微阵列比较基因组杂交技术诊断9p部分三体患儿一例

目的 确定1例生长发育迟缓、语言发育障碍患儿的核型,分析其染色体畸变与表型的相关性,探讨微阵列比较基因组杂交(array-based comparative genomic hybridization,array-CGH)在临床分子遗传学诊断中的应用及其优越性.方法 应用G显带对患儿及其父母进行核型分析,进一步采用array-CGH技术对患儿进行全基因组高分辨率扫描分析,确定其衍生染色体片段的来源.结果 G显带染色体分析显示患儿及其母亲均为inv(9)(p13q13)携带者,患儿13号染色体存在一衍生片段.array-CGH结果证实患儿衍生片段源自9号染色体短臂,确定为9p13.1-p24.3三体.患儿母亲array-CGH结果未见异常.结论 inv(9)(p13q13)与患儿异常表型无关,患儿的异常表型可归因于9p13.1-p24.3三体.同传统细胞遗传分析方法相比,array-CGH具有高分辨率和高精确性的优点.     

Application of bacterial artificial chromosome array-based comparative genomic hybridization and spectral karyotyping to the analysis of glioblastoma multiforme

Identification of genetic losses and gains is valuable in analysis of brain tumors. Locus-by-locus analyses have revealed correlations between prognosis and response to chemotherapy and loss or gain of specific genes and loci. These approaches are labor intensive and do not provide a global view of the genetic changes within the tumor cells. Bacterial artificial chromosome (BAC) arrays, which cover the genome with an average resolution of less than 1 MbP, allow defining the sum total of these genetic changes in a single comparative genomic hybridization (CGH) experiment. These changes are directly overlaid on the human genome sequence, thus providing the extent of the amplification or deletion, reflected by a megabase position, and gene content of the abnormal region. Although this array-based CGH approach (CGHa) seems to detect the extent of the genetic changes in tumors reliably, it has not been robustly tested. We compared genetic changes in four newly derived, early-passage glioma cell lines, using spectral karyotyping (SKY) and CGHa. Chromosome changes seen in cell lines under SKY analysis were also detected with CGHa. In addition, CGHa detected cryptic genetic gains and losses and resolved the nature of subtle marker chromosomes that could not be resolved with SKY, thus providing distinct advantages over previous technologies. There was remarkable general concordance between the CGHa results comparing the cell lines to the original tumor, except that the magnitude of the changes seen in the tumor sample was generally suppressed compared with the cell lines, a consequence of normal cells contaminating the tumor sample. CGHa revealed changes in cell lines that were not present in the original tumors and vice versa, even when analyzed at the earliest passage possible, which highlights the adaptation of the cells to in vitro culture. CGHa proved to be highly accurate and efficient for identifying genetic changes in tumor cells. This approach can accurately identify subtle, novel genetic abnormalities in tumors directly linked to the human genome sequence. CGHa far surpasses the resolution and information provided by conventional metaphase CGH, without relying on in vitro culture of tumors for metaphase spreads.     

Aneuploidy detection in single cells using DNA array-based comparative genomic hybridization

The use of metaphase comparative genomic hybridization (CGH) to screen all human chromosomes for aneuploidy in preimplantation embryos is hindered by the time required to perform the analysis. We report in this paper a novel approach to manufacture a DNA microarray for CGH for the detection of aneuploidy in single cells. We spotted human chromosome-specific libraries on glass slides that were depleted of repetitive sequences and tested our array CGH method in 14 experiments using either single male and/or single female lymphocytes. For the autosomes, the mean normalized ratios were all close to the expected ratio of 1.0 with overall 300/308 (97%) of the normalized ratios falling within the range 0.75 to 1.25. It was possible to deduce the correct copy number of the X chromosome in 13/14 (92.9%) separate array CGH experiments but the Y chromosome in only 4/14 (29%). We tested our microarray CGH method on a single fibroblast from each of three cell lines containing a specific chromosome aneuploidy (trisomy 13, 15 or 18) and in each case our microarray analysis was able to obtain a diagnosis based on the fact that the aneuploid chromosome gave the highest ratio (1.32, 1.27 and 1.27 respectively) with the ratios of all other chromosomes falling within the range 0.75-1.25. Requiring just 30 h, our method may be more suitable for PGD aneuploidy screening than metaphase CGH.     

Analysis of ovarian cancer cell lines using array-based comparative genomic hybridization

In this study, 23 ovarian cancer cell lines were screened using array-comparative genomic hybridization (aCGH) based on large-insert clones at about 1 Mb density from throughout the genome. The most frequent recurrent changes at the level of the chromosome arm were loss of chromosome 4 or 4q, loss of 18q and gain of 20 or 20q; other recurrent changes included losses of 6q, 8p, 9p, 11p, 15q, 16q, 17p, and 22q, and gain of 7q. Losses of 4q and 18q occurred together more often than expected. Evidence was found for two types of ovarian cancer, one typically near-triploid and characterized by a generally higher frequency of chromosomal changes (especially losses of 4p, 4q, 13q, 15q, 16p, 16q, 18p and 18q), and the other typically near-diploid/tetraploid and with fewer changes overall, but with relatively high frequencies of 9p loss, 9q gain, and 20p gain. Multiple novel changes (amplifications, homozygous deletions, discrete regions of gain or loss, small overlapping regions of change and frequently changed clones) were also detected, each of which might indicate the locations of oncogenes or tumour suppressor loci. For example, at least two regions of amplification on chromosome 11q13, one including cyclin D1 and the other the candidate oncogene PAK1, were found. Amplification on 11q22 near the progesterone receptor gene and a cluster of matrix metalloproteinase loci was also detected. Other potential oncogenes, which mapped to regions found by this study, included cyclin E and PIK3C2G. Candidate tumour suppressor genes in regions of loss included CDKN2C, SMAD4-interacting protein and RASSF2.     

Prenatal diagnosis of chromosomal abnormalities using array-based comparative genomic hybridization.

PURPOSE: This study was designed to evaluate the feasibility of using a targeted array-CGH strategy for prenatal diagnosis of genomic imbalances in a clinical setting of current pregnancies. METHODS: Women undergoing prenatal diagnosis were counseled and offered array-CGH (BCM V4.0) in addition to routine chromosome analysis. Array-CGH was performed with DNA directly from amniotic fluid cells with whole genome amplification, on chorionic villus samples with amplification as necessary, and on cultured cells without amplification. RESULTS: Ninety-eight pregnancies (56 amniotic fluid and 42 CVS specimens) were studied with complete concordance between karyotype and array results, including 5 positive cases with chromosomal abnormalities. There was complete concordance of array results for direct and cultured cell analysis in 57 cases tested by both methods. In 12 cases, the array detected copy number variation requiring testing of parental samples for optimal interpretation. Array-CGH results were available in an average of 6 and 16 days for direct and cultured cells, respectively. Patient acceptance of array-CGH testing was 74%. CONCLUSION: This study demonstrates the feasibility of using array-CGH for prenatal diagnosis, including reliance on direct analysis without culturing cells. Use of array-CGH should increase the detection of abnormalities relative to the risk, and is an option for an enhanced level of screening for chromosomal abnormalities in high risk pregnancies.     

Identification of consistent novel submegabase deletions in low-grade oligodendrogliomas using array-based comparative genomic hybridization

We have analyzed 18 low-grade gliomas using array comparative genomic hybridization (aCGH) with an average resolution of <500 kb. Because the majority of these tumors showed loss of chromosome arms 1p and 19q, we used custom statistical approaches to define submegabase hemizygous losses throughout the genome that correlated with 19q loss. As a result of this analysis, we have identified a approximately 550-kb region in 11q13 and a approximately 300-kb region in 13q12 that showed hemizygous deletion in virtually all the tumors analyzed regardless of their 1p/19q status. FISH analyses of interphase nuclei from the same tumors used for aCGH analysis confirmed the hemizygous loss. The identification of such specific changes provides a potentially very useful diagnostic marker for this subgroup of low-grade tumors. These regions of the genome define small numbers of candidate genes that are within the deletions. The aCGH analysis also defined the spectrum of gain and loss of genomic regions in low-grade oligodendrogliomas.     

1-Mb resolution array-based comparative genomic hybridization using a BAC clone set optimized for cancer gene analysis

Array-based comparative genomic hybridization (aCGH) is a recently developed tool for genome-wide determination of DNA copy number alterations. This technology has tremendous potential for disease-gene discovery in cancer and developmental disorders as well as numerous other applications. However, widespread utilization of a CGH has been limited by the lack of well characterized, high-resolution clone sets optimized for consistent performance in aCGH assays and specifically designed analytic software. We have assembled a set of approximately 4100 publicly available human bacterial artificial chromosome (BAC) clones evenly spaced at approximately 1-Mb resolution across the genome, which includes direct coverage of approximately 400 known cancer genes. This aCGH-optimized clone set was compiled from five existing sets, experimentally refined, and supplemented for higher resolution and enhancing mapping capabilities. This clone set is associated with a public online resource containing detailed clone mapping data, protocols for the construction and use of arrays, and a suite of analytical software tools designed specifically for aCGH analysis. These resources should greatly facilitate the use of aCGH in gene discovery.     

Genomewide array-based comparative genomic hybridization analysis of acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is typically associated with the t(15;17) that generates the PML-RARA fusion protein. Animal models have shown that although the fusion protein is necessary, it is insufficient for the development of APL, implying that additional mechanisms are responsible for full-blown leukemia. The mutation of specific genes has been implicated in leukemogenesis; however, alterations in gene copy number have not been well investigated. Here, we applied the genomewide array-comparative genomic hybridization technique to 30 APL clinical samples and 2 APL cell lines. It was found that (1) approximately half the clinical samples (14 of 30 APL cases) had no detectable chromosomal imbalances; and (2) the remaining 16 cases, including the cell lines, exhibited recurrent chromosomal imbalances, such as loss of 1p36, 2p11, 16p, and 17p, and gain of 8p, 8q, and 13q. These results suggest that chromosomal imbalances are largely absent in APL, although some nonrandom chromosomal imbalances could be linked to the development of APL in a limited number of cases.     

Diagnostic utility of array-based comparative genomic hybridization in a clinical setting

Array-based comparative genomic hybridization is a recently introduced technique for the detection of submicroscopic genomic imbalances (deletions or duplications) across the entire genome. To assess the potential utility of a widely available array-based comparative genomic hybridization platform that targets specific, clinically relevant, loci across the genome for cytogenetic diagnosis in a clinical setting, we reviewed the medical records of all 373 patients at Children's Hospital Boston who had normal chromosomal analysis and were tested with this targeted array-based comparative genomic hybridization over a 1-year period from November 1, 2004 to October 31, 2005. These patients were tested because of a suspicion of chromosomal abnormalities based on their clinical presentation. Thirty-six patients (9.7%) had abnormal array-based comparative genomic hybridization results. Twenty patients (5.4%) had potentially pathogenetic genomic imbalances and 16 patients (4.3%) had copy number variations that are not believed to be pathogenetic. Thirteen of 234 patients (5.6%) with mental retardation/global developmental delay, 10/114 patients (8.8%) with facial dysmorphism, 5/58 patients (8.6%) with multiple congenital anomalies, and 4/35 patients (11.4%) with both facial dysmorphism and multiple congenital anomalies had potentially pathogenetic genomic imbalances. Targeted array-based comparative genomic hybridization is a clinically available test that is useful in the evaluation of patients suspected of having chromosomal disorders. However, it is best used as an adjunct to chromosomal analysis when a clear genetic diagnosis is unavailable.     

Clinical application of array-based comparative genomic hybridization to define the relationship between multiple synchronous tumors.

Array-based comparative genomic hybridization (CGH) is a technique that allows genome wide screening of gains and losses in DNA copy number. In cases where multiple tumors are encountered, this genetic technique may prove useful in differentiating new primary tumors from recurrences. In this case report, we used array-based CGH to examine the genomic relationships among two leiomyosarcomas and two breast cancers in the same patient, three of which were diagnosed synchronously. Array-based CGH was performed on the four tumor samples using random prime amplified microdissected DNA. Samples were hybridized onto bacterial artificial chromosome arrays composed of approximately 2400 clones. Patterns of alterations within the tumors were compared and genetic alterations among the leiomyosarcomas and breast lesions were found. Overall, three distinct genetic profiles were observed. While the two leiomyosarcomas shared a similar pattern of genetic alterations, the two invasive breast lesions did not. The nearly identical pattern of genetic alterations belonging to the two metachronous leiomyosarcomas confirmed metastatic recurrence while the two different genetic profiles of the invasive ductal carcinomas suggest that the two lesions represented two distinct foci of multifocal disease rather than clonal extension of the primary tumor. We conclude that genetic analysis by array-based CGH can clearly elucidate the relationships between multiple tumors and may potentially serve as an important clinical tool.     

间变性大细胞淋巴瘤的阵列比较基因组杂交分析

目的 利用阵列比较基因组杂交(aCGH)技术探讨间变性大细胞淋巴瘤(ALCL)的分子遗传学异常.方法 采用免疫组织化学EnVision法及荧光原位杂交技术对25例ALCL进行间变性淋巴瘤激酶(ALK)蛋白及基因分子遗传学异常的检测;利用aCGH技术进行全基因组遗传学检测,并对检测结果与ALCL的ALK蛋白表达进行相关性分析.结果 25例ALCL中均有染色体片段的扩增/缺失,且扩增多于缺失.其中＞50％病例中存在染色体区域5p13.2、3q1.1、2q21.3、3p25.1、14q32.33、17q21.2的获得;30％ ～ 50％病例中存在染色体区域4q27、6p22.1、20p11.21、2q22.3、4q35.1、1p36.22、8p23.1、8p12、11q14.1、12q13.13、19p13.3的获得;36.0％ (9/25)及24.0％ (6/25)的ALCL病例中存在3q26.1及3q26.31染色体区域的缺失.染色体区域2q21.3、6p22.1及3p25.1的获得在ALK阳性与ALK阴性ALCL病例中差异有统计学意义(P＜0.05).结论 ALCL存在着较为复杂的分子遗传学变化,即遗传学不平衡性.其中,染色体片段的扩增多于缺失.位于2q21.3、6p22.1及3p25.1的遗传学不平衡在ALK阳性和ALK阴性ALCL之间存在显著差异,表明ALK阳性和阴性ALCL所涉及的遗传学异常不同,可能涉及不同的信号转导通路.     

Combined comparative genomic hybridization and genomic microarray for detection of gene amplifications in pulmonary artery intimal sarcomas and adrenocortical tumors

Identification of gene amplifications in human tumors is important for the understanding of tumorigenesis and may lead to discovery of diagnostic and prognostic markers. In this study, we used a microarray-based comparative genomic hybridization (CGH) technique, combined with conventional CGH, to identify gene amplifications in 43 tumors including eight pulmonary artery intimal sarcomas and 35 adrenocortical tumors. Conventional CGH revealed gains or amplifications of 12q13-q15 in six sarcomas and in two adrenocortical carcinomas. Using microarrays, we demonstrated that, among genes located on 12q13-q15, SAS/CDK4 were amplified in six sarcomas, and MDM2 and GLI in five and four sarcomas, respectively. The two adrenocortical tumors showed coamplifications of SAS/CDK4 and MDM2. Furthermore, PDGFRA (located on 4q12) amplification was identified in five sarcomas. Our data demonstrate: (1) amplifications of SAS/CDK4, MDM2, GLI, and PDGFRA are strongly associated with the tumorigenesis of pulmonary artery intimal sarcomas, whereas SAS/CDK4 and MDM2 coamplification may contribute to the progression of adrenocortical tumors; (2) microarray-based CGH is a useful tool for simultaneous detection of multiple gene amplifications, with a high sensitivity and resolution compared to that of conventional CGH.     

应用微阵列比较基因组杂交技术精确诊断不平衡染色体畸变

目的 探讨微阵列比较基因组杂交技术(array-based comparative genomic hybridization,array-CGH)在诊断不平衡染色体畸变中的应用价值.方法 选取4例常规G显带染色体核型分析未能确诊的不平衡染色体畸变病例,按照标准的Affymetrix SNP 6.0微阵列的操作手册进行杂交、洗涤及全基因组扫描,并通过相应的计算机软件分析结果.结果 通过array-CGH技术分析,明确了所有4例染色体不平衡畸变的诊断并且进行精确定位,其中对2例患者镜下染色体出现无法确定来源的额外条带进行了自身直接重复的确诊;对2例患者G显带无法识别的缺失合并重复的衍生染色体进行了精确诊断.结论 array-CGH技术在DNA水平上对染色体不平衡畸变的诊断具有独特的高分辨率、高敏感性和高特异性,并且能够精确定位,对染色体疾病作出基因型-表型关系的诊断具有重大的应用价值.     

微阵列比较基因组杂交技术检测先天性心脏畸形胎儿的隐藏基因组拷贝数变异

目的 检测1例先天性主动脉弓离断和室间隔缺损胎儿的基因组拷贝数变异(copy number variations,CNVs),寻找其致病的遗传学证据,探讨微阵列比较基因组杂交技术(array-based comparative genomic hybridization,array-CGH)在分子细胞遗传诊断中应用的可行性.方法 对该患儿脐血及其父母外周血进行常规G显带核型分析,发现胎儿核型为46,XX,t(7;9)(q12;q21),双亲核型正常.进而应用array-CGH芯片对患儿进行全基因组高分辨率扫描分析,采用荧光原位杂交技术(fluorescence in situ hybridization,FISH)对新发现的CNVs进行实验验证.结果 array-CGH分析发现胎儿基因组存在1个病理性亚显微结构的拷贝数变异:del(22)(q11.2)(17 370 128～19 790 009,2.42 Mb).FISH实验结果验证了此22q11.2微缺失的存在.结论 隐藏的22q11.2微缺失可能是此胎儿致病的原因;染色体平衡易位的先天缺陷胎儿可能会含有位于重排断裂点区域之外的亚显微结构基因组拷贝数变异;微阵列比较基因组杂交具有高分辨率、高通量和高准确性等优点,适用于亚显微基因组拷贝数变异的检测.     

微阵列比较基因组杂交技术检测先天性心脏畸形胎儿的隐藏基因组拷贝数变异

目的 检测1例先天性主动脉弓离断和室间隔缺损胎儿的基因组拷贝数变异(copy number variations,CNVs),寻找其致病的遗传学证据,探讨微阵列比较基因组杂交技术(array-based comparative genomic hybridization,array-CGH)在分子细胞遗传诊断中应用的可行性.方法 对该患儿脐血及其父母外周血进行常规G显带核型分析,发现胎儿核型为46,XX,t(7;9)(q12;q21),双亲核型正常.进而应用array-CGH芯片对患儿进行全基因组高分辨率扫描分析,采用荧光原位杂交技术(fluorescence in situ hybridization,FISH)对新发现的CNVs进行实验验证.结果 array-CGH分析发现胎儿基因组存在1个病理性亚显微结构的拷贝数变异:del(22)(q11.2)(17 370 128～19 790 009,2.42 Mb).FISH实验结果验证了此22q11.2微缺失的存在.结论 隐藏的22q11.2微缺失可能是此胎儿致病的原因;染色体平衡易位的先天缺陷胎儿可能会含有位于重排断裂点区域之外的亚显微结构基因组拷贝数变异;微阵列比较基因组杂交具有高分辨率、高通量和高准确性等优点,适用于亚显微基因组拷贝数变异的检测.

Abstract：

Objective To detect the copy number variation (CNV) of a fetus with interrupted aortic arch and ventricular septal defect, in order to explore the underlying genetic causes of the congenital malformation, and investigate the feasibility of array-based comparative genomic hybridization (array-CGH)in molecular cytogenetic diagnosis. Methods The whole genome of the fetus with de novo apparently balanced translocations [46, XX, t ( 7 ; 9 ) ( q12 ; q21 ) ] diagnosed by G-banding was scanned and analyzed by array-CGH, and the copy number variation was confirmed by fluorescence in situ hybridization (FISH).Results A pathologic submicroscopic CNV ldel(22) (q11. 2) (17 370 128-19 790 009,-2. 42 Mb)] was identified and mapped by array-CGH. FISH test confirmed the microdeletion detected by array-CGH.Conclusion The cryptic 22q11.2 deletion might be the reason leading to the congenital malformation of the fetus. This study provides evidence that apparently balanced translocations classified by conventional cytogenetic techniques may host additional submicroscopic CNVs which are not located at the breakpoints.Due to the high-resolution, high-throughput and high-accuracy, array-CGH is considered to be a powerful tool for submicroscopic CNVs detection.     

微阵列比较基因组杂交技术检测先天性心脏畸形胎儿的隐藏基因组拷贝数变异

目的 检测1例先天性主动脉弓离断和室间隔缺损胎儿的基因组拷贝数变异(copy number variations,CNVs),寻找其致病的遗传学证据,探讨微阵列比较基因组杂交技术(array-based comparative genomic hybridization,array-CGH)在分子细胞遗传诊断中应用的可行性.方法 对该患儿脐血及其父母外周血进行常规G显带核型分析,发现胎儿核型为46,XX,t(7;9)(q12;q21),双亲核型正常.进而应用array-CGH芯片对患儿进行全基因组高分辨率扫描分析,采用荧光原位杂交技术(fluorescence in situ hybridization,FISH)对新发现的CNVs进行实验验证.结果 array-CGH分析发现胎儿基因组存在1个病理性亚显微结构的拷贝数变异:del(22)(q11.2)(17 370 128～19 790 009,2.42 Mb).FISH实验结果验证了此22q11.2微缺失的存在.结论 隐藏的22q11.2微缺失可能是此胎儿致病的原因;染色体平衡易位的先天缺陷胎儿可能会含有位于重排断裂点区域之外的亚显微结构基因组拷贝数变异;微阵列比较基因组杂交具有高分辨率、高通量和高准确性等优点,适用于亚显微基因组拷贝数变异的检测.     

Gains, losses, and amplifications of genomic materials in primary gastric cancers analyzed by comparative genomic hybridization

By means of comparative genomic hybridization (CGH), we screened 58 primary gastric cancers for changes in copy number of DNA sequences. We detected frequent losses on Ip32-33 (21%), 3p21-23 (22%), 5q14-22 (36%), 6q16 (26%), 9p21-24 (22%), 16q (21%), 17p13 (48%), 18q11-21(33%), and 19(40%). Gains were most often noted at I p36 (22%), 8p22-23 (24%), 8q23-24 (29%), 11q12-13 (24%), 16p(21%), 20p (38%), 20q (45%), Xp21-22(38%), and Xq21-23 (43%), with high-level amplifications at 6p21(2%),7q31(10%), 8p22-23(5%), 8q23-24 (7%), 11q13(4%), 12p12-13(4%), 17q21(2%), 19q12-13(2%), and 20q13(2%). High-level amplification at 8p22-23 has never been reported in any other cancer type and its frequency was as high as that reported for the MYC, MET, and KRAS genes. We narrowed down the smallest common amplicon to 8p23.1 by reverse-painting FISH to prophase chromosomes. Southern blot analysis using one EST marker (D38736) clearly demonstrated that amplification of this exon-like sequence had occurred in all three tumors in which amplifications at 8p22-23 had been detected by CGH. Our data provide evidence for several, previously undescribed, genomic aberrations that are characteristic of gastric cancers.     

High-resolution array-based comparative genomic hybridization for distinguishing paraffin-embedded Spitz nevi and melanomas.

Distinguishing between Spitz nevus and melanoma presents a challenging task for clinicians and pathologists. Most of these lesions are submitted entirely in formalin for histologic analysis by conventional hematoxylin and eosin-stained sections, and fresh-frozen material for ancillary studies is rarely collected. Molecular techniques, such as comparative genomic hybridization (CGH), can detect chromosomal alterations in tumor DNA that differ between these 2 lesions. This study investigated the ability of high-resolution array-based CGH to serve as a diagnostic test in distinguishing Spitz nevus and melanoma using DNA isolated from formalin-fixed and paraffin-embedded samples. Two of 3 Spitz nevi exhibited no significant chromosomal alterations, while the third showed gain of the short arm of chromosome 11p. The latter finding has previously been described as characteristic of a subset of Spitz nevi. The 2 melanomas showed multiple copy number alterations characteristic of melanoma such as 1q amplification and chromosome 9 deletion. This study has shown the utility of array-based CGH as a potential molecular test in distinguishing Spitz nevus from melanoma. The assay is capable of using archival paraffin-embedded, formalin-fixed material; is technically easier to perform as compared with conventional CGH; is more sensitive than conventional CGH in being able to detect focal alterations; and can detect copy number alterations even with relatively small amounts of lesional tissue as is typical of many skin tumors.     

DNA copy number aberrations in intestinal-type gastric cancer revealed by array-based comparative genomic hybridization

Genomic instability can be divided into 2 categories: chromosomal instability (CIN) and microsatellite instability (MSI). CIN has been linked to aneuploidy and chromosomal aberrations, and high-level loss of heterozygosity (LOH-H) has been suggested to be an indicator of CIN. High-level MSI (MSI-H), which results from nonfunctional mismatch repair, has previously been suggested to be mutually exclusive with CIN. Four MSI-H and three LOH-H primary gastric tumors of intestinal histology were used for copy number analysis by array-based comparative genomic hybridization (aCGH) with 13,000 cDNA targets. The MSI-H group showed fewer gains (0-12, average 4.5) and losses (0-10, average 2.5) per tumor as compared to the LOH-H group (9-15 gains, average 11.6 and 1-6 losses, average 4). Two MSI-H tumors did not show any copy number changes and one showed only gains of whole chromosomes. The most common alterations were gains of 20q (5/7 samples), 1q, 8, and 10p (3/7 samples) and losses of 1p and 5p (3/7 samples). The minimal amplified regions in 1q and 20q were localized to 1q21.1 approximately q21.2, 1q21.3, 20q11.2, 20q13.12, and 20q13.3 approximately qter. No copy number change was found to be specific for MSI-H or LOH-H. The results suggest that the LOH-H phenotype revealed by microsatellite analysis predicts reliably copy number abnormalities on aCGH and that a subset of MSI-H and all LOH-H tumors share the CIN phenotype.