individually screened for mutation, BHD mutations were shown to have been acquired during tumour progression, after mutation of the BAX gene, in three of five cases. Taken together, these findings show that the BHD gene is a target gene in MSI endometrial carcinoma. However, its mutational frequency is lower than that of BAX, and BHD mutation tends to occur during neoplastic progression after the acquisition of mutations in another MSI target gene, BAX.