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1.
A. M. Ferraris Rosa Mangerini Gian Franco Gaetani Cristina Romei Aldo Pinchera Furio Pacini 《Human genetics》1997,99(2):202-205
Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome characterized by medullary thyroid
carcinoma (MTC) and other tumors. Since MTC can also occur in a sporadic form and as familial medullary thyroid carcinoma,
this neoplasm offers a unique opportunity to investigate the difference of origin, if any, between the sporadic and the hereditary
forms of a tumor. While sporadic malignancies have usually been found to result from a mutational event occurring at the single-cell
level and are therefore monoclonal, studies on hereditary neoplasms have been scarce and often produced conflicting results.
In order to determine the clonal origin of sporadic MTCs and of those occurring in MEN 2 syndromes we used a clonality assay
based on a polymorphic trinucleotide repeat of the X-linked human androgen-receptor gene. We found that 10 out of 11 MTCs
expressed a polyclonal pattern of X inactivation, including a significant percentage of the cases clinically defined as sporadic.
Received: 21 May 1996 / Revised: 14 August 1996 相似文献
2.
A E F Vieira M P Mello L L K Elias I F Lau L M Z Maciel A C Moreira M Castro 《Hormones et métabolisme》2002,34(4):202-206
Patients with Multiple Endocrine Neoplasia (MEN) type 2A are at risk for early medullary thyroid carcinoma (MTC). We performed different screening tests for MTC--a recently reported biochemical screening test using omeprazole-induced calcitonin (CT) stimulation and DNA analysis--in fifteen members of two non-consanguineous Brazilian families with MEN 2A. RET proto-oncogene analysis was carried out by direct DNA sequencing of PCR-amplified products for exons 10 and 11. Family 1 showed a germline mutation (C634Y) in three individuals; a sister and a brother with symptomatic MTC; the former also presented with pheochromocytoma and hyperparathyroidism, and her son was a nine-year-old boy of previously unknown status. Family 2 showed the C634R mutation only in the index case, who presented with cutaneous lichen amyloidosis in addition to MTC, pheochromocytoma and hyperparathyroidism. Neither her parents nor her four brothers showed this genetic abnormality, suggesting a de novo RET proto-oncogene mutation in this patient. The controls and patients presented normal basal gastrin levels and a significant increase after omeprazole. Basal CT levels were elevated in patients with MTC and undetectable in control and asymptomatic family members. No subject showed any increase in CT levels after omeprazole treatment. In conclusion, the two most frequent RET proto-oncogene mutations in MEN 2A are present in Brazilian families. In addition, the specificity of basal and omeprazole-stimulated calcitonin is rather limited, and the efficacy of the omeprazole test still needs to be systematically examined. Therefore, RET proto-oncogene analysis must be the first choice for a screening procedure to identify gene carriers in MEN 2A family members and to permit early prophylactic treatment of MTC. 相似文献
3.
S Yamamoto I Morimoto T Fujihira K Watanabe K Zeki K Yoshimoto F Zeze S Eto 《Endocrinologia japonica》1992,39(1):25-30
We describe familial cases of multiple endocrine neoplasia (MEN) 2B: A 48-year-old man is the proband. He had pheochromocytoma, medullary thyroid carcinomas (MTCs), parathyroid hyperplasia, mucosal neuromas, eversion of eyelids and Marfanoid appearance, and then underwent adrenalectomy and total thyroidectomy. Family screening revealed that his two daughters (10 and 8 years old) had mucosal neuromas and increased serum calcitonin (CT). Both of them had MTCs but no pheochromocytoma, and their MTCs were surgically removed. The father and his children have been in favorable condition since the operations. Southern blot analysis with 33 polymorphic DNA probes was done in MTCs obtained from two daughters. An RBP3 (10q11.2) locus linked to a predisposing gene on chromosome 10 was uninformative in either patient because of constitutional homozygosity. Loss of heterozygosity at the MYCL1 locus on chromosome 1p32 was observed in MTC from the younger sister, but no loss of heterozygosity was recognized in other loci examined. Deletion of the 1p32 locus may play a role in the development of MEN 2B. 相似文献
4.
Linkage of the multiple endocrine neoplasia type 2B gene (MEN2B) to chromosome 10 markers linked to MEN2A 总被引:10,自引:0,他引:10
R A Norum R G Lafreniere L W O'Neal T F Nikolai J P Delaney J C Sisson H Sobol G M Lenoir B A Ponder H F Willard 《Genomics》1990,8(2):313-317
The syndrome of multiple endocrine neoplasia type 2B (MEN 2B) resembles that of MEN 2A in that both include medullary carcinoma of the thyroid, pheochromocytoma, and autosomal dominant inheritance, but is distinct in that MEN 2B patients have neuromas of the mucous membranes. MEN2A has been linked to RBP3, D10S5, FNRB, D10S15, and D10Z1 near the centromere of chromosome 10. We examined linkage between MEN2B and RFLPs on chromosome 10 in all available members in two or three generations of 14 kindreds. The centromere marker D10Z1 was linked to MEN2B with a peak lod score of 5.42 at theta = 0.02. One possible recombinant was observed between D10Z1 and MEN2B. Multipoint analysis of RFLPs at FNRB, D10Z1, RBP3, and D10S15 gave a peak lod score of 7.12 at the midpoint between D10Z1 and RBP3 on the long arm (band q11). The most likely gene order FNRB-D10Z1-MEN2B was 27 times more likely than MEN2B-FNRB-D10Z1 and 31/2 times more likely than FNRB-MEN2B-D10Z1. Additional data will be required to establish the order of these loci with confidence. 相似文献
5.
The genetic defect in multiple endocrine neoplasia type 2A maps next to the centromere of chromosome 10 总被引:6,自引:6,他引:6 下载免费PDF全文
Jingshi Wu Nancy L. Carson Shirley Myers Andrew J. Pakstis Judith R. Kidd Carmela M. Castiglione Linda Anderson L. Suzanne Hoyle Myron Genel Maurice Verdy Charles E. Jackson Nancy E. Simpson Kenneth K. Kidd 《American journal of human genetics》1990,46(3):624-630
Multiple endocrine neoplasia type 2A (MEN2A) is a rare cancer syndrome that is inherited in an apparently autosomal dominant fashion. Previous linkage studies had assigned the MEN2A locus to chromosome 10 in the pericentromeric region. We recently have described several new easily scorable RFLPs for the chromosome 10-specific alpha satellite DNA (the D10Z1) locus that is known, on the basis of previous in situ hybridization experiments, to lie at the centromere. We report here tight linkage between MEN2A and D10Z1, as demonstrated by a maximum lod score of 12.02 at the recombination frequency of zero (1-lod-unit support interval 0-4 cM), indicating that the genetic defect in MEN2A lies in the immediate vicinity of the centromere. By means of a set of ordered polymorphic DNA markers from the pericentromeric region, multipoint as well as pairwise linkage analyses place the MEN2A locus at the middle of a small region (approximately 11 cM) bracketing the centromere with FNRB (at 10p11.2) and RBP3 (at 10q11.2) on either side, providing further support for the centromeric location of the MEN2A locus. Marked sex difference in recombination frequencies exists in this pericentromeric region: significantly (P less than .01) more female than male crossovers were observed across all of the adjacent intervals D10S24-FNRB, FNRB-D10Z1, and D10Z1-RBP3. However, a sex difference was not seen in the 7-cM interval from RBP3 to D10S5, suggesting that large variation in the sex difference in recombination can occur over small chromosomal regions.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
6.
Development of multiple endocrine neoplasia type 2A does not involve substantial deletions of chromosome 10 总被引:5,自引:0,他引:5
R M Landsvater C G Mathew B A Smith E M Marcus G J te Meerman C J Lips R A Geerdink Y Nakamura B A Ponder C H Buys 《Genomics》1989,4(3):246-250
In MEN2A both familial and sporadic cases are known. The familial cases show a dominant pattern of inheritance. In these respects, MEN2A resembles other tumors in whose etiology so-called tumor suppressor genes play a decisive role. The MEN2A locus has been assigned to chromosome 10 by linkage studies. Analysis of tumor DNA from 42 patients shows that markers on chromosome 10 were lost in only one tumor. Thus, these results contrast with previous studies which show that tumor development is generally associated with the loss of the whole or substantial parts of the chromosome on which the putative tumor suppressor gene is located. 相似文献
7.
K. M. Carlson J. Bracamontes C. E. Jackson R. Clark A. Lacroix S. A. Wells Jr P. J. Goodfellow 《American journal of human genetics》1994,55(6):1076-1082
Multiple endocrine neoplasia type 2B (MEN 2B) is characterized by medullary thyroid carcinoma, pheochromocytomas, mucosal neuromas, ganglioneuromas, and skeletal and ophthalmic abnormalities. It is observed as both inherited and sporadic disease, with an estimated 50% of cases arising de novo. A single point mutation in the catalytic core region of the receptor tyrosine kinase, RET, has been observed in germ-line DNA of MEN 2B patients. We have analyzed 25 cases of de novo disease in order to determine the parental origin of the mutated RET allele. In all cases the new mutation was of paternal origin. We observe a distortion of the sex ratio in both de novo MEN 2B patients and the affected offspring of MEN 2B transmitting males. These results suggests a differential susceptibility of RET to mutation in paternally and maternally derived DNA and a possible role for imprinting of RET during development. 相似文献
8.
Qi XP Ma JM Du ZF Ying RB Fei J Jin HY Han JS Wang JQ Chen XL Chen CY Liu WT Lu JJ Zhang JG Zhang XN 《PloS one》2011,6(5):e20353
Background
Whole exome sequencing provides a labor-saving and direct means of genetic diagnosis of hereditary disorders in which the pathogenic gene harbors a large cohort of exons. We set out to demonstrate a suitable example of genetic diagnosis of MEN 2A/FMTC (multiple endocrine neoplasia type 2/familial medullary thyroid carcinoma) using this approach.Methodology/Principal Findings
We sequenced the whole exome of six individuals from a large Chinese MEN2A/FMTC pedigree to identify the variants of the RET (REarranged during Transfection) protooncogene and followed this by validation. Then prophylactic or surgical thyroidectomy with modified or level VI lymph node dissection and adrenalectomy were performed for the carriers. The cases were closely followed up. Massively parallel sequencing revealed four missense mutations of RET. We unexpectedly discovered that the proband''s daughter with MEN 2A-related MTC presented a novel p.C634Y/V292M/R67H/R982C compound mutation, due to the involvement of p.C634Y in the proband with MEN 2A and p.V292M/R67H/R982C in the proband''s husband with FMTC. In the maternal origin, p.C634Y caused bilateral MTC in all 5 cases and bilateral pheochromocytoma in 2 of the 5; the earliest onset age was 28 years. In the paternal origin, one of the six p.V292M/R67H/R982C carriers presented bilateral MTC (70 years old), one only had bilateral C-cell hyperplasia (44 years), two had bilateral multi-nodules (46 and 48 years) and two showed no abnormality (22 and 19 years).Conclusions/Significance
The results confirmed the successful clinical utility of whole exome sequencing, and our data suggested that the p.C634Y/V292M/R67H/R982C mutation of RET exhibited a more aggressive clinical phenotype than p.C634Y or p.V292M/R67H/R982C, while p.V292M/R67H/R982C presented a relatively milder pathogenicity of MTC and likely predisposed to FMTC. 相似文献9.
I Schuffenecker S A Narod R A Ezekowitz H Sobol J Feunteun G M Lenoir 《Cytogenetics and cell genetics》1991,56(2):99-102
Human mannose-binding lectin (MBL) is a serum protein which appears to function as an opsonin in first line host defense. In situ hybridization studies assign the human MBL gene to chromosome 10q11.2----q21. A restriction fragment length polymorphism (RFLP) was found using TaqI with a 0.8-kb cDNA probe for MBL (probe 48-11), yielding heterozysity in 34% of individuals tested. Using this biallelic RFLP, linkage analysis of 30 families confirms the assignment of MBL to the region of multiple endocrine neoplasia, type 2a (MEN2A) with a maximum lod score of 7.54 at a recombination fraction of 0.00 (males) and 0.097 (females). The presence of two crossovers between MEN2A and MBL in these families indicates that a defect of MBL itself is not the cause of the hereditary thyroid cancer syndrome. The addition of MBL to the genetic map of the pericentromeric region of chromosome 10 should prove useful for improved localization of the MEN2A mutation. 相似文献
10.
Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. Le Groupe d'Etude des Tumeurs a Calcitonine. 下载免费PDF全文
I Schuffenecker N Ginet D Goldgar C Eng B Chambe A Boneu C Houdent D Pallo M Schlumberger C Thivolet G M Lenoir 《American journal of human genetics》1997,60(1):233-237
11.
Dominant mutations in the Ret receptor tyrosine kinase lead to the familial cancer syndrome multiple endocrine neoplasia type 2 (MEN2). Mammalian tissue culture studies suggest that RetMEN2 mutations significantly alter Ret-signaling properties, but the precise mechanisms by which RetMEN2 promotes tumorigenesis remain poorly understood. To determine the signal transduction pathways required for RetMEN2 activity, we analyzed analogous mutations in the Drosophila Ret ortholog dRet. Overexpressed dRetMEN2 isoforms targeted to the developing retina led to aberrant cell proliferation, inappropriate cell fate specification, and excessive Ras pathway activation. Genetic analysis indicated that dRetMEN2 acts through the Ras-ERK, Src, and Jun kinase pathways. A genetic screen for mutations that dominantly suppress or enhance dRetMEN2 phenotypes identified new genes that are required for the phenotypic outcomes of dRetMEN2 activity. Finally, we identified human orthologs for many of these genes and examined their status in human tumors. Two of these loci showed loss of heterozygosity (LOH) within both sporadic and MEN2-associated pheochromocytomas, suggesting that they may contribute to Ret-dependent oncogenesis. 相似文献
12.
《BMJ (Clinical research ed.)》1974,2(5917):461-462
13.
14.
15.
The familial observations of multiple endocrine neoplasia are rare such that there are only four known cases in France. In our family, two children and their mother are affected. Their mother, at the age of 16, was operated on a medullary thyroid cancer (MTC) and now presents with a phaeochromocytoma. Vanessa also presents with a MTC but without either phaeochromocytoma nor hyperparathyroidism. Her sister was then systematically screened and the only positive test was Pentagastrin. This allowed us to practice a thyroidectomy which will confirm the presence of a medullary thyroid cancer. In all three cases, the Marfan-like features, the abnormal facies and lingual neuromas are all features of the disease. These observations are of interest for the systemic familial screening of MTC by tumour markers (calcitonin, ACE) and by the Pentagastrin test, while awaiting for the use of specific probes on chromosome 10. 相似文献
16.
Background
This study aims to introduce the diagnosis and surgical treatment of the rare disease multiple endocrine neoplasia type 2A (MEN 2A).Methods
Thirteen cases of MEN 2A were diagnosed as medullary thyroid carcinoma (MTC) and pheochromocytoma by biochemical tests and imaging examination. They were treated by bilateral adrenal tumor excision or laparoscopic surgery.Results
Nine patients were treated by bilateral adrenal tumor excision and the remaining four were treated by laparoscopic surgery for pheochromocytoma. Ten patients were treated by total thyroidectomy and bilateral lymph nodes dissection and the remaining three were treated by unilateral thyroidectomy for MTC. Up to now, three patients have died of MTC distant metastasis.Conclusions
We confirmed that MEN 2A can be diagnosed by biochemical tests and imaging examination when genetic testing is not available. Surgical excision is the predominant way to treat MEN 2A; pheochromocytoma should be excised at first when pheochromocytoma and MTC occur simultaneously. 相似文献17.
A. Tunnacliffe M. S. Jackson E. Gardner D. R. Love J. K. Moore S. E. Mole L. M. Mulligan A. Graham G. Finocchiaro S. Ørstavik B. A. J. Ponder 《Human genetics》1994,93(3):313-318
Five intervals in the pericentromeric region of human chromosome 10 have been defined using a panel of somatic cell hybrids carrying portions of the chromosome. The map positions of twelve markers, consisting of four genes and eight anonymous DNA segments, have been localized by assignment to one of the five intervals. Several other markers could be placed in specific intervals by genetic linkage to assigned loci. When previously published data are incorporated, the summary map of the pericentromeric region encompasses thirty-two loci in bands 10p11.2-q11.2. 相似文献
18.
A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations 总被引:2,自引:0,他引:2
Iwashita T Murakami H Kurokawa K Kawai K Miyauchi A Futami H Qiao S Ichihara M Takahashi M 《Biochemical and biophysical research communications》2000,268(3):804-808
Multiple endocrine neoplasia (MEN) type 2B mutations have been reported at methionine 918 or alanine 883 in the tyrosine kinase domain of the RET proto-oncogene. Recently, a new combination of two germline missense mutations at valine 804 and tyrosine 806 was identified in a patient with MEN 2B-like clinical phenotypes including medullary thyroid carcinoma, mucosal neuroma, and marfanoid habitus. In this case, valine 804 and tyrosine 806 were replaced with methionine and cysteine, respectively. In the present study, biological activities of RET with these new mutations were compared with those with known MEN 2A or MEN 2B mutations. The transforming activity of RET with the V804M/Y806C mutation was about 8- to 13-fold higher than that of RET with a single V804M or Y806C mutation. Like RET with the M918T or A883F MEN 2B mutation, the transforming activity of RET with the V804M/Y806C mutation was not affected by substitution of phenylalanine for tyrosine 905 that abolished the activity of RET with the MEN 2A mutation. On the other hand, substitution of phenylalanine for tyrosines 864 and 952 drastically diminished the activity of RET with the V804M/Y806C, M918T or A883F mutation, suggesting that these three mutant proteins have similar biological properties. 相似文献
19.
Localization of the genetic defect in multiple endocrine neoplasia type 1 within a small region of chromosome 11 总被引:18,自引:7,他引:11 下载免费PDF全文
Yusuke Nakamura Catharina Larsson Cecile Julier Camilla Bystrm Britt Skogseid Samuel Wells Kjell
berg Mary Carlson Thomas Taggart Peter O'Connell Mark Leppert Jean-Marc Lalouel Magnus Nordenskjld Ray White 《American journal of human genetics》1989,44(5):751-755
Multiple endocrine neoplasia type I (MEN-1), a Mendelian disorder with an autosomal dominant mode of inheritance, causes hyperplasia in the parathyroid glands and hyperplasia or neoplasm in the anterior pituitary gland and/or the pancreatic islets. The genetic defect responsible for MEN-1 in three families was recently mapped to the long arm of chromosome II by linkage between the MEN-1 locus and the gene for skeletal muscle glycogen phosphorylase (PYGM) at 11q13. We have constructed a genetic linkage map of seven markers in the vicinity of the MEN-1 locus that has allowed us to map more precisely the gene associated with MEN-1; the target region has been narrowed to about 12 cM. The closely linked markers will be useful also for identification of likely carriers in families in which an allele responsible for MEN-1 segregates. 相似文献
20.
Exclusion of linkage of loci on chromosome 19 with multiple endocrine neoplasia, type 2 总被引:2,自引:0,他引:2
C Carter D F Easton C G Mathew G Welander H Telenius M Telenius-Berg B A Ponder 《Cytogenetics and cell genetics》1987,45(1):33-37
Linkage between seven loci on chromosome 19 and multiple endocrine neoplasia type 2a (MEN2A) was examined in a single large Swedish pedigree. A total of 50 cM was excluded from the male genetic map by pairwise analysis and an estimated 63 cM by multipoint analysis. Using existing data on the likelihood of different marker-marker distances and taking into account current exclusions on other chromosomes, the probability that the gene for MEN2A segregating in this pedigree could still be located on chromosome 19 is approximately 0.28%. 相似文献