共查询到20条相似文献，搜索用时 31 毫秒
1.
Wang Z Shen D Parsons DW Bardelli A Sager J Szabo S Ptak J Silliman N Peters BA van der Heijden MS Parmigiani G Yan H Wang TL Riggins G Powell SM Willson JK Markowitz S Kinzler KW Vogelstein B Velculescu VE 《Science (New York, N.Y.)》2004,304(5674):1164-1166
Tyrosine phosphorylation, regulated by protein tyrosine phosphatases (PTPs) and kinases (PTKs), is important in signaling pathways underlying tumorigenesis. A mutational analysis of the tyrosine phosphatase gene superfamily in human cancers identified 83 somatic mutations in six PTPs (PTPRF, PTPRG, PTPRT, PTPN3, PTPN13, PTPN14), affecting 26% of colorectal cancers and a smaller fraction of lung, breast, and gastric cancers. Fifteen mutations were nonsense, frameshift, or splice-site alterations predicted to result in truncated proteins lacking phosphatase activity. Five missense mutations in the most commonly altered PTP (PTPRT) were biochemically examined and found to reduce phosphatase activity. Expression of wild-type but not a mutant PTPRT in human cancer cells inhibited cell growth. These observations suggest that the mutated tyrosine phosphatases are tumor suppressor genes, regulating cellular pathways that may be amenable to therapeutic intervention. 相似文献
2.
Sjöblom T Jones S Wood LD Parsons DW Lin J Barber TD Mandelker D Leary RJ Ptak J Silliman N Szabo S Buckhaults P Farrell C Meeh P Markowitz SD Willis J Dawson D Willson JK Gazdar AF Hartigan J Wu L Liu C Parmigiani G Park BH Bachman KE Papadopoulos N Vogelstein B Kinzler KW Velculescu VE 《Science (New York, N.Y.)》2006,314(5797):268-274
3.
Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. 总被引：72，自引：0，他引：72
K W Kinzler M C Nilbert B Vogelstein T M Bryan D B Levy K J Smith A C Preisinger S R Hamilton P Hedge A Markham 《Science (New York, N.Y.)》1991,251(4999):1366-1370
Recent studies have suggested the existence of a tumor suppressor gene located at chromosome region 5q21. DNA probes from this region were used to study a panel of sporadic colorectal carcinomas. One of these probes, cosmid 5.71, detected a somatically rearranged restriction fragment in the DNA from a single tumor. Further analysis of the 5.71 cosmid revealed two regions that were highly conserved in rodent DNA. These sequences were used to identify a gene, MCC (mutated in colorectal cancer), which encodes an 829-amino acid protein with a short region of similarity to the G protein-coupled m3 muscarinic acetylcholine receptor. The rearrangement in the tumor disrupted the coding region of the MCC gene. Moreover, two colorectal tumors were found with somatically acquired point mutations in MCC that resulted in amino acid substitutions. MCC is thus a candidate for the putative colorectal tumor suppressor gene located at 5q21. Further studies will be required to determine whether the gene is mutated in other sporadic tumors or in the germ line of patients with an inherited predisposition to colonic tumorigenesis. 相似文献
4.
Women with mutations in the breast cancer susceptibility gene BRCA1 are predisposed to breast and ovarian cancers. Why the BRCA1 protein suppresses tumor development specifically in ovarian hormone-sensitive tissues remains unclear. We demonstrate that mammary glands of nulliparous Brca1/p53-deficient mice accumulate lateral branches and undergo extensive alveologenesis, a phenotype that occurs only during pregnancy in wild-type mice. Progesterone receptors, but not estrogen receptors, are overexpressed in the mutant mammary epithelial cells because of a defect in their degradation by the proteasome pathway. Treatment of Brca1/p53-deficient mice with the progesterone antagonist mifepristone (RU 486) prevented mammary tumorigenesis. These findings reveal a tissue-specific function for the BRCA1 protein and raise the possibility that antiprogesterone treatment may be useful for breast cancer prevention in individuals with BRCA1 mutations. 相似文献
5.
Chromosome aberrations and cancer 总被引：32，自引：0，他引：32
6.
Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas 总被引：175，自引：0，他引：175
S J Baker E R Fearon J M Nigro S R Hamilton A C Preisinger J M Jessup P vanTuinen D H Ledbetter D F Barker Y Nakamura R White B Vogelstein 《Science (New York, N.Y.)》1989,244(4901):217-221
Previous studies have demonstrated that allelic deletions of the short arm of chromosome 17 occur in over 75% of colorectal carcinomas. Twenty chromosome 17p markers were used to localize the common region of deletion in these tumors to a region contained within bands 17p12 to 17p13.3. This region contains the gene for the transformation-associated protein p53. Southern and Northern blot hybridization experiments provided no evidence for gross alterations of the p53 gene or surrounding sequences. As a more rigorous test of the possibility that p53 was a target of the deletions, the p53 coding regions from two tumors were analyzed; these two tumors, like most colorectal carcinomas, had allelic deletions of chromosome 17p and expressed considerable amounts of p53 messenger RNA from the remaining allele. The remaining p53 allele was mutated in both tumors, with an alanine substituted for valine at codon 143 of one tumor and a histidine substituted for arginine at codon 175 of the second tumor. Both mutations occurred in a highly conserved region of the p53 gene that was previously found to be mutated in murine p53 oncogenes. The data suggest that p53 gene mutations may be involved in colorectal neoplasia, perhaps through inactivation of a tumor suppressor function of the wild-type p53 gene. 相似文献
7.
Jones S Zhang X Parsons DW Lin JC Leary RJ Angenendt P Mankoo P Carter H Kamiyama H Jimeno A Hong SM Fu B Lin MT Calhoun ES Kamiyama M Walter K Nikolskaya T Nikolsky Y Hartigan J Smith DR Hidalgo M Leach SD Klein AP Jaffee EM Goggins M Maitra A Iacobuzio-Donahue C Eshleman JR Kern SE Hruban RH Karchin R Papadopoulos N Parmigiani G Vogelstein B Velculescu VE Kinzler KW 《Science (New York, N.Y.)》2008,321(5897):1801-1806
8.
p53 mutations in human cancers 总被引：404，自引：0，他引：404
Mutations in the evolutionarily conserved codons of the p53 tumor suppressor gene are common in diverse types of human cancer. The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues, and hemopoietic tissues. Analysis of these mutations can provide clues to the etiology of these diverse tumors and to the function of specific regions of p53. Transitions predominate in colon, brain, and lymphoid malignancies, whereas G:C to T:A transversions are the most frequent substitutions observed in cancers of the lung and liver. Mutations at A:T base pairs are seen more frequently in esophageal carcinomas than in other solid tumors. Most transitions in colorectal carcinomas, brain tumors, leukemias, and lymphomas are at CpG dinucleotide mutational hot spots. G to T transversions in lung, breast, and esophageal carcinomas are dispersed among numerous codons. In liver tumors in persons from geographic areas in which both aflatoxin B1 and hepatitis B virus are cancer risk factors, most mutations are at one nucleotide pair of codon 249. These differences may reflect the etiological contributions of both exogenous and endogenous factors to human carcinogenesis. 相似文献
9.
Agrawal N Frederick MJ Pickering CR Bettegowda C Chang K Li RJ Fakhry C Xie TX Zhang J Wang J Zhang N El-Naggar AK Jasser SA Weinstein JN Treviño L Drummond JA Muzny DM Wu Y Wood LD Hruban RH Westra WH Koch WM Califano JA Gibbs RA Sidransky D Vogelstein B Velculescu VE Papadopoulos N Wheeler DA Kinzler KW Myers JN 《Science (New York, N.Y.)》2011,333(6046):1154-1157
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA, and HRAS, we identified mutations in FBXW7 and NOTCH1. Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type. 相似文献
10.
Parsons DW Li M Zhang X Jones S Leary RJ Lin JC Boca SM Carter H Samayoa J Bettegowda C Gallia GL Jallo GI Binder ZA Nikolsky Y Hartigan J Smith DR Gerhard DS Fults DW VandenBerg S Berger MS Marie SK Shinjo SM Clara C Phillips PC Minturn JE Biegel JA Judkins AR Resnick AC Storm PB Curran T He Y Rasheed BA Friedman HS Keir ST McLendon R Northcott PA Taylor MD Burger PC Riggins GJ Karchin R Parmigiani G Bigner DD Yan H Papadopoulos N Vogelstein B Kinzler KW Velculescu VE 《Science (New York, N.Y.)》2011,331(6016):435-439
Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high-density microarrays and sequenced all known protein-coding genes and microRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis. 相似文献
11.
Lee E Iskow R Yang L Gokcumen O Haseley P Luquette LJ Lohr JG Harris CC Ding L Wilson RK Wheeler DA Gibbs RA Kucherlapati R Lee C Kharchenko PV Park PJ;Cancer Genome Atlas Research Network 《Science (New York, N.Y.)》2012,337(6097):967-971
Transposable elements (TEs) are abundant in the human genome, and some are capable of generating new insertions through RNA intermediates. In cancer, the disruption of cellular mechanisms that normally suppress TE activity may facilitate mutagenic retrotranspositions. We performed single-nucleotide resolution analysis of TE insertions in 43 high-coverage whole-genome sequencing data sets from five cancer types. We identified 194 high-confidence somatic TE insertions, as well as thousands of polymorphic TE insertions in matched normal genomes. Somatic insertions were present in epithelial tumors but not in blood or brain cancers. Somatic L1 insertions tend to occur in genes that are commonly mutated in cancer, disrupt the expression of the target genes, and are biased toward regions of cancer-specific DNA hypomethylation, highlighting their potential impact in tumorigenesis. 相似文献
12.
Identification of a chromosome 18q gene that is altered in colorectal cancers 总被引：141，自引：0，他引：141
E R Fearon K R Cho J M Nigro S E Kern J W Simons J M Ruppert S R Hamilton A C Preisinger G Thomas K W Kinzler 《Science (New York, N.Y.)》1990,247(4938):49-56
Allelic deletions involving chromosome 18q occur in more than 70 percent of colorectal cancers. Such deletions are thought to signal the existence of a tumor suppressor gene in the affected region, but until now a candidate suppressor gene on this chromosomal arm had not been identified. A contiguous stretch of DNA comprising 370 kilobase pairs (kb) has now been cloned from a region of chromosome 18q suspected to reside near this gene. Potential exons in the 370-kb region were defined by human-rodent sequence identities, and the expression of potential exons was assessed by an "exon-connection" strategy based on the polymerase chain reaction. Expressed exons were used as probes for cDNA screening to obtain clones that encoded a portion of a gene termed DCC; this cDNA was encoded by at least eight exons within the 370-kb genomic region. The predicted amino acid sequence of the cDNA specified a protein with sequence similarity to neural cell adhesion molecules and other related cell surface glycoproteins. While the DCC gene was expressed in most normal tissues, including colonic mucosa, its expression was greatly reduced or absent in most colorectal carcinomas tested. Somatic mutations within the DCC gene observed in colorectal cancers included a homozygous deletion of the 5' end of the gene, a point mutation within one of the introns, and ten examples of DNA insertions within a 0.17-kb fragment immediately downstream of one of the exons. The DCC gene may play a role in the pathogenesis of human colorectal neoplasia, perhaps through alteration of the normal cell-cell interactions controlling growth. 相似文献
13.
Bettegowda C Agrawal N Jiao Y Sausen M Wood LD Hruban RH Rodriguez FJ Cahill DP McLendon R Riggins G Velculescu VE Oba-Shinjo SM Marie SK Vogelstein B Bigner D Yan H Papadopoulos N Kinzler KW 《Science (New York, N.Y.)》2011,333(6048):1453-1455
Oligodendrogliomas are the second most common malignant brain tumor in adults and exhibit characteristic losses of chromosomes 1p and 19q. To identify the molecular genetic basis for this alteration, we performed exomic sequencing of seven tumors. Among other changes, we found that the CIC gene (homolog of the Drosophila gene capicua) on chromosome 19q was somatically mutated in six cases and that the FUBP1 gene [encoding far-upstream element (FUSE) binding protein] on chromosome 1p was somatically mutated in two tumors. Examination of 27 additional oligodendrogliomas revealed 12 and 3 more tumors with mutations of CIC and FUBP1, respectively, 58% of which were predicted to result in truncations of the encoded proteins. These results suggest a critical role for these genes in the biology and pathology of oligodendrocytes. 相似文献
14.
Concerted nonsyntenic allelic loss in human colorectal carcinoma 总被引：12，自引：0，他引：12
D J Law S Olschwang J P Monpezat D Lefran?ois D Jagelman N J Petrelli G Thomas A P Feinberg 《Science (New York, N.Y.)》1988,241(4868):961-965
Familial polyposis coli (FPC) is caused by an autosomal dominant gene on chromosome 5, and it has been proposed that colorectal cancer in the general population arises from loss or inactivation of the FPC gene, analogous to recessive tumor genes in retinoblastoma and Wilms' tumor. Since allelic loss can be erroneously scored in nonhomogeneous samples, tumor cell populations were first microdissected from 24 colorectal carcinomas, an additional nine cancers were engrafted in nude mice, and nuclei were flow-sorted from an additional two. Of 31 cancers informative for chromosome 5 markers, only 6 (19%) showed loss of heterozygosity of chromosome 5 alleles, compared to 19 of 34 (56%) on chromosome 17, and 17 of 33 (52%) on chromosome 18. Therefore, it appears that (i) FPC is a true dominant for adenomatosis but not a common recessive gene for colon cancer; and (ii) simple Mendelian models involving loss of alleles at a single locus may be inappropriate for understanding common human solid tumors. 相似文献
15.
16.
Solimini NL Xu Q Mermel CH Liang AC Schlabach MR Luo J Burrows AE Anselmo AN Bredemeyer AL Li MZ Beroukhim R Meyerson M Elledge SJ 《Science (New York, N.Y.)》2012,337(6090):104-109
Tumors exhibit numerous recurrent hemizygous focal deletions that contain no known tumor suppressors and are poorly understood. To investigate whether these regions contribute to tumorigenesis, we searched genetically for genes with cancer-relevant properties within these hemizygous deletions. We identified STOP and GO genes, which negatively and positively regulate proliferation, respectively. STOP genes include many known tumor suppressors, whereas GO genes are enriched for essential genes. Analysis of their chromosomal distribution revealed that recurring deletions preferentially overrepresent STOP genes and underrepresent GO genes. We propose a hypothesis called the cancer gene island model, whereby gene islands encompassing high densities of STOP genes and low densities of GO genes are hemizygously deleted to maximize proliferative fitness through cumulative haploinsufficiencies. Because hundreds to thousands of genes are hemizygously deleted per tumor, this mechanism may help to drive tumorigenesis across many cancer types. 相似文献
17.
18.
Rivera MN Kim WJ Wells J Driscoll DR Brannigan BW Han M Kim JC Feinberg AP Gerald WL Vargas SO Chin L Iafrate AJ Bell DW Haber DA 《Science (New York, N.Y.)》2007,315(5812):642-645
Wilms tumor is a pediatric kidney cancer associated with inactivation of the WT1 tumor-suppressor gene in 5 to 10% of cases. Using a high-resolution screen for DNA copy-number alterations in Wilms tumor, we identified somatic deletions targeting a previously uncharacterized gene on the X chromosome. This gene, which we call WTX, is inactivated in approximately one-third of Wilms tumors (15 of 51 tumors). Tumors with mutations in WTX lack WT1 mutations, and both genes share a restricted temporal and spatial expression pattern in normal renal precursors. In contrast to biallelic inactivation of autosomal tumor-suppressor genes, WTX is inactivated by a monoallelic "single-hit" event targeting the single X chromosome in tumors from males and the active X chromosome in tumors from females. 相似文献
19.
Genetic mechanisms of tumor suppression by the human p53 gene 总被引：68，自引：0，他引：68
Mutations of the gene encoding p53, a 53-kilodalton cellular protein, are found frequently in human tumor cells, suggesting a crucial role for this gene in human oncogenesis. To model the stepwise mutation or loss of both p53 alleles during tumorigenesis, a human osteosarcoma cell line, Saos-2, was used that completely lacked endogenous p53. Single copies of exogenous p53 genes were then introduced by infecting cells with recombinant retroviruses containing either point-mutated or wild-type versions of the p53 cDNA sequence. Expression of wild-type p53 suppressed the neoplastic phenotype of Saos-2 cells, whereas expression of mutated p53 conferred a limited growth advantage to cells in the absence of wild-type p53. Wild-type p53 was phenotypically dominant to mutated p53 in a two-allele configuration. These results suggest that, as with the retinoblastoma gene, mutation of both alleles of the p53 gene is essential for its role in oncogenesis. 相似文献
20.
D Sidransky A Von Eschenbach Y C Tsai P Jones I Summerhayes F Marshall M Paul P Green S R Hamilton P Frost 《Science (New York, N.Y.)》1991,252(5006):706-709
Although bladder cancers are very common, little is known about their molecular pathogenesis. In this study, invasive bladder cancers were evaluated for the presence of gene mutations in the p53 suppressor gene. Of 18 tumors evaluated, 11 (61 percent) were found to have genetic alterations of p53. The alterations included ten point mutations resulting in single amino acid substitutions, and one 24-base pair deletion. In all but one case, the mutations were associated with chromosome 17p allelic deletions, leaving the cells with only mutant forms of the p53 gene products. Through the use of the polymerase chain reaction and oligomer-specific hybridization, p53 mutations were identified in 1 to 7 percent of the cells within the urine sediment of each of three patients tested. The p53 mutations are the first genetic alterations demonstrated to occur in a high proportion of primary invasive bladder cancers. Detection of such mutations ex vivo has clinical implications for monitoring individuals whose tumor cells are shed extracorporeally. 相似文献