Subject(s)
Genes, Tumor Suppressor , Germ-Line Mutation/genetics , Hyperparathyroidism/genetics , Mutation/genetics , Proteins/genetics , Adult , Aged , Amino Acid Sequence , Child , DNA Mutational Analysis , Female , France , Humans , Male , Middle Aged , Mosaicism/genetics , Pedigree , Proteins/chemistry , Proto-Oncogene Proteins/genetics , Receptors, Calcium-Sensing/genetics , Tumor Suppressor ProteinsABSTRACT
BACKGROUND: Hyperparathyroidism is a common endocrinopathy characterised by the formation of parathyroid tumours. In this study, we determine the role of the recently identified gene, HRPT2, in parathyroid tumorigenesis. METHODS: Mutation analysis of HRPT2 was undertaken in 60 parathyroid tumours: five HPT-JT, three FIHP, three MEN 1, one MEN 2A, 25 sporadic adenomas, 17 hyperplastic glands, two lithium associated tumours, and four sporadic carcinomas. Loss of heterozygosity at 1q24-32 was performed on a subset of these tumours. RESULTS: HRPT2 somatic mutations were detected in four of four sporadic parathyroid carcinoma samples, and germline mutations were found in five of five HPT-JT parathyroid tumours (two families) and two parathyroid tumours from one FIHP family. One HPT-JT tumour with germline mutation also harboured a somatic mutation. In total, seven novel and one previously reported mutation were identified. "Two-hits" (double mutations or one mutation and loss of heterozygosity at 1q24-32) affecting HRPT2 were found in two sporadic carcinomas, two HPT-JT-related and two FIHP related tumours. CONCLUSIONS: The results in this study support the role of HRPT2 as a tumour suppressor gene in sporadic parathyroid carcinoma, and provide further evidence for HRPT2 as the causative gene in HPT-JT, and a subset of FIHP. In light of the strong association between mutations of HRPT2 and sporadic parathyroid carcinoma demonstrated in this study, it is hypothesised that HRPT2 mutation is an early event that may lead to parathyroid malignancy and suggest intragenic mutation of HRPT2 as a marker of malignant potential in both familial and sporadic parathyroid tumours.
Subject(s)
Parathyroid Neoplasms/genetics , Proteins/genetics , Adult , Aged , Chi-Square Distribution , Chromosomes, Human, Pair 1/genetics , DNA Mutational Analysis , DNA, Complementary/chemistry , DNA, Complementary/genetics , DNA, Neoplasm/chemistry , DNA, Neoplasm/genetics , Family Health , Female , Humans , Hyperparathyroidism/genetics , Loss of Heterozygosity , Male , Microsatellite Repeats , Middle Aged , Mutation , Parathyroid Neoplasms/pathology , Polymorphism, Genetic , Syndrome , Tumor Suppressor ProteinsSubject(s)
Colorectal Neoplasms/genetics , Estrone/genetics , Base Sequence , DNA Methylation , DNA Mutational Analysis , DNA, Neoplasm/chemistry , DNA, Neoplasm/genetics , DNA, Neoplasm/metabolism , Humans , Loss of Heterozygosity , Microsatellite Repeats/genetics , Mutation , Mutation, Missense , Promoter Regions, Genetic/geneticsABSTRACT
Amongst hyperparathyroidism-related syndromes, hyperparathyroidism-jaw tumour syndrome is one of the least common and relatively unknown but its clinical and genetic aspects are not less interesting or important. With the recent identification of its genes, we can now better characterize the disease, both clinically and genetically, which will certainly impact the field of endocrinology and oncology. In this article, we review the clinico-pathological features and genetic basis of this syndrome with the hope that it will create awareness and interest in this disease amongst clinicians and basic scientists.
Subject(s)
Hyperparathyroidism/genetics , Jaw Neoplasms/genetics , Genes, Tumor Suppressor , Humans , Hyperparathyroidism/pathology , Jaw Neoplasms/pathology , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Maxillary Neoplasms/genetics , Maxillary Neoplasms/pathology , Multiple Endocrine Neoplasia Type 1 , Parathyroid Neoplasms/pathology , SyndromeABSTRACT
Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant cancer syndrome characterised by benign skin tumours, renal tumours, and spontaneous pneumothorax. The gene has been mapped to chromosome 17p11.2 and recently identified, expressing a novel protein called folliculin. We report the clinical and genetic studies of four sporadic BHD cases and four families with a total of 23 affected subjects. Haplotype analysis of these families using BHD linked markers showed they did not share the same affected alleles, excluding common ancestry. Mutation analysis of the BHD gene identified two germline mutations on exon 11 (c.1733insC and c.1733delC) in three of four families as well as two of four sporadic cases. A novel somatic mutation, c.1732delTCinsAC, was detected in a BHD related chromophobe renal carcinoma. Our results confirmed the (C)8 tract in exon 11 as a mutational hot spot in BHD and should always be considered for future genetic testing. Our observation also indicated that the second hit (of Knudson's two hit theory) in some BHD related tumours is in the form of somatic mutation rather than LOH. In a large French family in which eight affected subjects carry the c.1733delC mutation, a phenocopy who has multiple episodes of spontaneous pneumothorax was identified. A total of five mutation carriers (aged between 37 to 66) did not have any evidence of BHD features, suggesting either reduced penetrance or late age of onset of the disease. In addition, six out of eight affected subjects who have positive germline mutation have confirmed neoplastic colonic polyps, indicating that colorectal neoplasia is an associated feature of BHD in some families. Our studies have observed several interesting genetic features in BHD: (1) the poly (C) tract in exon 11 as a mutational hot spot; (2) the existence of phenocopy; (3) reduced penetrance or late age of onset of disease; (4) association with colorectal neoplasia in some families; and (5) somatic mutation instead of LOH as the second hit in BHD tumours.
