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1.
Sriram KB Larsen JE Savarimuthu Francis SM Wright CM Clarke BE Duhig EE Brown KM Hayward NK Yang IA Bowman RV Fong KM 《PloS one》2012,7(2):e30398
Background
Primary tumor recurrence commonly occurs after surgical resection of lung squamous cell carcinoma (SCC). Little is known about the genes driving SCC recurrence.Methods
We used array comparative genomic hybridization (aCGH) to identify genes affected by copy number alterations that may be involved in SCC recurrence. Training and test sets of resected primary lung SCC were assembled. aCGH was used to determine genomic copy number in a training set of 62 primary lung SCCs (28 with recurrence and 34 with no evidence of recurrence) and the altered copy number of candidate genes was confirmed by quantitative PCR (qPCR). An independent test set of 72 primary lung SCCs (20 with recurrence and 52 with no evidence of recurrence) was used for biological validation. mRNA expression of candidate genes was studied using qRT-PCR. Candidate gene promoter methylation was evaluated using methylation microarrays and Sequenom EpiTYPER analysis.Results
18q22.3 loss was identified by aCGH as being significantly associated with recurrence (p = 0.038). Seven genes within 18q22.3 had aCGH copy number loss associated with recurrence but only SOCS6 copy number was both technically replicated by qPCR and biologically validated in the test set. SOCS6 copy number loss correlated with reduced mRNA expression in the study samples and in the samples with copy number loss, there was a trend for increased methylation, albeit non-significant. Overall survival was significantly poorer in patients with SOCS6 loss compared to patients without SOCS6 loss in both the training (30 vs. 43 months, p = 0.023) and test set (27 vs. 43 months, p = 0.010).Conclusion
Reduced copy number and mRNA expression of SOCS6 are associated with disease recurrence in primary lung SCC and may be useful prognostic biomarkers. 相似文献2.
Dong-Hao Jin Seong-Eun Park Jeeyun Lee Kyung-Mi Kim Sung Kim Duk-Hwan Kim Joobae Park 《PloS one》2015,10(9)
The present study was aimed at discovering DNA copy number alterations (CNAs) involved in the carcinogenesis of stomach and at understanding their clinicopathological significances in the Korean population. DNA copy numbers were analyzed using Agilent 244K or 400K array comparative genomic hybridization (aCGH) in fresh-frozen tumor and matched normal tissues from 40 gastric cancer patients. Some of the detected CNA regions were validated using multiplex ligation-dependent probe amplification (MLPA) in six of the 40 patients and customized Agilent 60K aCGH in an independent set of 48 gastric cancers. The mRNA levels of genes at common CNA regions were analyzed using quantitative real-time PCR. Copy number gains were more common than losses across the entire genome in tumor tissues compared to matched normal tissues. The mean number of alterations per case was 64 for gains and 40 for losses, and the median aberration length was 44016 bp for gains and 4732 bp for losses. Copy number gains were frequently detected at 7p22.1 (20%), 8q24.21 (27%–30%), 8q24.3 (22%–48%), 13q34 (20%–31%), and 20q11-q13 (25%–30%), and losses at 3p14.2 (43%), 4q35.2 (27%), 6q26 (23%), and 17p13.3 (20%–23%). CNAs at 7p22.1, 13q34, and 17p13.3 have not been reported in other populations. Most of the copy number losses were associated with down-regulation of mRNA levels, but the correlation between copy number gains and mRNA expression levels varied in a gene-dependent manner. In addition, copy number gains tended to occur more commonly in intestinal-type cancers than in diffuse-type cancers. In conclusion, the present study suggests that copy number gains at 8q24 and 20q11-q13 and losses at 3p14.2 may be common events in gastric cancer but CNAs at 7p22.1, 13q34, and 17p13.3 may be Korean-specific. 相似文献
3.
Sabatier R Finetti P Adelaide J Guille A Borg JP Chaffanet M Lane L Birnbaum D Bertucci F 《PloS one》2011,6(11):e27656
Introduction
ECRG4/C2ORF40 is a potential tumor suppressor gene (TSG) recently identified in esophageal carcinoma. Its expression, gene copy number and prognostic value have never been explored in breast cancer.Methods
Using DNA microarray and array-based comparative genomic hybridization (aCGH), we examined ECRG4 mRNA expression and copy number alterations in 353 invasive breast cancer samples and normal breast (NB) samples. A meta-analysis was done on a large public retrospective gene expression dataset (n = 1,387) in search of correlations between ECRG4 expression and histo-clinical features including survival.Results
ECRG4 was underexpressed in 94.3% of cancers when compared to NB. aCGH data revealed ECRG4 loss in 18% of tumors, suggesting that DNA loss is not the main mechanism of underexpression. Meta-analysis showed that ECRG4 expression was significantly higher in tumors displaying earlier stage, smaller size, negative axillary lymph node status, lower grade, and normal-like subtype. Higher expression was also associated with disease-free survival (DFS; HR = 0.84 [0.76–0.92], p = 0.0002) and overall survival (OS; HR = 0.72 [0.63–0.83], p = 5.0E-06). In multivariate analysis including the other histo-clinical prognostic features, ECRG4 expression remained the only prognostic factor for DFS and OS.Conclusions
Our data suggest that ECRG4 is a candidate TSG in breast cancer, the expression of which may help improve the prognostication. If functional analyses confirm this TSG role, restoring ECRG4 expression in the tumor may represent a promising therapeutic approach. 相似文献4.
Jian-Wei Liang Zhi-Zhou Shi Tian-Yun Shen Xu Che Zheng Wang Su-Sheng Shi Xin Xu Yan Cai Ping Zhao Cheng-Feng Wang Zhi-Xiang Zhou Ming-Rong Wang 《PloS one》2014,9(12)
Background
Genomic aberration is a common feature of human cancers and also is one of the basic mechanisms that lead to overexpression of oncogenes and underexpression of tumor suppressor genes. Our study aims to identify frequent genomic changes in pancreatic cancer.Materials and Methods
We used array comparative genomic hybridization (array CGH) to identify recurrent genomic alterations and validated the protein expression of selected genes by immunohistochemistry.Results
Sixteen gains and thirty-two losses occurred in more than 30% and 60% of the tumors, respectively. High-level amplifications at 7q21.3–q22.1 and 19q13.2 and homozygous deletions at 1p33–p32.3, 1p22.1, 1q22, 3q27.2, 6p22.3, 6p21.31, 12q13.2, 17p13.2, 17q21.31 and 22q13.1 were identified. Especially, amplification of AKT2 was detected in two carcinomas and homozygous deletion of CDKN2C in other two cases. In 15 independent validation samples, we found that AKT2 (19q13.2) and MCM7 (7q22.1) were amplified in 6 and 9 cases, and CAMTA2 (17p13.2) and PFN1 (17p13.2) were homozygously deleted in 3 and 1 cases. AKT2 and MCM7 were overexpressed, and CAMTA2 and PFN1 were underexpressed in pancreatic cancer tissues than in morphologically normal operative margin tissues. Both GISTIC and Genomic Workbench software identified 22q13.1 containing APOBEC3A and APOBEC3B as the only homozygous deletion region. And the expression levels of APOBEC3A and APOBEC3B were significantly lower in tumor tissues than in morphologically normal operative margin tissues. Further validation showed that overexpression of PSCA was significantly associated with lymph node metastasis, and overexpression of HMGA2 was significantly associated with invasive depth of pancreatic cancer.Conclusion
These recurrent genomic changes may be useful for revealing the mechanism of pancreatic carcinogenesis and providing candidate biomarkers. 相似文献5.
6.
Stéphanie Cornen Arnaud Guille José Adéla?de Lynda Addou-Klouche Pascal Finetti Marie-Rose Saade Marwa Manai Nadine Carbuccia Ismahane Bekhouche Anne Letessier Stéphane Raynaud Emmanuelle Charafe-Jauffret Jocelyne Jacquemier Salvatore Spicuglia Hugues de The Patrice Viens Fran?ois Bertucci Daniel Birnbaum Max Chaffanet 《PloS one》2014,9(1)
Breast cancers (BCs) of the luminal B subtype are estrogen receptor-positive (ER+), highly proliferative, resistant to standard therapies and have a poor prognosis. To better understand this subtype we compared DNA copy number aberrations (CNAs), DNA promoter methylation, gene expression profiles, and somatic mutations in nine selected genes, in 32 luminal B tumors with those observed in 156 BCs of the other molecular subtypes. Frequent CNAs included 8p11-p12 and 11q13.1-q13.2 amplifications, 7q11.22-q34, 8q21.12-q24.23, 12p12.3-p13.1, 12q13.11-q24.11, 14q21.1-q23.1, 17q11.1-q25.1, 20q11.23-q13.33 gains and 6q14.1-q24.2, 9p21.3-p24,3, 9q21.2, 18p11.31-p11.32 losses. A total of 237 and 101 luminal B-specific candidate oncogenes and tumor suppressor genes (TSGs) presented a deregulated expression in relation with their CNAs, including 11 genes previously reported associated with endocrine resistance. Interestingly, 88% of the potential TSGs are located within chromosome arm 6q, and seven candidate oncogenes are potential therapeutic targets. A total of 100 candidate oncogenes were validated in a public series of 5,765 BCs and the overexpression of 67 of these was associated with poor survival in luminal tumors. Twenty-four genes presented a deregulated expression in relation with a high DNA methylation level. FOXO3, PIK3CA and TP53 were the most frequent mutated genes among the nine tested. In a meta-analysis of next-generation sequencing data in 875 BCs, KCNB2 mutations were associated with luminal B cases while candidate TSGs MDN1 (6q15) and UTRN (6q24), were mutated in this subtype. In conclusion, we have reported luminal B candidate genes that may play a role in the development and/or hormone resistance of this aggressive subtype. 相似文献
7.
Background
Malignant fibrous histiocytomas (MFHs), or undifferentiated pleomorphic sarcomas, are in general high-grade tumours with extensive chromosomal aberrations. In order to identify recurrent chromosomal regions of gain and loss, as well as novel gene targets of potential importance for MFH development and/or progression, we have analysed DNA copy number changes in 33 MFHs using microarray-based comparative genomic hybridisation (array CGH).Principal findings
In general, the tumours showed numerous gains and losses of large chromosomal regions. The most frequent minimal recurrent regions of gain were 1p33-p32.3, 1p31.3-p31.2 and 1p21.3 (all gained in 58% of the samples), as well as 1q21.2-q21.3 and 20q13.2 (both 55%). The most frequent minimal recurrent regions of loss were 10q25.3-q26.11, 13q13.3-q14.2 and 13q14.3-q21.1 (all lost in 64% of the samples), as well as 2q36.3-q37.2 (61%), 1q41 (55%) and 16q12.1-q12.2 (52%). Statistical analyses revealed that gain of 1p33-p32.3 and 1p21.3 was significantly associated with better patient survival (P = 0.021 and 0.046, respectively). Comparison with similar array CGH data from 44 leiomyosarcomas identified seven chromosomal regions; 1p36.32-p35.2, 1p21.3-p21.1, 1q32.1-q42.13, 2q14.1-q22.2, 4q33-q34.3, 6p25.1-p21.32 and 7p22.3-p13, which were significantly different in copy number between the MFHs and leiomyosarcomas.Conclusions
A number of recurrent regions of gain and loss have been identified, some of which were associated with better patient survival. Several specific chromosomal regions with significant differences in copy number between MFHs and leiomyosarcomas were identified, and these aberrations may be used as additional tools for the differential diagnosis of MFHs and leiomyosarcomas. 相似文献8.
Jarkko Soronen Pirkka-Pekka Laurila Jussi Naukkarinen Ida Surakka Samuli Ripatti Matti Jauhiainen Vesa M Olkkonen Hannele Yki-Järvinen 《BMC medical genomics》2012,5(1):1-13
Background
To elucidate gene expression associated with copy number changes, we performed a genome-wide copy number and expression microarray analysis of 25 pairs of gastric tissues.Methods
We applied laser capture microdissection (LCM) to obtain samples for microarray experiments and profiled DNA copy number and gene expression using 244K CGH Microarray and Human Exon 1.0 ST Microarray.Results
Obviously, gain at 8q was detected at the highest frequency (70%) and 20q at the second (63%). We also identified molecular genetic divergences for different TNM-stages or histological subtypes of gastric cancers. Interestingly, the C20orf11 amplification and gain at 20q13.33 almost separated moderately differentiated (MD) gastric cancers from poorly differentiated (PD) type. A set of 163 genes showing the correlations between gene copy number and expression was selected and the identified genes were able to discriminate matched adjacent noncancerous samples from gastric cancer samples in an unsupervised two-way hierarchical clustering. Quantitative RT-PCR analysis for 4 genes (C20orf11, XPO5, PUF60, and PLOD3) of the 163 genes validated the microarray results. Notably, some candidate genes (MCM4 and YWHAZ) and its adjacent genes such as PRKDC, UBE2V2, ANKRD46, ZNF706, and GRHL2, were concordantly deregulated by genomic aberrations.Conclusions
Taken together, our results reveal diverse chromosomal region alterations for different TNM-stages or histological subtypes of gastric cancers, which is helpful in researching clinicopathological classification, and highlight several interesting genes as potential biomarkers for gastric cancer. 相似文献9.
Engler DA Gupta S Growdon WB Drapkin RI Nitta M Sergent PA Allred SF Gross J Deavers MT Kuo WL Karlan BY Rueda BR Orsulic S Gershenson DM Birrer MJ Gray JW Mohapatra G 《PloS one》2012,7(2):e30996
Ovarian cancer is the fifth leading cause of cancer death in women. Ovarian cancers display a high degree of complex genetic alterations involving many oncogenes and tumor suppressor genes. Analysis of the association between genetic alterations and clinical endpoints such as survival will lead to improved patient management via genetic stratification of patients into clinically relevant subgroups. In this study, we aim to define subgroups of high-grade serous ovarian carcinomas that differ with respect to prognosis and overall survival. Genome-wide DNA copy number alterations (CNAs) were measured in 72 clinically annotated, high-grade serous tumors using high-resolution oligonucleotide arrays. Two clinically annotated, independent cohorts were used for validation. Unsupervised hierarchical clustering of copy number data derived from the 72 patient cohort resulted in two clusters with significant difference in progression free survival (PFS) and a marginal difference in overall survival (OS). GISTIC analysis of the two clusters identified altered regions unique to each cluster. Supervised clustering of two independent large cohorts of high-grade serous tumors using the classification scheme derived from the two initial clusters validated our results and identified 8 genomic regions that are distinctly different among the subgroups. These 8 regions map to 8p21.3, 8p23.2, 12p12.1, 17p11.2, 17p12, 19q12, 20q11.21 and 20q13.12; and harbor potential oncogenes and tumor suppressor genes that are likely to be involved in the pathogenesis of ovarian carcinoma. We have identified a set of genetic alterations that could be used for stratification of high-grade serous tumors into clinically relevant treatment subgroups. 相似文献
10.
Background
The development and progression of hepatocellular carcinoma (HCC) is significantly correlated to the accumulation of genomic alterations. Array-based comparative genomic hybridization (array CGH) has been applied to a wide range of tumors including HCCs for the genome-wide high resolution screening of DNA copy number changes. However, the relevant chromosomal variations that play a central role in the development of HCC still are not fully elucidated.Methods
In present study, in order to further characterize the copy number alterations (CNAs) important to HCC development, we conducted a meta-analysis of four published independent array-CGH datasets including total 159 samples.Results
Eighty five significant gains (frequency ≥25%) were mostly mapped to five broad chromosomal regions including 1q, 6p, 8q, 17q and 20p, as well as two narrow regions 5p15.33 and 9q34.2-34.3. Eighty eight significant losses (frequency ≥25%) were most frequently present in 4q, 6q, 8p, 9p, 13q, 14q, 16q, and 17p. Significant correlations existed between chromosomal aberrations either located on the same chromosome or the different chromosomes. HCCs with different etiologies largely exhibited surprisingly similar profiles of chromosomal aberrations with only a few exceptions. Furthermore, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that the genes affected by these chromosomal aberrations were significantly enriched in 31 canonical pathways with the highest enrichment observed for antiviral immunity pathways.Conclusions
Taken together, our findings provide novel and important clues for the implications of antiviral immunity-related gene pathways in the pathogenesis and progression of HCC. 相似文献11.
Introduction
In breast cancer, the basal-like subtype has high levels of genomic instability relative to other breast cancer subtypes with many basal-like-specific regions of aberration. There is evidence that this genomic instability extends to smaller scale genomic aberrations, as shown by a previously described micro-deletion event in the PTEN gene in the Basal-like SUM149 breast cancer cell line.Methods
We sought to identify if small regions of genomic DNA copy number changes exist by using a high density, gene-centric Comparative Genomic Hybridizations (CGH) array on cell lines and primary tumors. A custom tiling array for CGH (244,000 probes, 200 bp tiling resolution) was created to identify small regions of genomic change, which was focused on previously identified basal-like-specific, and general cancer genes. Tumor genomic DNA from 94 patients and 2 breast cancer cell lines was labeled and hybridized to these arrays. Aberrations were called using SWITCHdna and the smallest 25% of SWITCHdna-defined genomic segments were called micro-aberrations (<64 contiguous probes, ∼ 15 kb).Results
Our data showed that primary tumor breast cancer genomes frequently contained many small-scale copy number gains and losses, termed micro-aberrations, most of which are undetectable using typical-density genome-wide aCGH arrays. The basal-like subtype exhibited the highest incidence of these events. These micro-aberrations sometimes altered expression of the involved gene. We confirmed the presence of the PTEN micro-amplification in SUM149 and by mRNA-seq showed that this resulted in loss of expression of all exons downstream of this event. Micro-aberrations disproportionately affected the 5′ regions of the affected genes, including the promoter region, and high frequency of micro-aberrations was associated with poor survival.Conclusion
Using a high-probe-density, gene-centric aCGH microarray, we present evidence of small-scale genomic aberrations that can contribute to gene inactivation. These events may contribute to tumor formation through mechanisms not detected using conventional DNA copy number analyses. 相似文献12.
Yang JJ Cho LY Ma SH Ko KP Shin A Choi BY Han DS Song KS Kim YS Chang SH Shin HR Kang D Yoo KY Park SK 《PloS one》2011,6(6):e21155
Background
CagA cellular interaction via activation of the ERK signaling pathway may be a starting point in the development of gastric cancer. This study aimed to evaluate whether genes involved in ERK downstream signaling pathways activated by CagA are susceptible genetic markers for gastric cancer.Methods
In the discovery phase, a total of 580 SNPs within +/−5 kbp of 30 candidate genes were genotyped to examine an association with gastric cancer risk in the Korean Multi-center Cancer Cohort (100 incident gastric cancer case-control sets). The most significant SNPs (raw or permutated p value<0.02) identified in the discovery analysis were re-evaluated in the extension phase using unconditional logistic regression model (400 gastric cancer case-control sets). Combined analyses including pooled- and meta-analysis were conducted to summarize all the results.Results
24 SNPs in eight genes (ERK, Dock180, C3G, Rap1, Src, CrkL, Mek and Crk) were significantly associated with gastric cancer risk in the individual SNP analyses in the discovery phase (p<0.05). In the extension analyses, ERK rs5999749, Dock180 rs4635002 and C3G rs7853122 showed marginally significant gene-dose effects for gastric cancer. Consistently, final combined analysis presented the SNPs as significantly associated with gastric cancer risk (OR = 1.56, [95% CI: 1.19–2.06], OR = 0.61, [95% CI: 0.43–0.87], OR = 0.59, [95% CI: 0.54–0.76], respectively).Conclusions
Our findings suggest that ERK rs5999749, Dock180 rs4635002 and C3G rs7853122 are genetic determinants in gastric carcinogenesis. 相似文献13.
Julie Earl Daniel Rico Enrique Carrillo-de-Santa-Pau Benjamín Rodríguez-Santiago Marinela Méndez-Pertuz Herbert Auer Gonzalo Gómez Herbert Barton Grossman David G Pisano Wolfgang A Schulz Luis A Pérez-Jurado Alfredo Carrato Dan Theodorescu Stephen Chanock Alfonso Valencia Francisco X Real 《BMC genomics》2015,16(1)
Background
Urothelial bladder cancer is a highly heterogeneous disease. Cancer cell lines are useful tools for its study. This is a comprehensive genomic characterization of 40 urothelial bladder carcinoma (UBC) cell lines including information on origin, mutation status of genes implicated in bladder cancer (FGFR3, PIK3CA, TP53, and RAS), copy number alterations assessed using high density SNP arrays, uniparental disomy (UPD) events, and gene expression.Results
Based on gene mutation patterns and genomic changes we identify lines representative of the FGFR3-driven tumor pathway and of the TP53/RB tumor suppressor-driven pathway. High-density array copy number analysis identified significant focal gains (1q32, 5p13.1-12, 7q11, and 7q33) and losses (i.e. 6p22.1) in regions altered in tumors but not previously described as affected in bladder cell lines. We also identify new evidence for frequent regions of UPD, often coinciding with regions reported to be lost in tumors. Previously undescribed chromosome X losses found in UBC lines also point to potential tumor suppressor genes. Cell lines representative of the FGFR3-driven pathway showed a lower number of UPD events.Conclusions
Overall, there is a predominance of more aggressive tumor subtypes among the cell lines. We provide a cell line classification that establishes their relatedness to the major molecularly-defined bladder tumor subtypes. The compiled information should serve as a useful reference to the bladder cancer research community and should help to select cell lines appropriate for the functional analysis of bladder cancer genes, for example those being identified through massive parallel sequencing.Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1450-3) contains supplementary material, which is available to authorized users. 相似文献14.
Yang JJ Cho LY Ko KP Shin A Ma SH Choi BY Han DS Song KS Kim YS Lee JY Han BG Chang SH Shin HR Kang D Yoo KY Park SK 《PloS one》2012,7(2):e31020
Objectives
To evaluate whether genes that encode CagA-interacting molecules (SRC, PTPN11, CRK, CRKL, CSK, c-MET and GRB2) are associated with gastric cancer risk and whether an interaction between these genes and phytoestrogens modify gastric cancer risk.Methods
In the discovery phase, 137 candidate SNPs in seven genes were analyzed in 76 incident gastric cancer cases and 322 matched controls from the Korean Multi-Center Cancer Cohort. Five significant SNPs in three genes (SRC, c-MET and CRK) were re-evaluated in 386 cases and 348 controls in the extension phase. Odds ratios (ORs) for gastric cancer risk were estimated adjusted for age, smoking, H. pylori seropositivity and CagA strain positivity. Summarized ORs in the total study population (462 cases and 670 controls) were presented using pooled- and meta-analysis. Plasma concentrations of phytoestrogens (genistein, daidzein, equol and enterolactone) were measured using the time-resolved fluoroimmunoassay.Results
SRC rs6122566, rs6124914, c-MET rs41739, and CRK rs7208768 showed significant genetic effects for gastric cancer in both the pooled and meta-analysis without heterogeneity (pooled OR = 3.96 [95% CI 2.05–7.65], 1.24 [95% CI = 1.01–1.53], 1.19 [95% CI = 1.01–1.41], and 1.37 [95% CI = 1.15–1.62], respectively; meta OR = 4.59 [95% CI 2.74–7.70], 1.36 [95% CI = 1.09–1.70], 1.20 [95% CI = 1.00–1.44], and 1.32 [95% CI = 1.10–1.57], respectively). Risk allele of CRK rs7208768 had a significantly increased risk for gastric cancer at low phytoestrogen levels (p interaction<0.05).Conclusions
Our findings suggest that SRC, c-MET and CRK play a key role in gastric carcinogenesis by modulating CagA signal transductions and interaction between CRK gene and phytoestrogens modify gastric cancer risk. 相似文献15.
Vui King Vincent-Chong Arif Anwar Lee Peng Karen-Ng Sok Ching Cheong Yi-Hsin Yang Padmaja Jayaprasad Pradeep Zainal Ariff Abdul Rahman Siti Mazlipah Ismail Zuraiza Mohamad Zaini Narayanan Prepageran Thomas George Kallarakkal Anand Ramanathan Nur Aaina Binti Mohd Mohayadi Nurul Shielawati Binti Mohamed Rosli Wan Mahadzir Wan Mustafa Mannil Thomas Abraham Keng Kiong Tay Rosnah Binti Zain 《PloS one》2013,8(2)
16.
Inês Crespo Hermínio T?o Ana Belen Nieto Olinda Rebelo Patrícia Domingues Ana Luísa Vital Maria del Carmen Patino Marcos Barbosa Maria Celeste Lopes Catarina Resende Oliveira Alberto Orfao María Dolores Tabernero 《PloS one》2012,7(9)
Background
Glioblastoma multiforme (GBM) displays multiple amplicons and homozygous deletions that involve relevant pathogenic genes and other genes whose role remains unknown.Methodology
Single-nucleotide polymorphism (SNP)-arrays were used to determine the frequency of recurrent amplicons and homozygous deletions in GBM (n = 46), and to evaluate the impact of copy number alterations (CNA) on mRNA levels of the genes involved.Principal Findings
Recurrent amplicons were detected for chromosomes 7 (50%), 12 (22%), 1 (11%), 4 (9%), 11 (4%), and 17 (4%), whereas homozygous deletions involved chromosomes 9p21 (52%) and 10q (22%). Most genes that displayed a high correlation between DNA CNA and mRNA levels were coded in the amplified chromosomes. For some amplicons the impact of DNA CNA on mRNA expression was restricted to a single gene (e.g., EGFR at 7p11.2), while for others it involved multiple genes (e.g., 11 and 5 genes at 12q14.1–q15 and 4q12, respectively). Despite homozygous del(9p21) and del(10q23.31) included multiple genes, association between these DNA CNA and RNA expression was restricted to the MTAP gene.Conclusions
Overall, our results showed a high frequency of amplicons and homozygous deletions in GBM with variable impact on the expression of the genes involved, and they contributed to the identification of other potentially relevant genes. 相似文献17.
Hassan Ashktorab Alejandro A. Sch?ffer Mohammad Daremipouran Duane T. Smoot Edward Lee Hassan Brim 《PloS one》2010,5(1)
Background
Colon cancer (CRC) development often includes chromosomal instability (CIN) leading to amplifications and deletions of large DNA segments. Epidemiological, clinical, and cytogenetic studies showed that there are considerable differences between CRC tumors from African Americans (AAs) and Caucasian patients. In this study, we determined genomic copy number aberrations in sporadic CRC tumors from AAs, in order to investigate possible explanations for the observed disparities.Methodology/Principal Findings
We applied genome-wide array comparative genome hybridization (aCGH) using a 105k chip to identify copy number aberrations in samples from 15 AAs. In addition, we did a population comparative analysis with aCGH data in Caucasians as well as with a widely publicized list of colon cancer genes (CAN genes). There was an average of 20 aberrations per patient with more amplifications than deletions. Analysis of DNA copy number of frequently altered chromosomes revealed that deletions occurred primarily in chromosomes 4, 8 and 18. Chromosomal duplications occurred in more than 50% of cases on chromosomes 7, 8, 13, 20 and X. The CIN profile showed some differences when compared to Caucasian alterations.Conclusions/Significance
Chromosome X amplification in male patients and chromosomes 4, 8 and 18 deletions were prominent aberrations in AAs. Some CAN genes were altered at high frequencies in AAs with EXOC4, EPHB6, GNAS, MLL3 and TBX22 as the most frequently deleted genes and HAPLN1, ADAM29, SMAD2 and SMAD4 as the most frequently amplified genes. The observed CIN may play a distinctive role in CRC in AAs. 相似文献18.
Background
Array-based comparative genomic hybridization (aCGH) is a high-throughput method for measuring genome-wide DNA copy number changes. Current aCGH methods have limited resolution, sensitivity and reproducibility. Microarrays for aCGH are available only for a few organisms and combination of aCGH data with expression data is cumbersome.Results
We present a novel method of using commercial oligonucleotide expression microarrays for aCGH, enabling DNA copy number measurements and expression profiles to be combined using the same platform. This method yields aCGH data from genomic DNA without complexity reduction at a median resolution of approximately 17,500 base pairs. Due to the well-defined nature of oligonucleotide probes, DNA amplification and deletion can be defined at the level of individual genes and can easily be combined with gene expression data.Conclusion
A novel method of gene resolution analysis of copy number variation (graCNV) yields high-resolution maps of DNA copy number changes and is applicable to a broad range of organisms for which commercial oligonucleotide expression microarrays are available. Due to the standardization of oligonucleotide microarrays, graCNV results can reliably be compared between laboratories and can easily be combined with gene expression data using the same platform. 相似文献19.
Gallegos Ruiz MI Floor K Roepman P Rodriguez JA Meijer GA Mooi WJ Jassem E Niklinski J Muley T van Zandwijk N Smit EF Beebe K Neckers L Ylstra B Giaccone G 《PloS one》2008,3(3):e0001722