共查询到20条相似文献,搜索用时 31 毫秒
1.
Galen Hostetter Su Young Kim Stephanie Savage Gerald C. Gooden Michael Barrett Jian Zhang Lalitamba Alla April Watanabe Janine Einspahr Anil Prasad Brian J. Nickoloff John Carpten Jeffrey Trent David Alberts Michael Bittner 《Nucleic acids research》2010,38(2):e9
Genomic technologies, such as array comparative genomic hybridization (aCGH), increasingly offer definitive gene dosage profiles in clinical samples. Historically, copy number profiling was limited to large fresh-frozen tumors where intact DNA could be readily extracted. Genomic analyses of pre-neoplastic tumors and diagnostic biopsies are often limited to DNA processed by formalin-fixation and paraffin-embedding (FFPE). We present specialized protocols for DNA extraction and processing from FFPE tissues utilizing DNase processing to generate randomly fragmented DNA. The protocols are applied to FFPE clinical samples of varied tumor types, from multiple institutions and of varied block age. Direct comparative analyses with regression coefficient were calculated on split-sample (portion fresh/portion FFPE) of colorectal tumor samples. We show equal detection of a homozygous loss of SMAD4 at the exon-level in the SW480 cell line and gene-specific alterations in the split tumor samples. aCGH application to a set of archival FFPE samples of skin squamous cell carcinomas detected a novel hemizygous deletion in INPP5A on 10q26.3. Finally we present data on derivative of log ratio, a particular sensitive detector of measurement variance, for 216 sequential hybridizations to assess protocol reliability over a wide range of FFPE samples. 相似文献
2.
Cancer progression is often driven by an accumulation of genetic changes but also accompanied by increasing genomic instability. These processes lead to a complicated landscape of copy number alterations (CNAs) within individual tumors and great diversity across tumor samples. High resolution array-based comparative genomic hybridization (aCGH) is being used to profile CNAs of ever larger tumor collections, and better computational methods for processing these data sets and identifying potential driver CNAs are needed. Typical studies of aCGH data sets take a pipeline approach, starting with segmentation of profiles, calls of gains and losses, and finally determination of frequent CNAs across samples. A drawback of pipelines is that choices at each step may produce different results, and biases are propagated forward. We present a mathematically robust new method that exploits probe-level correlations in aCGH data to discover subsets of samples that display common CNAs. Our algorithm is related to recent work on maximum-margin clustering. It does not require pre-segmentation of the data and also provides grouping of recurrent CNAs into clusters. We tested our approach on a large cohort of glioblastoma aCGH samples from The Cancer Genome Atlas and recovered almost all CNAs reported in the initial study. We also found additional significant CNAs missed by the original analysis but supported by earlier studies, and we identified significant correlations between CNAs. 相似文献
3.
Artur Gurgul Kacper Żukowski Brygida Ślaska Ewelina Semik Klaudia Pawlina Tomasz Ząbek Igor Jasielczuk Monika Bugno-Poniewierska 《Journal of applied genetics》2014,55(3):353-363
In recent years, characterization of a copy number variation (CNV) of the genomic DNA has provided evidence for the relationship of this type of genetic variation with the occurrence of a broad spectrum of diseases, including cancer lesions. Copy number variants (CNVs) also occur in the genomes of healthy individuals as a result of abnormal recombination processes in germ cells and have a hereditary character contributing to the natural genetic diversity. Recent image analysis methods and advanced computational techniques allow for identification of CNVs using SNPs genotyping microarrays based on the analysis of signal intensity observed for markers located in the specific genomic regions. In this study we used CanineHD BeadChip assay (Illumina) to identify both natural and cancer-induced CNVs in the genomes of different dog breeds and in different cancer types occurring in this species. The obtained results showed that structural aberrations are a common phenomenon arising during a tumor progression and are more complex and widespread in tumors of mesenchymal tissue origin than in epithelial tissue originating tumors. The tumor derived CNVs, in comparison to healthy samples, were characterized by larger sizes of regions, higher number of amplifications, and in some cases encompassed genes with potential effect on tumor progression. 相似文献
4.
Array-based comparative genomic hybridization (aCGH) enables the measurement of DNA copy number across thousands of locations in a genome. The main goals of analyzing aCGH data are to identify the regions of copy number variation (CNV) and to quantify the amount of CNV. Although there are many methods for analyzing single-sample aCGH data, the analysis of multi-sample aCGH data is a relatively new area of research. Further, many of the current approaches for analyzing multi-sample aCGH data do not appropriately utilize the additional information present in the multiple samples. We propose a procedure called the Fused Lasso Latent Feature Model (FLLat) that provides a statistical framework for modeling multi-sample aCGH data and identifying regions of CNV. The procedure involves modeling each sample of aCGH data as a weighted sum of a fixed number of features. Regions of CNV are then identified through an application of the fused lasso penalty to each feature. Some simulation analyses show that FLLat outperforms single-sample methods when the simulated samples share common information. We also propose a method for estimating the false discovery rate. An analysis of an aCGH data set obtained from human breast tumors, focusing on chromosomes 8 and 17, shows that FLLat and Significance Testing of Aberrant Copy number (an alternative, existing approach) identify similar regions of CNV that are consistent with previous findings. However, through the estimated features and their corresponding weights, FLLat is further able to discern specific relationships between the samples, for example, identifying 3 distinct groups of samples based on their patterns of CNV for chromosome 17. 相似文献
5.
Kyle E McElroy Stefan Müller Dunja K Lamatsch Laura Bankers Peter D Fields Joseph R Jalinsky Joel Sharbrough Jeffrey L Boore John M Logsdon Jr Maurine Neiman 《Molecular biology and evolution》2021,38(9):3581
How does asexual reproduction influence genome evolution? Although is it clear that genomic structural variation is common and important in natural populations, we know very little about how one of the most fundamental of eukaryotic traits—mode of genomic inheritance—influences genome structure. We address this question with the New Zealand freshwater snail Potamopyrgus antipodarum, which features multiple separately derived obligately asexual lineages that coexist and compete with otherwise similar sexual lineages. We used whole-genome sequencing reads from a diverse set of sexual and asexual individuals to analyze genomic abundance of a critically important gene family, rDNA (the genes encoding rRNAs), that is notable for dynamic and variable copy number. Our genomic survey of rDNA in P. antipodarum revealed two striking results. First, the core histone and 5S rRNA genes occur between tandem copies of the 18S–5.8S–28S gene cluster, a unique architecture for these crucial gene families. Second, asexual P. antipodarum harbor dramatically more rDNA–histone copies than sexuals, which we validated through molecular and cytogenetic analysis. The repeated expansion of this genomic region in asexual P. antipodarum lineages following distinct transitions to asexuality represents a dramatic genome structural change associated with asexual reproduction—with potential functional consequences related to the loss of sexual reproduction. 相似文献
6.
Identification of cancer genes using a statistical framework for multiexperiment analysis of nondiscretized array CGH data
下载免费PDF全文
![点击此处可从《Nucleic acids research》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Klijn C Holstege H de Ridder J Liu X Reinders M Jonkers J Wessels L 《Nucleic acids research》2008,36(2):e13
Tumor formation is in part driven by DNA copy number alterations (CNAs), which can be measured using microarray-based Comparative Genomic Hybridization (aCGH). Multiexperiment analysis of aCGH data from tumors allows discovery of recurrent CNAs that are potentially causal to cancer development. Until now, multiexperiment aCGH data analysis has been dependent on discretization of measurement data to a gain, loss or no-change state. Valuable biological information is lost when a heterogeneous system such as a solid tumor is reduced to these states. We have developed a new approach which inputs nondiscretized aCGH data to identify regions that are significantly aberrant across an entire tumor set. Our method is based on kernel regression and accounts for the strength of a probe's signal, its local genomic environment and the signal distribution across multiple tumors. In an analysis of 89 human breast tumors, our method showed enrichment for known cancer genes in the detected regions and identified aberrations that are strongly associated with breast cancer subtypes and clinical parameters. Furthermore, we identified 18 recurrent aberrant regions in a new dataset of 19 p53-deficient mouse mammary tumors. These regions, combined with gene expression microarray data, point to known cancer genes and novel candidate cancer genes. 相似文献
7.
Genetic architecture of sexual and asexual populations of the aphid Rhopalosiphum padi based on allozyme and microsatellite markers 总被引:7,自引:0,他引:7
Cyclical parthenogens, including aphids, are attractive models for comparing the genetic outcomes of sexual and asexual reproduction, which determine their respective evolutionary advantages. In this study, we examined how reproductive mode shapes genetic structure of sexual (cyclically parthenogenetic) and asexual (obligately parthenogenetic) populations of the aphid Rhopalosiphum padi by comparing microsatellite and allozyme data sets. Allozymes showed little polymorphism, confirming earlier studies with these markers. In contrast, microsatellite loci were highly polymorphic and showed patterns very discordant from allozyme loci. In particular, microsatellites revealed strong heterozygote excess in asexual populations, whereas allozymes showed heterozygote deficits. Various hypotheses are explored that could account for the conflicting results of these two types of genetic markers. A strong differentiation between reproductive modes was found with both types of markers. Microsatellites indicated that sexual populations have high allelic polymorphism and heterozygote deficits (possibly because of population subdivision, inbreeding or selection). Little geographical differentiation was found among sexual populations confirming the large dispersal ability of this aphid. In contrast, asexual populations showed less allelic polymorphism but high heterozygosity at most loci. Two alternative hypotheses are proposed to explain this heterozygosity excess: allele sequence divergence during long-term asexuality or hybrid origin of asexual lineages. Clonal diversity of asexual lineages of R. padi was substantial suggesting that they could have frozen genetic diversity from the pool of sexual lineages. Several widespread asexual genotypes were found to persist through time, as already seen in other aphid species, a feature seemingly consistent with the general-purpose genotype hypothesis. 相似文献
8.
Characterization of a canine homolog of human Aichivirus 总被引:1,自引:0,他引:1
Kapoor A Simmonds P Dubovi EJ Qaisar N Henriquez JA Medina J Shields S Lipkin WI 《Journal of virology》2011,85(21):11520-11525
Many of our fatal "civilization" infectious diseases have arisen from domesticated animals. Although picornaviruses infect most mammals, infection of a companion animal is not known. Here we describe the identification and genomic characterization of the first canine picornavirus. Canine kobuvirus (CKoV), identified in stool samples from dogs with diarrhea, has a genomic organization typical of a picornavirus and encodes a 2,469-amino-acid polyprotein flanked by 5' and 3' untranslated regions. Comparative phylogenetic analysis using various structural and nonstructural proteins of CKoV confirmed it as the animal virus homolog most closely related to human Aichivirus (AiV). Bayesian Markov chain Monte Carlo analysis suggests a mean recent divergence time of CKoV and AiV within the past 20 to 50 years, well after the domestication of canines. The discovery of CKoV provides new insights into the origin and evolution of AiV and the species specificity and pathogenesis of kobuviruses. 相似文献
9.
González LM Sanz-Esponera J Saez C Alvarez T Sierra E Sanz-Ortega J 《Histology and histopathology》2003,18(1):1-5
We report a case of an esophageal collision tumor composed of adenocarcinoma and oat cell carcinoma. Both tumors appeared to arise from dysplastic Barrett's mucosae in a 75-year-old man. Immunohistochemical stains and electron microscopy demonstrated a separate identity for each of the tumors in collision. Molecular analysis of microsatellite regions was performed in different microdissected areas. Identical loss of heterozygosity (LOH) at 9p21 and 17p13 was determined in the three different microdissected areas of the adenocarcinoma component. LOH was not determined in any area of the oat cell carcinoma. This is the first study that analyzes the allele status of an esophageal collision tumor. Our findings suggest a biclonal origin for both components of the collision tumor. 相似文献
10.
Craig JM Vena N Ramkissoon S Idbaih A Fouse SD Ozek M Sav A Hill DA Margraf LR Eberhart CG Kieran MW Norden AD Wen PY Loda M Santagata S Ligon KL Ligon AH 《PloS one》2012,7(6):e38881
Whole-genome copy number analysis platforms, such as array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) arrays, are transformative research discovery tools. In cancer, the identification of genomic aberrations with these approaches has generated important diagnostic and prognostic markers, and critical therapeutic targets. While robust for basic research studies, reliable whole-genome copy number analysis has been unsuccessful in routine clinical practice due to a number of technical limitations. Most important, aCGH results have been suboptimal because of the poor integrity of DNA derived from formalin-fixed paraffin-embedded (FFPE) tissues. Using self-hybridizations of a single DNA sample we observed that aCGH performance is significantly improved by accurate DNA size determination and the matching of test and reference DNA samples so that both possess similar fragment sizes. Based on this observation, we developed a novel DNA fragmentation simulation method (FSM) that allows customized tailoring of the fragment sizes of test and reference samples, thereby lowering array failure rates. To validate our methods, we combined FSM with Universal Linkage System (ULS) labeling to study a cohort of 200 tumor samples using Agilent 1 M feature arrays. Results from FFPE samples were equivalent to results from fresh samples and those available through the glioblastoma Cancer Genome Atlas (TCGA). This study demonstrates that rigorous control of DNA fragment size improves aCGH performance. This methodological advance will permit the routine analysis of FFPE tumor samples for clinical trials and in daily clinical practice. 相似文献
11.
Oligonucleotide array comparative genomic hybridization (aCGH) was applied on fifteen gastric cancer (GCA) samples to reveal information of DNA copy number changes at an exon-level resolution. Twelve of the samples represented the intestinal (IGCA) and three the diffuse (DGCA) type of GCA. The samples had previously been assessed for genetic stability by microsatellite analysis and categorized into microsatellite phenotypes according to the type of alterations. As compared to our previous results obtained using cDNA platforms, the oligonucleotide platforms revealed more aberrations per sample (0-45 vs. 0-22). A total of 22 amplifications were detected by the oligonucleotide arrays. Ten of the amplicons had also been detected on the cDNA platform, but five of them spanned only one or a few cDNA clones, thus resembling apparent outliers. Two tumors showed five or more amplifications by oligonucleotide aCGH, suggesting the presence of an amplifier phenotype. The amplifications occurred irrespective of the microsatellite phenotypes. None of the DGCA tumors showed more than one aberration, whereas the IGCA tumors showed several aberrations. The increased resolution of the oligonucleotide arrays enabled the detection of amplicon boundaries at gene level, allowing, e.g., the determination of the 17q12 core amplicon and interstitial losses within the 8p23.1-->p22 and 20q13.2-->q13.1 amplifications. Previously no losses have been reported within amplified regions in GCA. In addition to novel amplified regions, the oligonucleotide array results describe novel targets for amplicons at 8p11 (SFRP1), 11p12 (LRRC4C), and 19q13.2 (CEACAM6). 相似文献
12.
Elisa Boldrin Enrica Rumiato Matteo Fassan Rocco Cappellesso Massimo Rugge Vanna Chiarion-Sileni Alberto Ruol Rita Alfieri Matteo Cagol Carlo Castoro Alberto Amadori Daniela Saggioro 《PloS one》2015,10(1)
BackgroundDevelopment of novel therapeutic drugs and regimens for cancer treatment has led to improvements in patient long-term survival. This success has, however, been accompanied by the increased occurrence of second primary cancers. Indeed, patients who received regional radiotherapy for Hodgkin’s Lymphoma (HL) or breast cancer may develop, many years later, a solid metachronous tumor in the irradiated field. Despite extensive epidemiological studies, little information is available on the genetic changes involved in the pathogenesis of these solid therapy-related neoplasms.MethodsUsing microsatellite markers located in 7 chromosomal regions frequently deleted in sporadic esophageal cancer, we investigated loss of heterozygosity (LOH) and microsatellite instability (MSI) in 46 paired (normal and tumor) samples. Twenty samples were of esophageal carcinoma developed in HL or breast cancer long-term survivors: 14 squamous cell carcinomas (ESCC) and 6 adenocarcinomas (EADC), while 26 samples, used as control, were of sporadic esophageal cancer (15 ESCC and 11 EADC).ResultsWe found that, though the overall LOH frequency at the studied chromosomal regions was similar among metachronous and sporadic tumors, the latter exhibited a statistically different higher LOH frequency at 17q21.31 (p = 0.018). By stratifying for tumor histotype we observed that LOH at 3p24.1, 5q11.2 and 9p21.3 were more frequent in ESCC than in EADC suggesting a different role of the genetic determinants located nearby these regions in the development of the two esophageal cancer histotypes.ConclusionsAltogether, our results strengthen the genetic diversity among ESCC and EADC whether they occurred spontaneously or after therapeutic treatments. The presence of histotype-specific alterations in esophageal carcinoma arisen in HL or breast cancer long-term survivors suggests that their transformation process, though the putative different etiological origin, may retrace sporadic ESCC and EADC carcinogenesis. 相似文献
13.
Array comparative genomic hybridization (aCGH) is a laboratory technique to measure chromosomal copy number changes. A clear biological interpretation of the measurements is obtained by mapping these onto an ordinal scale with categories loss/normal/gain of a copy. The pattern of gains and losses harbors a level of tumor specificity. Here, we present WECCA (weighted clustering of called aCGH data), a method for weighted clustering of samples on the basis of the ordinal aCGH data. Two similarities to be used in the clustering and particularly suited for ordinal data are proposed, which are generalized to deal with weighted observations. In addition, a new form of linkage, especially suited for ordinal data, is introduced. In a simulation study, we show that the proposed cluster method is competitive to clustering using the continuous data. We illustrate WECCA using an application to a breast cancer data set, where WECCA finds a clustering that relates better with survival than the original one. 相似文献
14.
Stacia M. DeSantis E. Andrés Houseman Brent A. Coull David N. Louis Gayatry Mohapatra Rebecca A. Betensky 《Biometrics》2009,65(4):1296-1305
Summary Array CGH is a high‐throughput technique designed to detect genomic alterations linked to the development and progression of cancer. The technique yields fluorescence ratios that characterize DNA copy number change in tumor versus healthy cells. Classification of tumors based on aCGH profiles is of scientific interest but the analysis of these data is complicated by the large number of highly correlated measures. In this article, we develop a supervised Bayesian latent class approach for classification that relies on a hidden Markov model to account for the dependence in the intensity ratios. Supervision means that classification is guided by a clinical endpoint. Posterior inferences are made about class‐specific copy number gains and losses. We demonstrate our technique on a study of brain tumors, for which our approach is capable of identifying subsets of tumors with different genomic profiles, and differentiates classes by survival much better than unsupervised methods. 相似文献
15.
Henry M. Wood Ornella Belvedere Caroline Conway Catherine Daly Rebecca Chalkley Melissa Bickerdike Claire McKinley Phil Egan Lisa Ross Bruce Hayward Joanne Morgan Leslie Davidson Ken MacLennan Thian K. Ong Kostas Papagiannopoulos Ian Cook David J. Adams Graham R. Taylor Pamela Rabbitts 《Nucleic acids research》2010,38(14):e151
The use of next-generation sequencing technologies to produce genomic copy number data has recently been described. Most approaches, however, reply on optimal starting DNA, and are therefore unsuitable for the analysis of formalin-fixed paraffin-embedded (FFPE) samples, which largely precludes the analysis of many tumour series. We have sought to challenge the limits of this technique with regards to quality and quantity of starting material and the depth of sequencing required. We confirm that the technique can be used to interrogate DNA from cell lines, fresh frozen material and FFPE samples to assess copy number variation. We show that as little as 5 ng of DNA is needed to generate a copy number karyogram, and follow this up with data from a series of FFPE biopsies and surgical samples. We have used various levels of sample multiplexing to demonstrate the adjustable resolution of the methodology, depending on the number of samples and available resources. We also demonstrate reproducibility by use of replicate samples and comparison with microarray-based comparative genomic hybridization (aCGH) and digital PCR. This technique can be valuable in both the analysis of routine diagnostic samples and in examining large repositories of fixed archival material. 相似文献
16.
Amplifying small amounts of tumor DNA allows detection of DNA copy number abberations with array-CGH
Array comparative genomic hybridization (aCGH) is a powerful tool to detect relative DNA copy number at a resolution limited only by the coverage of bacterial artificial chromosomes (BACs) used to print the genomic array. The amount of DNA needed to perform a reliable aCGH analysis has been a limiting factor, especially on minute tissue samples where limited DNA is available. Here we report a simple, highly sensitive and reliable aCGH method to analyze samples of no more than 1 ng genomic DNA. The speed and simplicity of the technique are ideal for studies on small clinical samples such as needle biopsies. 相似文献
17.
F Delmotte N Leterme J Bonhomme C Rispe J C Simon 《Proceedings. Biological sciences / The Royal Society》2001,268(1483):2291-2299
Cyclical parthenogens, including aphids, are important models for studying the evolution of sex. However, little is known about transitions to asexuality in aphids, although the mode of origin of asexual lineages has important consequences for their level of genetic diversity, ecological adaptability and the outcome of competition with their sexual relatives. Thus, we surveyed nuclear, mitochondrial and biological data obtained on cyclical and obligate parthenogens of the bird cherry-oat aphid, Rhopalosiphum padi (L), to investigate the frequency of transitions from sexuality to permanent asexuality. Many instances of asexual lineages retaining the ability to produce males are known in aphids, so particular attention was paid to the existence of occasional matings between females from sexual lineages and males produced by asexual lineages, which have the potential to produce new asexual lineages. Phylogenetic inference based on microsatellite and mitochondrial data indicates at least three independent origins of asexuality in R. padi, yielding the strongest evidence to date for multiple origins of asexuality in an aphid. Moreover, several lines of evidence demonstrate that transitions to asexuality result from two mechanisms: a complete spontaneous loss of sex and repeated gene flow from essentially asexual lineages into sexual ones. 相似文献
18.
Zuccari DA Castro R Gavioli AF Mancini UM Frade CS Leonel C 《Genetics and molecular research : GMR》2012,11(1):153-165
Caveolin-1 (Cav-1) is a structural protein present in invaginations of the cell membrane. In human breast cancer, the cav-1 gene is believed to be a tumor suppressor gene associated with inhibition of tumor metastasis. However, little is known about its expression, regulation and function in canine mammary tumors. Expression levels of cav-1 were investigated using real-time PCR and immunohistochemical detection with an anti-human Cav-1 antibody. Gene expression stability of different samples was analyzed using the geNorm software. Mammary tumors from 51 female dogs were compared to normal mammary tissue from 10 female dogs. Malignant mammary cells showed a loss of Cav-1 expression by quantitative RT-PCR and weak Cav-1 staining by immunohistochemistry compared to normal mammary gland tissue. There was a significant relationship between outcome and immunostaining as well as with tumor size, indicating that caveolin subexpression has a positive predictive value and is related to higher survival and smaller tumor size. Our findings indicate that Cav-1 is a potential prognostic marker for canine mammary tumors. 相似文献
19.
Despite recent technological advances in DNA sequencing, incomplete coverage remains to be an issue in population genomics, in particular for studies that include ancient samples. Here, we describe an approach to estimate population divergence times for non-overlapping sequence data that is based on probabilities of different genealogical topologies under a structured coalescent model. We show that the approach can be adapted to accommodate common problems such as sequencing errors and postmortem nucleotide misincorporations, and we use simulations to investigate biases involved with estimating genealogical topologies from empirical data. The approach relies on three reference genomes and should be particularly useful for future analysis of genomic data that comprise of nonoverlapping sets of sequences, potentially from different points in time. We applied the method to shotgun sequence data from an ancient wolf together with extant dogs and wolves and found striking resemblance to previously described fine-scale population structure among dog breeds. When comparing modern dogs to four geographically distinct wolves, we find that the divergence time between dogs and an Indian wolf is smallest, followed by the divergence times to a Chinese wolf and a Spanish wolf, and a relatively long divergence time to an Alaskan wolf, suggesting that the origin of modern dogs is somewhere in Eurasia, potentially southern Asia. We find that less than two-thirds of all loci in the boxer and poodle genomes are more similar to each other than to a modern gray wolf and that--assuming complete isolation without gene flow--the divergence time between gray wolves and modern European dogs extends to 3,500 generations before the present, corresponding to approximately 10,000 years ago (95% confidence interval [CI]: 9,000-13,000). We explicitly study the effect of gene flow between dogs and wolves on our estimates and show that a low rate of gene flow is compatible with an even earlier domestication date ~30,000 years ago (95% CI: 15,000-90,000). This observation is in agreement with recent archaeological findings and indicates that human behavior necessary for domestication of wild animals could have appeared much earlier than the development of agriculture. 相似文献
20.
To MD Quigley DA Mao JH Del Rosario R Hsu J Hodgson G Jacks T Balmain A 《Molecular cancer research : MCR》2011,9(10):1339-1345
Alterations in DNA copy number contribute to the development and progression of cancers and are common in epithelial tumors. We have used array Comparative Genomic Hybridization (aCGH) to visualize DNA copy number alterations across the genomes of lung tumors in the Kras(LA2) model of lung cancer. Copy number gain involving the Kras locus, as focal amplification or whole chromosome gain, is the most common alteration in these tumors and with a prevalence that increased significantly with increasing tumor size. Furthermore, Kras amplification was the only major genomic event among the smallest lung tumors, suggesting that this alteration occurs early during the development of mutant Kras-driven lung cancers. Recurring gains and deletions of other chromosomes occur progressively more frequently among larger tumors. These results are in contrast to a previous aCGH analysis of lung tumors from Kras(LA2) mice on a mixed genetic background, in which relatively few DNA copy number alterations were observed regardless of tumor size. Our model features the Kras(LA2) allele on the inbred FVB/N mouse strain, and in this genetic background, there is a highly statistically significant increase in level of genomic instability with increasing tumor size. These data suggest that recurring DNA copy alterations are important for tumor progression in the Kras(LA2) model of lung cancer and that the requirement for these alterations may be dependent on the genetic background of the mouse strain. 相似文献