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11.
12.
Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation 总被引:22,自引:1,他引:22
Marsh DJ; Coulon V; Lunetta KL; Rocca-Serra P; Dahia PL; Zheng Z; Liaw D; Caron S; Duboue B; Lin AY; Richardson AL; Bonnetblanc JM; Bressieux JM; Cabarrot-Moreau A; Chompret A; Demange L; Eeles RA; Yahanda AM; Fearon ER; Fricker JP; Gorlin RJ; Hodgson SV; Huson S; Lacombe D; Eng C 《Human molecular genetics》1998,7(3):507-515
The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403
amino acid dual specificity phosphatase (protein tyrosine phosphatase;
PTPase), was shown recently to play a broad role in human malignancy.
Somatic PTEN deletions and mutations were observed in sporadic breast,
brain, prostate and kidney cancer cell lines and in several primary tumours
such as endometrial carcinomas, malignant melanoma and thyroid tumours. In
addition, PTEN was identified as the susceptibility gene for two hamartoma
syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or
Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD
families and seven BZS families was screened for germline PTEN mutations.
PTEN mutations were identified in 30 of 37 (81%) CD families, including
missense and nonsense point mutations, deletions, insertions, a
deletion/insertion and splice site mutations. These mutations were
scattered over the entire length of PTEN , with the exception of the first,
fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified
in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD
mutations identified in this exon. Seven of 30 (23%) were within the core
motif, the majority (five of seven) of which were missense mutations,
possibly pointing to the functional significance of this region. Germline
PTEN mutations were identified in four of seven (57%) BZS families studied.
Interestingly, none of these mutations was observed in the PTPase core
motif. It is also worthy of note that a single nonsense point mutation,
R233X, was observed in the germline DNA from two unrelated CD families and
one BZS family. Genotype-phenotype studies were not performed on this small
group of BZS families. However, genotype-phenotype analysis inthe group of
CD families revealed two possible associations worthy of follow-up in
independent analyses. The first was an association noted in the group of CD
families with breast disease. A correlation was observed between the
presence/absence of a PTEN mutation and the type of breast involvement
(unaffected versus benign versus malignant). Specifically and more
directly, an association was also observed between the presence of a PTEN
mutation and malignant breast disease. Secondly, there appeared to be an
interdependent association between mutations upstream and within the PTPase
core motif, the core motif containing the majority of missense mutations,
and the involvement of all major organ systems (central nervous system,
thyroid, breast, skin and gastrointestinal tract). However, these
observations would need to be confirmed by studying a larger number of CD
families.
相似文献
13.
Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1 总被引:10,自引:0,他引:10
Lemmens I; Van de Ven WJ; Kas K; Zhang CX; Giraud S; Wautot V; Buisson N; De Witte K; Salandre J; Lenoir G; Pugeat M; Calender A; Parente F; Quincey D; Gaudray P; De Wit MJ; Lips CJ; Hoppener JW; Khodaei S; Grant AL; Weber G; Kytola S; Teh BT; Farnebo F; Thakker RV 《Human molecular genetics》1997,6(7):1177-1183
14.
15.
Yang GC; Croaker D; Zhang AL; Manglick P; Cartmill T; Cass D 《Human molecular genetics》1998,7(6):1047-1052
Lethal white foal syndrome (LWFS) is a congenital anomaly of horses
characterized by a white coat colour and aganglionosis of the bowel, which
is similar to Hirschsprung disease (HSCR). We decided to investigate
possible mutations of the endothelin-B receptor gene ( EDNRB ) in LWFS as
recent studies in mutant rodents and some patients have demonstrated EDNRB
defects. First, we identified a full-length cDNA for horse EDNRB . This
cDNA fragment contained a 1329 bp open reading frame which encoded 443
amino acid residues. The predicted amino acid sequence was 89, 91 and 85%
identical to human, bovine and mouse as well as rat EDNRB respectively, but
only 55% identical to the human, bovine and rat endothelin A receptor
(EDNRA). Secondly, sequence analysis, together with allele-specific PCR and
the amplification- created restriction site (ACRS) technique, revealed a
dinucleotide TC-- >AG mutation, which changed isoleucine to lysine in
the predicted first transmembrane domain of the EDNRB protein. This was
associated with LWFS when homozygous and with the overo phenotype when
heterozygous.
相似文献
16.
Debelenko LV; Brambilla E; Agarwal SK; Swalwell JI; Kester MB; Lubensky IA; Zhuang Z; Guru SC; Manickam P; Olufemi SE; Chandrasekharappa SC; Crabtree JS; Kim YS; Heppner C; Burns AL; Spiegel AM; Marx SJ; Liotta LA; Collins FS; Travis WD; Emmert-Buck MR 《Human molecular genetics》1997,6(13):2285-2290
Lung carcinoids occur sporadically and rarely in association with multiple
endocrine neoplasia type 1 (MEN1). There are no well defined genetic
abnormalities known to occur in these tumors. We studied 11 sporadic lung
carcinoids for loss of heterozygosity (LOH) at the locus of the MEN1 gene
on chromosome 11q13, and for mutations of the MEN1 gene using dideoxy
fingerprinting. Additionally, a lung carcinoid from a MEN1 patient was
studied. In four of 11 (36%) sporadic tumors, both copies of the MEN1 gene
were inactivated. All four tumors showed the presence of a MEN1 gene
mutation and loss of the other allele. Observed mutations included a 1 bp
insertion, a 1 bp deletion, a 13 bp deletion and a single nucleotide
substitution affecting a donor splice site. Each mutation predicts
truncation or potentially complete loss of menin. The remaining seven
tumors showed neither the presence of a MEN1 gene mutation nor 11q13 LOH.
The tumor from the MEN1 patient showed LOH at chromosome 11q13 and a
complex germline MEN1 gene mutation. The data implicate the MEN1 gene in
the pathogenesis of sporadic lung carcinoids, representing the first
defined genetic alteration in these tumors.
相似文献
17.
Nonhereditary p53 mutations in T-cell acute lymphoblastic leukemia are associated with the relapse phase 总被引:2,自引:0,他引:2
We have previously reported that greater than 60% of human leukemic T- cell lines possess mutations in the p53 tumor suppressor gene. To determine whether T-cell acute lymphoblastic leukemia (T-ALL) patient samples possess p53 mutations, we screened peripheral blood-and bone marrow-derived leukemia samples, taken at diagnosis and at relapse, for p53 mutations. Exons 4 through 9 and selected intron regions of the p53 gene were analyzed using polymerase chain reaction-single-strand conformation polymorphism and direct sequencing. p53 mutations were found in 0 of 15 T-ALL diagnosis samples, as compared with 10 of 36 (28%) T-ALL relapse samples. To determine whether p53 mutations play a role in the recurrence (relapse) of T-ALL, two special groups of T-ALL patients were studied: (1) a group of 8 relapse patients whose disease was refractory to chemotherapeutic treatment, and (2) a group of 6 "paired" T-ALL cell samples from patients for whom we possess both diagnosis and relapse samples. Three of 8 relapsed patients (37.5%) whose disease was refractory to the reinduction of remission by chemotherapy possessed missense mutations of the p53 gene. All 3 cases had mutations in exon 5. Among the paired samples, 3 of 6 patients harbored p53 mutations at disease recurrence, but possessed only wild- type p53 alleles at diagnosis. One case had mutation on exon 4, 1 case in exon 5, and 1 case in exon 8 with loss of heterozygosity. These data clearly indicate that recurrence of T-ALL is associated with missense mutations in p53. Our results indicate that (1) mutations of p53 do occur in T-ALL in vivo, and such mutations are associated with the relapse phase of the disease; and (2) p53 mutation is involved in the progression of T-ALL. This conclusion is supported by our observation that the introduction of T-ALL-derived mutant p53 expression constructs into T-ALL cell lines further increases their growth rate in culture, enhances cell cloning in methylcellulose, and increases tumor formation in nude mice. 相似文献
18.
碱离子水饮用后血小板聚集率的的变化(附30例报告) 总被引:1,自引:0,他引:1
目的:报告30例饮用豪斯牌碱离子水前、后血小板聚集率的变化。方法:饮用碱离子水前、后(2~3月,>3~6月)作比浊法血小板聚集试验,以1分钟、5分钟及5分钟内最大聚集率(Max%)为指标,同时检测部分血粘度指标及凝血因子,并用自动生化仪检测血糖、血脂、主要电解质及部分肝、肾功能。结果:饮碱离子水后,血小板聚集率明显下降,而以疾病组(Max>80%)下降尤为明显,P均<0.001。饮碱离子水后血小板聚集率的下降,部分可能与损伤的血管内皮得到修复有关。主要电解质及部分肝、肾功能无明显异常改变。结论:由于心、脑血管血栓性疾病患者血小板聚集率多明显升高,饮碱离子水后血小板聚集率明显下降,且长期饮用对主要电解质及部分肝、肾功能无明显异常改变,作者认为碱离子水使用方例、安全、有效、价廉,因而对心、脑血管血栓性疾病防治方面可能是一种积极的辅助方法,值得临床进一步探索。 相似文献
19.
Lee M Krug Christopher G Azzoli Mark G Kris Vincent A Miller Nushmia Z Khokhar William Tong Michelle S Ginsberg Ennapadam Venkatraman Leslie Tyson Barbara Pizzo Valerie Baez Kenneth K Ng F M Sirotnak 《Clinical cancer research》2003,9(6):2072-2078
PURPOSE: 10-propargyl-10-deazaaminopterin (PDX) has superior antitumor efficacy in mouse xenograft models, likely attributable to increased uptake by the RFC-1 folate transporter and greater intracellular polyglutamylation. In a previous Phase I trial, stomatitis was the dose-limiting (and only clinically significant) toxicity of PDX. The recommended Phase II dose was 150 mg/m(2) i.v. every 2 weeks. Responses observed in patients with non-small cell lung cancer (NSCLC) in the Phase I trial prompted this Phase II trial. EXPERIMENTAL DESIGN: Patients had stage IIIB or IV NSCLC and either no previous chemotherapy or progression after initial response or stable disease to one previous chemotherapy regimen. Initially, PDX was administered at a dose of 150 mg/m(2) every 2 weeks. However, to decrease the frequency of stomatitis, the last 10 patients were treated at a dose of 135 mg/m(2). We planned to correlate PDX effects with folate and homocysteine levels and the expression of genes associated with folate transport and polyglutamylation. RESULTS: Thirty-nine patients were enrolled, 38 of whom were evaluable for response. Four patients had confirmed, major objective responses (10% based on intent to treat, 95% confidence interval 3-25) lasting 4, 9, 12, and 15 months. Twelve patients (31%) had stable disease. The median survival was 13.5 months. The predicted 1- and 2-year survival rates were 56 and 36%, respectively. Two patients (5%) suffered grade 4 stomatitis, and 6 (15%) had grade 3. No clinically significant myelosuppression occurred. No correlation between homocysteine or serum folate levels and severity of stomatitis was observed. Area under the curve (calculated using a limited sampling model) correlated with mucositis grade. A trend was noted between folate transporter expression and treatment effect. CONCLUSIONS: The broad applicability of this new antifolate with limited toxicity and proven efficacy in NSCLC encourage further development of this compound. Several trials are now underway combining PDX with other chemotherapeutic agents and testing its efficacy in other cancers. 相似文献
20.
T L?pp?nen AL Saukkonen W Serlo P Tapanainen A Ruokonen M Knip 《Archives of disease in childhood》1997,77(1):32-37
OBJECTIVE: Children with hydrocephalus are characterised by slow linear growth in prepuberty, accelerated physical maturation during puberty, and reduced final height. We aimed to study the possible roles of growth hormone, insulin-like growth factor-I (IGF-I), and IGF binding protein-3 (IGFBP-3) in this growth pattern. STUDY DESIGN: One hundred and fourteen patients with shunted hydrocephalus (62 males) aged 5 to 20 years, of whom 17 had spina bifida (six males), and 73 healthy controls (38 males) were studied. Anthropometric measures, body mass index, and body fat mass were assessed and the stage of puberty was determined. Serum growth hormone and plasma IGF-I and IGFBP-3 concentrations were measured. RESULTS: The patients comprised 44 (26 males) who were prepubertal and 70 (36 males) pubertal or postpubertal, while 32 of the controls (19 males) were prepubertal and 41 (19 males) pubertal or postpubertal. The prepubertal children with hydrocephalus had lower IGF-I (p = 0.002) and IGFBP-3 concentrations (p < 0.001) than the controls, and the pubertal children had four times lower basal growth hormone concentrations (p < 0.001). There was a correlation between height SD score and IGF-I levels in the total patient population (r = 0.23; p = 0.01). Peripheral IGF-I concentrations peaked at pubertal stages 2-3 in the female patients and at stage 4 in the controls. The prepubertal patients on antiepileptic treatment, carbamazepine in most cases (73%), had higher IGF-I (p = 0.01) and IGFBP-3 concentrations (p = 0.03) than those who had never been treated with antiepileptic drugs, but still lower IGFBP-3 levels than the controls (p = 0.01). CONCLUSION: Based on these findings, it can be concluded that reduced growth hormone secretion may contribute to the pattern of slow linear growth and reduced final height observed in these patients. 相似文献