共查询到20条相似文献,搜索用时 31 毫秒
1.
Zang ZJ Cutcutache I Poon SL Zhang SL McPherson JR Tao J Rajasegaran V Heng HL Deng N Gan A Lim KH Ong CK Huang D Chin SY Tan IB Ng CC Yu W Wu Y Lee M Wu J Poh D Wan WK Rha SY So J Salto-Tellez M Yeoh KG Wong WK Zhu YJ Futreal PA Pang B Ruan Y Hillmer AM Bertrand D Nagarajan N Rozen S Teh BT Tan P 《Nature genetics》2012,44(5):570-574
Gastric cancer is a major cause of global cancer mortality. We surveyed the spectrum of somatic alterations in gastric cancer by sequencing the exomes of 15 gastric adenocarcinomas and their matched normal DNAs. Frequently mutated genes in the adenocarcinomas included TP53 (11/15 tumors), PIK3CA (3/15) and ARID1A (3/15). Cell adhesion was the most enriched biological pathway among the frequently mutated genes. A prevalence screening confirmed mutations in FAT4, a cadherin family gene, in 5% of gastric cancers (6/110) and FAT4 genomic deletions in 4% (3/83) of gastric tumors. Frequent mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) also occurred in 47% of the gastric cancers. We detected ARID1A mutations in 8% of tumors (9/110), which were associated with concurrent PIK3CA mutations and microsatellite instability. In functional assays, we observed both FAT4 and ARID1A to exert tumor-suppressor activity. Somatic inactivation of FAT4 and ARID1A may thus be key tumorigenic events in a subset of gastric cancers. 相似文献
2.
Wang K Kan J Yuen ST Shi ST Chu KM Law S Chan TL Kan Z Chan AS Tsui WY Lee SP Ho SL Chan AK Cheng GH Roberts PC Rejto PA Gibson NW Pocalyko DJ Mao M Xu J Leung SY 《Nature genetics》2011,43(12):1219-1223
Gastric cancer is a heterogeneous disease with multiple environmental etiologies and alternative pathways of carcinogenesis. Beyond mutations in TP53, alterations in other genes or pathways account for only small subsets of the disease. We performed exome sequencing of 22 gastric cancer samples and identified previously unreported mutated genes and pathway alterations; in particular, we found genes involved in chromatin modification to be commonly mutated. A downstream validation study confirmed frequent inactivating mutations or protein deficiency of ARID1A, which encodes a member of the SWI-SNF chromatin remodeling family, in 83% of gastric cancers with microsatellite instability (MSI), 73% of those with Epstein-Barr virus (EBV) infection and 11% of those that were not infected with EBV and microsatellite stable (MSS). The mutation spectrum for ARID1A differs between molecular subtypes of gastric cancer, and mutation prevalence is negatively associated with mutations in TP53. Clinically, ARID1A alterations were associated with better prognosis in a stage-independent manner. These results reveal the genomic landscape, and highlight the importance of chromatin remodeling, in the molecular taxonomy of gastric cancer. 相似文献
3.
Guichard C Amaddeo G Imbeaud S Ladeiro Y Pelletier L Maad IB Calderaro J Bioulac-Sage P Letexier M Degos F Clément B Balabaud C Chevet E Laurent A Couchy G Letouzé E Calvo F Zucman-Rossi J 《Nature genetics》2012,44(6):694-698
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Here, we performed high-resolution copy-number analysis on 125 HCC tumors and whole-exome sequencing on 24 of these tumors. We identified 135 homozygous deletions and 994 somatic mutations of genes with predicted functional consequences. We found new recurrent alterations in four genes (ARID1A, RPS6KA3, NFE2L2 and IRF2) not previously described in HCC. Functional analyses showed tumor suppressor properties for IRF2, whose inactivation, exclusively found in hepatitis B virus (HBV)-related tumors, led to impaired TP53 function. In contrast, inactivation of chromatin remodelers was frequent and predominant in alcohol-related tumors. Moreover, association of mutations in specific genes (RPS6KA3-AXIN1 and NFE2L2-CTNNB1) suggested that Wnt/β-catenin signaling might cooperate in liver carcinogenesis with both oxidative stress metabolism and Ras/mitogen-activated protein kinase (MAPK) pathways. This study provides insight into the somatic mutational landscape in HCC and identifies interactions between mutations in oncogene and tumor suppressor gene mutations related to specific risk factors. 相似文献
4.
Li M Zhao H Zhang X Wood LD Anders RA Choti MA Pawlik TM Daniel HD Kannangai R Offerhaus GJ Velculescu VE Wang L Zhou S Vogelstein B Hruban RH Papadopoulos N Cai J Torbenson MS Kinzler KW 《Nature genetics》2011,43(9):828-829
Through exomic sequencing of ten hepatitis C virus (HCV)-associated hepatocellular carcinomas (HCC) and subsequent evaluation of additional affected individuals, we discovered novel inactivating mutations of ARID2 in four major subtypes of HCC (HCV-associated HCC, hepatitis B virus (HBV)-associated HCC, alcohol-associated HCC and HCC with no known etiology). Notably, 18.2% of individuals with HCV-associated HCC in the United States and Europe harbored ARID2 inactivation mutations, suggesting that ARID2 is a tumor suppressor gene that is relatively commonly mutated in this tumor subtype. 相似文献
5.
Ong CK Subimerb C Pairojkul C Wongkham S Cutcutache I Yu W McPherson JR Allen GE Ng CC Wong BH Myint SS Rajasegaran V Heng HL Gan A Zang ZJ Wu Y Wu J Lee MH Huang D Ong P Chan-on W Cao Y Qian CN Lim KH Ooi A Dykema K Furge K Kukongviriyapan V Sripa B Wongkham C Yongvanit P Futreal PA Bhudhisawasdi V Rozen S Tan P Teh BT 《Nature genetics》2012,44(6):690-693
Opisthorchis viverrini-related cholangiocarcinoma (CCA), a fatal bile duct cancer, is a major public health concern in areas endemic for this parasite. We report here whole-exome sequencing of eight O. viverrini-related tumors and matched normal tissue. We identified and validated 206 somatic mutations in 187 genes using Sanger sequencing and selected 15 genes for mutation prevalence screening in an additional 46 individuals with CCA (cases). In addition to the known cancer-related genes TP53 (mutated in 44.4% of cases), KRAS (16.7%) and SMAD4 (16.7%), we identified somatic mutations in 10 newly implicated genes in 14.8-3.7% of cases. These included inactivating mutations in MLL3 (in 14.8% of cases), ROBO2 (9.3%), RNF43 (9.3%) and PEG3 (5.6%), and activating mutations in the GNAS oncogene (9.3%). These genes have functions that can be broadly grouped into three biological classes: (i) deactivation of histone modifiers, (ii) activation of G protein signaling and (iii) loss of genome stability. This study provides insight into the mutational landscape contributing to O. viverrini-related CCA. 相似文献
6.
Santen GW Aten E Sun Y Almomani R Gilissen C Nielsen M Kant SG Snoeck IN Peeters EA Hilhorst-Hofstee Y Wessels MW den Hollander NS Ruivenkamp CA van Ommen GJ Breuning MH den Dunnen JT van Haeringen A Kriek M 《Nature genetics》2012,44(4):379-380
We identified de novo truncating mutations in ARID1B in three individuals with Coffin-Siris syndrome (CSS) by exome sequencing. Array-based copy-number variation (CNV) analysis in 2,000 individuals with intellectual disability revealed deletions encompassing ARID1B in 3 subjects with phenotypes partially overlapping that of CSS. Taken together with published data, these results indicate that haploinsufficiency of the ARID1B gene, which encodes an epigenetic modifier of chromatin structure, is an important cause of CSS and is potentially a common cause of intellectual disability and speech impairment. 相似文献
7.
Sung WK Zheng H Li S Chen R Liu X Li Y Lee NP Lee WH Ariyaratne PN Tennakoon C Mulawadi FH Wong KF Liu AM Poon RT Fan ST Chan KL Gong Z Hu Y Lin Z Wang G Zhang Q Barber TD Chou WC Aggarwal A Hao K Zhou W Zhang C Hardwick J Buser C Xu J Kan Z Dai H Mao M Reinhard C Wang J Luk JM 《Nature genetics》2012,44(7):765-769
To survey hepatitis B virus (HBV) integration in liver cancer genomes, we conducted massively parallel sequencing of 81 HBV-positive and 7 HBV-negative hepatocellular carcinomas (HCCs) and adjacent normal tissues. We found that HBV integration is observed more frequently in the tumors (86.4%) than in adjacent liver tissues (30.7%). Copy-number variations (CNVs) were significantly increased at HBV breakpoint locations where chromosomal instability was likely induced. Approximately 40% of HBV breakpoints within the HBV genome were located within a 1,800-bp region where the viral enhancer, X gene and core gene are located. We also identified recurrent HBV integration events (in ≥ 4 HCCs) that were validated by RNA sequencing (RNA-seq) and Sanger sequencing at the known and putative cancer-related TERT, MLL4 and CCNE1 genes, which showed upregulated gene expression in tumor versus normal tissue. We also report evidence that suggests that the number of HBV integrations is associated with patient survival. 相似文献
8.
Mutations truncating the EP300 acetylase in human cancers 总被引:21,自引:0,他引:21
Gayther SA Batley SJ Linger L Bannister A Thorpe K Chin SF Daigo Y Russell P Wilson A Sowter HM Delhanty JD Ponder BA Kouzarides T Caldas C 《Nature genetics》2000,24(3):300-303
9.
Gui Y Guo G Huang Y Hu X Tang A Gao S Wu R Chen C Li X Zhou L He M Li Z Sun X Jia W Chen J Yang S Zhou F Zhao X Wan S Ye R Liang C Liu Z Huang P Liu C Jiang H Wang Y Zheng H Sun L Liu X Jiang Z Feng D Chen J Wu S Zou J Zhang Z Yang R Zhao J Xu C Yin W Guan Z Ye J Zhang H Li J Kristiansen K Nickerson ML Theodorescu D Li Y Zhang X Li S Wang J Yang H Wang J Cai Z 《Nature genetics》2011,43(9):875-878
Transitional cell carcinoma (TCC) is the most common type of bladder cancer. Here we sequenced the exomes of nine individuals with TCC and screened all the somatically mutated genes in a prevalence set of 88 additional individuals with TCC with different tumor stages and grades. In our study, we discovered a variety of genes previously unknown to be mutated in TCC. Notably, we identified genetic aberrations of the chromatin remodeling genes (UTX, MLL-MLL3, CREBBP-EP300, NCOR1, ARID1A and CHD6) in 59% of our 97 subjects with TCC. Of these genes, we showed UTX to be altered substantially more frequently in tumors of low stages and grades, highlighting its potential role in the classification and diagnosis of bladder cancer. Our results provide an overview of the genetic basis of TCC and suggest that aberration of chromatin regulation might be a hallmark of bladder cancer. 相似文献
10.
Bi-allelic inactivation of TCF1 in hepatic adenomas 总被引:9,自引:0,他引:9
Bluteau O Jeannot E Bioulac-Sage P Marqués JM Blanc JF Bui H Beaudoin JC Franco D Balabaud C Laurent-Puig P Zucman-Rossi J 《Nature genetics》2002,32(2):312-315
11.
Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas 总被引:1,自引:0,他引:1
Wu G Broniscer A McEachron TA Lu C Paugh BS Becksfort J Qu C Ding L Huether R Parker M Zhang J Gajjar A Dyer MA Mullighan CG Gilbertson RJ Mardis ER Wilson RK Downing JR Ellison DW Zhang J Baker SJ;St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project 《Nature genetics》2012,44(3):251-253
To identify somatic mutations in pediatric diffuse intrinsic pontine glioma (DIPG), we performed whole-genome sequencing of DNA from seven DIPGs and matched germline tissue and targeted sequencing of an additional 43 DIPGs and 36 non-brainstem pediatric glioblastomas (non-BS-PGs). We found that 78% of DIPGs and 22% of non-BS-PGs contained a mutation in H3F3A, encoding histone H3.3, or in the related HIST1H3B, encoding histone H3.1, that caused a p.Lys27Met amino acid substitution in each protein. An additional 14% of non-BS-PGs had somatic mutations in H3F3A causing a p.Gly34Arg alteration. 相似文献
12.
Tsurusaki Y Okamoto N Ohashi H Kosho T Imai Y Hibi-Ko Y Kaname T Naritomi K Kawame H Wakui K Fukushima Y Homma T Kato M Hiraki Y Yamagata T Yano S Mizuno S Sakazume S Ishii T Nagai T Shiina M Ogata K Ohta T Niikawa N Miyatake S Okada I Mizuguchi T Doi H Saitsu H Miyake N Matsumoto N 《Nature genetics》2012,44(4):376-378
By exome sequencing, we found de novo SMARCB1 mutations in two of five individuals with typical Coffin-Siris syndrome (CSS), a rare autosomal dominant anomaly syndrome. As SMARCB1 encodes a subunit of the SWItch/Sucrose NonFermenting (SWI/SNF) complex, we screened 15 other genes encoding subunits of this complex in 23 individuals with CSS. Twenty affected individuals (87%) each had a germline mutation in one of six SWI/SNF subunit genes, including SMARCB1, SMARCA4, SMARCA2, SMARCE1, ARID1A and ARID1B. 相似文献
13.
Quesada V Conde L Villamor N Ordóñez GR Jares P Bassaganyas L Ramsay AJ Beà S Pinyol M Martínez-Trillos A López-Guerra M Colomer D Navarro A Baumann T Aymerich M Rozman M Delgado J Giné E Hernández JM González-Díaz M Puente DA Velasco G Freije JM Tubío JM Royo R Gelpí JL Orozco M Pisano DG Zamora J Vázquez M Valencia A Himmelbauer H Bayés M Heath S Gut M Gut I Estivill X López-Guillermo A Puente XS Campo E López-Otín C 《Nature genetics》2012,44(1):47-52
Here we perform whole-exome sequencing of samples from 105 individuals with chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults in Western countries. We found 1,246 somatic mutations potentially affecting gene function and identified 78 genes with predicted functional alterations in more than one tumor sample. Among these genes, SF3B1, encoding a subunit of the spliceosomal U2 small nuclear ribonucleoprotein (snRNP), is somatically mutated in 9.7% of affected individuals. Further analysis in 279 individuals with CLL showed that SF3B1 mutations were associated with faster disease progression and poor overall survival. This work provides the first comprehensive catalog of somatic mutations in CLL with relevant clinical correlates and defines a large set of new genes that may drive the development of this common form of leukemia. The results reinforce the idea that targeting several well-known genetic pathways, including mRNA splicing, could be useful in the treatment of CLL and other malignancies. 相似文献
14.
Amary MF Damato S Halai D Eskandarpour M Berisha F Bonar F McCarthy S Fantin VR Straley KS Lobo S Aston W Green CL Gale RE Tirabosco R Futreal A Campbell P Presneau N Flanagan AM 《Nature genetics》2011,43(12):1262-1265
Ollier disease and Maffucci syndrome are characterized by multiple central cartilaginous tumors that are accompanied by soft tissue hemangiomas in Maffucci syndrome. We show that in 37 of 40 individuals with these syndromes, at least one tumor has a mutation in isocitrate dehydrogenase 1 (IDH1) or in IDH2, 65% of which result in a R132C substitution in the protein. In 18 of 19 individuals with more than one tumor analyzed, all tumors from a given individual shared the same IDH1 mutation affecting Arg132. In 2 of 12 subjects, a low level of mutated DNA was identified in non-neoplastic tissue. The levels of the metabolite 2HG were measured in a series of central cartilaginous and vascular tumors, including samples from syndromic and nonsyndromic subjects, and these levels correlated strongly with the presence of IDH1 mutations. The findings are compatible with a model in which IDH1 or IDH2 mutations represent early post-zygotic occurrences in individuals with these syndromes. 相似文献
15.
Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype 总被引:4,自引:0,他引:4
Brems H Chmara M Sahbatou M Denayer E Taniguchi K Kato R Somers R Messiaen L De Schepper S Fryns JP Cools J Marynen P Thomas G Yoshimura A Legius E 《Nature genetics》2007,39(9):1120-1126
We report germline loss-of-function mutations in SPRED1 in a newly identified autosomal dominant human disorder. SPRED1 is a member of the SPROUTY/SPRED family of proteins that act as negative regulators of RAS->RAF interaction and mitogen-activated protein kinase (MAPK) signaling. The clinical features of the reported disorder resemble those of neurofibromatosis type 1 and consist of multiple café-au-lait spots, axillary freckling and macrocephaly. Melanocytes from a café-au-lait spot showed, in addition to the germline SPRED1 mutation, an acquired somatic mutation in the wild-type SPRED1 allele, indicating that complete SPRED1 inactivation is needed to generate a café-au-lait spot in this syndrome. This disorder is yet another member of the recently characterized group of phenotypically overlapping syndromes caused by mutations in the genes encoding key components of the RAS-MAPK pathway. To our knowledge, this is the first report of mutations in the SPRY (SPROUTY)/SPRED family of genes in human disease. 相似文献
16.
Thomas RK Baker AC Debiasi RM Winckler W Laframboise T Lin WM Wang M Feng W Zander T MacConaill L Macconnaill LE Lee JC Nicoletti R Hatton C Goyette M Girard L Majmudar K Ziaugra L Wong KK Gabriel S Beroukhim R Peyton M Barretina J Dutt A Emery C Greulich H Shah K Sasaki H Gazdar A Minna J Armstrong SA Mellinghoff IK Hodi FS Dranoff G Mischel PS Cloughesy TF Nelson SF Liau LM Mertz K Rubin MA Moch H Loda M Catalona W Fletcher J Signoretti S Kaye F Anderson KC Demetri GD Dummer R Wagner S 《Nature genetics》2007,39(3):347-351
Systematic efforts are underway to decipher the genetic changes associated with tumor initiation and progression. However, widespread clinical application of this information is hampered by an inability to identify critical genetic events across the spectrum of human tumors with adequate sensitivity and scalability. Here, we have adapted high-throughput genotyping to query 238 known oncogene mutations across 1,000 human tumor samples. This approach established robust mutation distributions spanning 17 cancer types. Of 17 oncogenes analyzed, we found 14 to be mutated at least once, and 298 (30%) samples carried at least one mutation. Moreover, we identified previously unrecognized oncogene mutations in several tumor types and observed an unexpectedly high number of co-occurring mutations. These results offer a new dimension in tumor genetics, where mutations involving multiple cancer genes may be interrogated simultaneously and in 'real time' to guide cancer classification and rational therapeutic intervention. 相似文献
17.
Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors 总被引:5,自引:0,他引:5
Al-Tassan N Chmiel NH Maynard J Fleming N Livingston AL Williams GT Hodges AK Davies DR David SS Sampson JR Cheadle JP 《Nature genetics》2002,30(2):227-232
Inherited defects of base excision repair have not been associated with any human genetic disorder, although mutations of the genes mutM and mutY, which function in Escherichia coli base excision repair, lead to increased transversions of G:C to T:A. We have studied family N, which is affected with multiple colorectal adenomas and carcinoma but lacks an inherited mutation of the adenomatous polyposis coli gene (APC) that is associated with familial adenomatous polyposis. Here we show that 11 tumors from 3 affected siblings contain 18 somatic inactivating mutations of APC and that 15 of these mutations are G:C-->A transversions--a significantly greater proportion than is found in sporadic tumors or in tumors associated with familial adenomatous polyposis. Analysis of the human homolog of mutY, MYH, showed that the siblings were compound heterozygotes for the nonconservative missense variants Tyr165Cys and Gly382Asp. These mutations affect residues that are conserved in mutY of E. coli (Tyr82 and Gly253). Tyrosine 82 is located in the pseudo-helix-hairpin-helix (HhH) motif and is predicted to function in mismatch specificity. Assays of adenine glycosylase activity of the Tyr82Cys and Gly253Asp mutant proteins with 8-oxoG:A and G:A substrates show that their activity is reduced significantly. Our findings link the inherited variants in MYH to the pattern of somatic APC mutation in family N and implicate defective base excision repair in predisposition to tumors in humans. 相似文献
18.
Stephens P Edkins S Davies H Greenman C Cox C Hunter C Bignell G Teague J Smith R Stevens C O'Meara S Parker A Tarpey P Avis T Barthorpe A Brackenbury L Buck G Butler A Clements J Cole J Dicks E Edwards K Forbes S Gorton M Gray K Halliday K Harrison R Hills K Hinton J Jones D Kosmidou V Laman R Lugg R Menzies A Perry J Petty R Raine K Shepherd R Small A Solomon H Stephens Y Tofts C Varian J Webb A West S Widaa S Yates A Brasseur F Cooper CS Flanagan AM Green A Knowles M Leung SY Looijenga LH 《Nature genetics》2005,37(6):590-592
We examined the coding sequence of 518 protein kinases, approximately 1.3 Mb of DNA per sample, in 25 breast cancers. In many tumors, we detected no somatic mutations. But a few had numerous somatic mutations with distinctive patterns indicative of either a mutator phenotype or a past exposure. 相似文献
19.
Germline mutations in HRAS proto-oncogene cause Costello syndrome 总被引:17,自引:0,他引:17
Aoki Y Niihori T Kawame H Kurosawa K Ohashi H Tanaka Y Filocamo M Kato K Suzuki Y Kure S Matsubara Y 《Nature genetics》2005,37(10):1038-1040
Costello syndrome is a multiple congenital anomaly and mental retardation syndrome characterized by coarse face, loose skin, cardiomyopathy and predisposition to tumors. We identified four heterozygous de novo mutations of HRAS in 12 of 13 affected individuals, all of which were previously reported as somatic and oncogenic mutations in various tumors. Our observations suggest that germline mutations in HRAS perturb human development and increase susceptibility to tumors. 相似文献
20.
Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR 总被引:9,自引:0,他引:9
Bell DW Gore I Okimoto RA Godin-Heymann N Sordella R Mulloy R Sharma SV Brannigan BW Mohapatra G Settleman J Haber DA 《Nature genetics》2005,37(12):1315-1316
Somatic activating mutations in EGFR identify a subset of non-small cell lung cancer that respond to tyrosine kinase inhibitors. Acquisition of drug resistance is linked to a specific secondary somatic mutation, EGFR T790M. Here we describe a family with multiple cases of non-small cell lung cancer associated with germline transmission of this mutation. Four of six tumors analyzed showed a secondary somatic activating EGFR mutation, arising in cis with the germline EGFR mutation T790M. These observations implicate altered EGFR signaling in genetic susceptibility to lung cancer. 相似文献