PPM1D is a potential target for 17q gain in neuroblastoma

Neuroblastomas (NBs) show complex patterns of genetic abnormalities, which may include amplification of the MYCN gene, deletion of 1p, or a gain of DNA at 17q, the last being the most frequent observation in NB tumors. However, the specific genes and the molecular mechanisms responsible for development and progression of NB remain poorly understood. We investigated aberrations of DNA copy number in 25 NB cell lines using comparative genomic hybridization and identified a minimal common region of gain at 17q23. Although gain of distal 17q is the most powerful genetic predictor of adverse outcome currently available for patients with NB, thus far, no potential target genes have been reported for that region. Therefore, we defined the 17q23 amplicon in detail and determined expression levels of 15 genes located within the smallest region of overlap observed among our NB cell lines to identify the most likely target gene(s). Among them, seven (CLTC, VMP1, delta-tubulin, RPS6KB1, FLJ22087, APPBP2, and PPM1D) were consistently overexpressed through increases in regional copy number. Analysis of expression levels of those seven genes in 32 primary NB tumors revealed a significant correlation between higher expression and poorer clinical outcome only with respect to PPM1D. Moreover, down-regulation of PPM1D by transfection of an antisense oligonucleotide suppressed the growth of NB cell lines to a remarkable degree, at least partly by participating in a process leading to apoptotic cell death. Taken together, our results indicate that PPM1D is the most likely target of the 17q23 gain/amplification in NB tumors and may have an important role in the pathogenesis of this disease.     

Genome-wide-array-based comparative genomic hybridization reveals genetic homogeneity and frequent copy number increases encompassing CCNE1 in fallopian tube carcinoma

Fallopian tube carcinoma (FTC) is a rare, poorly studied and aggressive cancer, associated with poor survival. Since tumorigenesis is related to the acquisition of genetic changes, we used genome-wide array comparative genomic hybridization to analyse copy number aberrations occurring in FTC in order to obtain a better understanding of FTC carcinogenesis and to identify prognostic events and targets for therapy. We used arrays of 2464 genomic clones, providing approximately 1.4 Mb resolution across the genome to map genomic DNA copy number aberrations quantitatively from 14 FTC onto the human genome sequence. All tumors showed a high frequency of copy number aberrations with recurrent gains on 3q, 6p, 7q, 8q, 12p, 17q, 19 and 20q, and losses involving chromosomes 4, 5q, 8p, 16q, 17p, 18q and X. Recurrent regions of amplification included 1p34, 8p11-q11, 8q24, 12p, 17p13, 17q12-q21, 19p13, 19q12-q13 and 19q13. Candidate, known oncogenes mapping to these amplicons included CMYC (8q24), CCNE1 (19q12-q21) and AKT2 (19q13), whereas PIK3CA and KRAS, previously suggested to be candidate driver genes for amplification, mapped outside copy number maxima on 3q and 12p, respectively. The FTC were remarkably homogeneous, with some recurrent aberrations occurring in more than 70% of samples, which suggests a stereotyped pattern of tumor evolution.     

DNA sequence copy number increase at 8q: a potential new prognostic marker in high-grade osteosarcoma

Histologic response to chemotherapy is currently the best prognostic parameter in high-grade osteosarcoma but it can be evaluated only after several weeks of chemotherapy. Thus a prognostic parameter known at the time of diagnosis would be of great clinical benefit. In the present study, we present the results of 31 primary high-grade osteosarcomas analyzed by comparative genomic hybridization (CGH). CGH allows for genome-wide screening of a tumor by detecting alterations in DNA sequence copy number. The most frequent aberrations were copy number increases at 1q21 in 58% of the tumors and at 8q (8q21.3-q22 in 52% and 8cen-q13 in 45%), followed by copy number increases at 14q24-qter (35%) and Xp11.2-p21 (35%). The most common losses were detected at 6q16 (32%) and 6q21-q22 (32%). Patients with a copy number increase at 8q21.3-q22 and/or at 8cen-q13 had a statistically significant poor distant disease-free survival (p = 0.003) and showed a trend toward short overall survival (p = 0.04). Patients with a copy number increase at 1q21 showed a trend toward short overall survival (p = 0.04). Thus, specific genetic aberrations detected at the time of the diagnosis could be used in prognostic evaluation of high-grade osteosarcoma.     

Genetic aberrations detected by comparative genomic hybridization in ovarian clear cell adenocarcinomas

Genetic abnormalities were detected by comparative genomic hybridization (CGH) in 12 ovarian clear cell adenocarcinomas. DNA sequence copy number abnormalities (CNAs) occurring in more than 20% of the cancers included increased copy numbers of 8q11-q13, 8q21-q22, 8q23, 8q24-qter, 17q25-qter, 20q13-qter and 21q22-qter and reduced copy numbers of 19p. Increases in copy numbers of 8q11-q13, 8q21-q22, 8q23 and 8q24-qter occurred more frequently in disease-free patients than in recurrent/non-surviving patients (p < 0.05). However, increases in copy numbers of 17q25-qter and 20q13-qter occurred more frequently in recurrent/non-surviving patients than in disease-free patients (p < 0.05). Furthermore, increases in copy numbers of 17q25-qter and 20q13-qter occurred together (p < 0.05). Additionally, there were negative correlations between increases in copy numbers of 8q21-q22 and 17q25-qter, and between 8q21-q22 and 20q13-qter (p < 0.05). It appears that ovarian clear cell adenocarcinomas can be classified into two subtypes, one being cancer with an increase in copy numbers of 8q and the other being cancer with increases in copy numbers of 17q25-qter and 20q13-qter.     

Using array-comparative genomic hybridization to define molecular portraits of primary breast cancers

We analysed 148 primary breast cancers using BAC-arrays containing 287 clones representing cancer-related gene/loci to obtain genomic molecular portraits. Gains were detected in 136 tumors (91.9%) and losses in 123 tumors (83.1%). Eight tumors (5.4%) did not have any genomic aberrations in the 281 clones analysed. Common (more than 15% of the samples) gains were observed at 8q11-qtel, 1q21-qtel, 17q11-q12 and 11q13, whereas common losses were observed at 16q12-qtel, 11ptel-p15.5, 1p36-ptel, 17p11.2-p12 and 8ptel-p22. Patients with tumors registering either less than 5% (median value) or less than 11% (third quartile) total copy number changes had a better overall survival (log-rank test: P=0.0417 and P=0.0375, respectively). Unsupervised hierarchical clustering based on copy number changes identified four clusters. Women with tumors from the cluster with amplification of three regions containing known breast oncogenes (11q13, 17q12 and 20q13) had a worse prognosis. The good prognosis group (Nottingham Prognostic Index (NPI) 相似文献   

Combined cDNA array comparative genomic hybridization and serial analysis of gene expression analysis of breast tumor progression

To identify genetic changes involved in the progression of breast carcinoma, we did cDNA array comparative genomic hybridization (CGH) on a panel of breast tumors, including 10 ductal carcinoma in situ (DCIS), 18 invasive breast carcinomas, and two lymph node metastases. We identified 49 minimal commonly amplified regions (MCRs) that included known (1q, 8q24, 11q13, 17q21-q23, and 20q13) and several uncharacterized (12p13 and 16p13) regional copy number gains. With the exception of the 17q21 (ERBB2) amplicon, the overall frequency of copy number alterations was higher in invasive tumors than that in DCIS, with several of them present only in invasive cancer. Amplification of candidate loci was confirmed by quantitative PCR in breast carcinomas and cell lines. To identify putative targets of amplicons, we developed a method combining array CGH and serial analysis of gene expression (SAGE) data to correlate copy number and expression levels for each gene within MCRs. Using this approach, we were able to distinguish a few candidate targets from a set of coamplified genes. Analysis of the 12p13-p12 amplicon identified four putative targets: TEL/ETV6, H2AFJ, EPS8, and KRAS2. The amplification of all four candidates was confirmed by quantitative PCR and fluorescence in situ hybridization, but only H2AFJ and EPS8 were overexpressed in breast tumors with 12p13 amplification compared with a panel of normal mammary epithelial cells. These results show the power of combined array CGH and SAGE analysis for the identification of candidate amplicon targets and identify H2AFJ and EPS8 as novel putative oncogenes in breast cancer.     

Comparative genomic hybridization analysis of 38 breast cancer cell lines: a basis for interpreting complementary DNA microarray data

Breast cancer cell lines provide a useful starting point for the discovery and functional analysis of genes involved in breast cancer. Here, we studied 38 established breast cancer cell lines by comparative genomic hybridization (CGH) to determine recurrent genetic alterations and the extent to which these cell lines resemble uncultured tumors. The following chromosomal gains were observed: 8q (75%), 1q (61%), 20q (55%), 7p (44%), 3q (39%), 5p (39%), 7q (39%), 17q (33%), 1p (30%), and 20p (30%), and the most common losses were: 8p (58%), 18q (58%), 1p (42%), Xp (42%), Xq (42%), 4p (36%), 11q (36%), 18p (33%), 10q (30%), and 19p (28%). Furthermore, 35 recurrent high-level amplification sites were identified, most often involving 8q23 (37%), 20q13 (29%), 3q25-q26 (24%), 17q22-q23 (16%), 17q23-q24 (16%), 1p13 (11%), 1q32 (11%), 5p13 (11%), 5p14 (11%), 11q13 (11%), 17q12-q21 (11%), and 7q21-q22 (11%). A comparison of DNA copy number changes found in the cell lines with those reported in 17 published studies (698 tumors) of uncultured tumors revealed a substantial degree of overlap. CGH copy number profiles may facilitate identification of important new genes located at the hotspots of such chromosomal alterations. This was illustrated by analyzing expression levels of 1236 genes using cDNA microarrays in four of the cell lines. Several highly overexpressed genes (such as RCH1 at 17q23, TOPO II at 17q21-q22, as well as CAS and MYBL2 at 20q13) were involved in these recurrent DNA amplifications. In conclusion, DNA copy number profiles were generated by CGH for most of the publicly available breast cancer cell lines and were made available on a web site (http://www.nhgri.nih.gov/DIR/CGB/++ +CR2000). This should facilitate the correlative analysis of gene expression and copy number as illustrated here by the finding by cDNA microarrays of several overexpressed genes that were amplified.     

Genetic imbalances revealed by comparative genomic hybridization in osteosarcomas

Osteosarcomas are the most frequent bone sarcomas. The molecular chromosomal aberrations in osteosarcomas were analyzed by comparative genomic hybridization (CGH). We studied 47 frozen tumors (41 primary samples, 6 relapses) in osteosarcoma patients registered in the Cooperative Osteosarcoma Study (COSS) protocol. Genomic imbalances were detected in 40 of 41 primary tumors and 6 of 6 relapsed tumors. Gains were more frequent than losses (ratio of 1.3:1). The median number of changes was 16 and 12 in primary and relapsed osteosarcomas, respectively. The median number of aberrations in primary high-grade osteosarcomas (17.0) was significantly higher than in low- or intermediate-grade osteosarcoma subtypes (3.0) (p = 0.038). The most frequent gains included 8q, 1p21-p31 and 1q21-q24, and the most frequent losses were 10q, 5q and 13q. High-level gains were observed on 8q23-q24, 17p13 and 1q21-q24. A gain of 19p (p < 0.001) or loss of 9p (p = 0.027) was more frequent in poor responders than in good responders. Univariate analysis revealed that patients with primary metastases (p = 0.002), poor histologic responses (p = 0.005), high-level gains of 19p (p = 0.012) or losses of 13q14 (p = 0.042) had significantly lower event-free survival (EFS), whereas patients with a loss of 5q (p = 0.007) or a loss of 10q21-22 (p = 0.017) had significantly higher EFS than patients without these aberrations. Multivariate analysis demonstrated that primary metastasis, loss of 13q14 and loss of 5q were independent prognostic factors. The findings of our study seem to be useful for evaluating the prognosis of patients and may finally lead to treatment strategies based on genetic background of osteosarcoma.     

Integrated profiling of basal and luminal breast cancers

Basal and luminal are two molecular subtypes of breast cancer with opposite histoclinical features. We report a combined, high-resolution analysis of genome copy number and gene expression in primary basal and luminal breast cancers. First, we identified and compared genomic alterations in 45 basal and 48 luminal tumors by using 244K oligonucleotide array comparative genomic hybridization (aCGH). We found various genome gains and losses and rare high-level gene amplifications that may provide therapeutic targets. We show that gain of 10p is a new alteration in basal breast cancer and that a subregion of the 8p12 amplification is specific of luminal tumors. Rare high-level amplifications contained BCL2L2, CCNE, EGFR, FGFR2, IGF1R, NOTCH2, and PIK3CA. Potential gene breaks involved ETV6 and FLT3. Second, we analyzed both aCGH and gene expression profiles for 42 basal and 32 luminal breast cancers. The results support the existence of specific oncogenic pathways in basal and luminal breast cancers, involving several potential oncogenes and tumor suppressor genes (TSG). In basal tumors, 73 candidate oncogenes were identified in chromosome regions 1q21-23, 10p14, and 12p13 and 28 candidate TSG in regions 4q32-34 and 5q11-23. In luminal breast cancers, 33 potential oncogenes were identified in 1q21-23, 8p12-q21, 11q13, and 16p12-13 and 61 candidate TSG in 16q12-13, 16q22-24, and 17p13. HORMAD1 (P = 6.5 x 10(-5)) and ZNF703 (P = 7 x 10(-4)) were the most significant basal and luminal potential oncogenes, respectively. Finally, among 10p candidate oncogenes associated with basal subtype, we validated CDC123/C10orf7 protein as a basal marker.     

Distinct genomic profiles in hereditary breast tumors identified by array-based comparative genomic hybridization

Mutations in BRCA1 and BRCA2 account for a significant proportion of hereditary breast cancers. Earlier studies have shown that inherited and sporadic tumors progress along different somatic genetic pathways and that global gene expression profiles distinguish between these groups. To determine whether genomic profiles similarly discriminate among BRCA1, BRCA2, and sporadic tumors, we established DNA copy number profiles using comparative genomic hybridization to BAC-clone microarrays providing <1 Mb resolution. Tumor DNA was obtained from BRCA1 (n = 14) and BRCA2 (n = 12) mutation carriers, as well as sporadic cases (n = 26). Overall, BRCA1 tumors had a higher frequency of copy number alterations than sporadic breast cancers (P = 0.00078). In particular, frequent losses on 4p, 4q, and 5q in BRCA1 tumors and frequent gains on 7p and 17q24 in BRCA2 tumors distinguish these from sporadic tumors. Distinct amplicons at 3q27.1-q27.3 were identified in BRCA1 tumors and at 17q23.3-q24.2 in BRCA2 tumors. A homozygous deletion on 5q12.1 was found in a BRCA1 tumor. Using a set of 169 BAC clones that detect significantly (P < 0.001) different frequencies of copy number changes in inherited and sporadic tumors, these could be discriminated into separate groups using hierarchical clustering. By comparing DNA copy number and RNA expression for genes in these regions, several candidate genes affected by up- or down-regulation were identified. Moreover, using support vector machines, we correctly classified BRCA1 and BRCA2 tumors (P < 0.0000004 and 0.00005, respectively). Further validation may prove this tumor classifier to be useful for selecting familial breast cancer cases for further mutation screening, particularly, as these data can be obtained using archival tissue.     

Integrated gene copy number and expression microarray analysis of gastric cancer highlights potential target genes

We performed an integrated array comparative genomic hybridization (aCGH) and expression microarray analysis of 8 normal gastric tissues and 38 primary tumors, including 25 intestinal and 13 diffuse gastric adenocarcinomas to identify genes whose expression is deregulated in association with copy number alteration. Our aim was also to identify molecular genetic alterations that are specific to particular clinicopathological characteristics of gastric cancer. Distinct molecular genetic profiles were identified for intestinal and diffuse gastric cancers and for tumors obtained from 2 different locations of the stomach. Interestingly, the ERBB2 amplification and gains at 20q13.12-q13.33 almost exclusively discriminated intestinal cancers from the diffuse type. In addition, the 17q12-q25 gain was characteristic to cancers located in corpus and the 20q13.12-q13.13 gain was more common in the antrum. Statistical analysis was performed using integrated copy number and expression data to identify genes showing differential expression associated with a copy number alteration. Genes with the highest statistical significance included ERBB2, MUC1, GRB7, PPP1R1B and PPARBP with concomitant changes in copy number and expression. Immunohistochemical analysis of ERBB2 and MUC1 on a tissue microarray containing 78 independent gastric tissues showed statistically significant differences (p < 0.05 and <0.001) in immunopositivity in the intestinal (31 and 70%) and diffuse subtypes (14 and 41%), respectively. In conclusion, our results demonstrate that intestinal and diffuse type gastric cancers as well as cancers located in different sites of the stomach have distinct molecular profiles which may have clinical value.     

Array comparative genomic hybridization reveals distinct DNA copy number differences between gastrointestinal stromal tumors and leiomyosarcomas

Leiomyosarcomas are spindle cell tumors showing smooth muscle differentiation. Until recently, most gastrointestinal stromal tumors (GIST) were also classified as smooth muscle tumors, but now GISTs are recognized as a separate entity, defined as spindle cell and/or epithelioid tumors localized in the gastrointestinal tract. Using microarray-based comparative genomic hybridization (array CGH), we have created a detailed map of DNA copy number changes for 7 GISTs and 12 leiomyosarcomas. Considerable gains and losses of chromosomal segments were observed in both tumor types. The most frequent aberration observed in GISTs was loss of chromosomes 14 and 22, with minimal recurrent regions in 14q11.2-q32.33 (71% of the tumors) and 22q12.2-q13.31 (100%). In leiomyosarcomas, frequent loss of chromosome 10 and 13q was observed, with minimal recurrent regions in 10q21.3 (75%) and 13q14.2-q14.3 (75%). Recurrent high-level amplification of 17p13.1-p11.2 was detected in leiomyosarcomas. Expression profiling using cDNA microarrays revealed four candidate genes in this region with high expression (AURKB, SREBF1, MFAP4, and FLJ10847). Altered expression of AURKB and SREBF1 has been observed previously in other malignancies. Hierarchical clustering of all samples separated GISTs and leiomyosarcomas into two distinct clusters. Statistical analysis identified six chromosomal regions, 1p36.11-p13.1, 9q21.11-9q34.3, 14q11.2-q23.2, 14q31.3-q32.33, 15q24.3-q26.3, and 22q11.21-q13.31, which were significantly different in copy number between GISTs and leiomyosarcomas. Our results show the potential of using array comparative genomic hybridization to classify histologically similar tumors such as GISTs and leiomyosarcomas.     

High-resolution genomic profiling reveals association of chromosomal aberrations on 1q and 16p with histologic and genetic subgroups of invasive breast cancer.

PURPOSE: Invasive ductal carcinoma and invasive lobular carcinoma (ILC) represent the major histologic subtypes of invasive breast cancer. They differ with regard to presentation, metastatic spread, and epidemiologic features. To elucidate the genetic basis of these differences, we analyzed copy number imbalances that differentiate the histologic subtypes.EXPERIMENTAL DESIGN: High-resolution genomic profiling of 40 invasive breast cancers using matrix-comparative genomic hybridization with an average resolution of 0.5 Mb was conducted on bacterial artificial chromosome microarrays. The data were subjected to classification and unsupervised hierarchical cluster analyses. Expression of candidate genes was analyzed in tumor samples.RESULTS: The highest discriminating power was achieved when combining the aberration patterns of chromosome arms 1q and 16p, which were significantly more often gained in ILC. These regions were further narrowed down to subregions 1q24.2-25.1, 1q25.3-q31.3, and 16p11.2. Located within the candidate gains on 1q are two genes, FMO2 and PTGS2, known to be overexpressed in ILC relative to invasive ductal carcinoma. Assessment of four candidate genes on 16p11.2 by real-time quantitative PCR revealed significant overexpression of FUS and ITGAX in ILC with 16p copy number gain. Unsupervised hierarchical cluster analysis identified three molecular subgroups that are characterized by different aberration patterns, in particular concerning gain of MYC (8q24) and the identified candidate regions on 1q24.2-25.1, 1q25.3-q31.3, and 16p11.2. These genetic subgroups differed with regard to histology, tumor grading, frequency of alterations, and estrogen receptor expression.CONCLUSIONS: Molecular profiling using bacterial artificial chromosome arrays identified DNA copy number imbalances on 1q and 16p as significant classifiers of histologic and molecular subgroups.     

Genetic aberrations in prostate cancer by microarray analysis

The aim of this study was to screen genetic as well as expression alterations in prostate cancer. Array comparative genomic hybridization (aCGH) to a 16K cDNA microarray was performed to analyze DNA sequence copy number alterations in 5 prostate cancer cell lines and 13 xenografts. The aCGH confirmed the previously implicated common gains and losses, such as gains at 1q, 7, 8q, 16p and 17q and losses at 2q, 4p/q, 6q, 8p, 13q, 16q, 17p and 18q, which have previously been identified by chromosomal CGH (cCGH). Because of the higher resolution of aCGH, the minimal commonly altered regions were significantly narrowed-down. For example, the gain of 8q was mapped to three independent regions, 8q13.3-q21.11, 8q22.2 and 8q24.13-q24.3. In addition, a novel recurrent gain at 9p13-q21 was identified. The concomitant expression analysis indicated that genome-wide DNA sequence copy number (gene dosage) was significantly associated with the expression level (p < 0.0001). The analyses indicated several individual genes whose expression was associated with the gene copy number. For example, gains of PTK2 and FZD6, were associated with the increased expression, whereas losses of TNFRSF10B (alias DR5) and ITGA4 with decreased expression. In conclusion, the aCGH mapping data will aid in the identification of genes altered in prostate cancer. The combined expression and copy number analysis suggested that even a low-level copy number change may have significant effect on gene expression, and thus on the development of prostate cancer.     

Clonal chromosomal aberrations in simian virus 40-transfected human thyroid cells and in derived tumors developed after in vitro irradiation.

In vitro model cell systems are important tools for studying mechanisms of radiation-induced neoplastic transformation of human epithelial cells. In our study, the human thyroid epithelial cell line HTori-3 was analyzed cytogenetically following exposure to different doses of alpha- and gamma-irradiation and subsequent tumor formation in athymic nude mice. Combining results from G-banding, comparative genomic hybridization, and spectral karyotyping, chromosome abnormalities could be depicted in the parental line HTori-3 and in nine different HTori lines established from the developed tumors. A number of chromosomal aberrations were found to be characteristic for simian virus 40 immortalization and/or radiation-induced transformation of human thyroid epithelial cells. Common chromosomal changes in cell lines originating from different irradiation experiments were loss of 8q23 and 13cen-q21 as well as gain of 1q32-qter and 2q11.2-q14.1. By comparison of chromosomal aberrations in cell lines exhibiting a different tumorigenic behavior, cytogenetic markers important for the tumorigenic process were studied. It appeared that deletions on chromosomes 9q32-q34 and 7q21-q31 as well as an increased copy number of chromosome 20 were important for the tumorigenic phenotype. A comparative breakpoint analysis of the marker chromosomes found and those observed in radiation-induced childhood thyroid tumors from Belarus revealed a coincidence for a number of chromosome bands. Thus, the data support the usefulness of the established cell system as an in vitro model to study important steps during radiation-induced malignant transformation in human thyroid cells.     

Comparative genomic hybridization in patients with supratentorial and infratentorial primitive neuroectodermal tumors.

BACKGROUND: Intracranial primitive neuroectodermal tumors (PNETs) occur in the supratentorial and infratentorial regions of the brain. Although histologically similar, the natural history of the tumor at each site differs. The study goal was to determine whether there was evidence of a genetic difference between supratentorial and infratentorial PNETs. METHODS: Using comparative genomic hybridization (CGH), 53 PNETs were analyzed to determine copy number aberrations. Forty-three tumors were located in the cerebellum (IPNETs), and ten were supratentorial PNETs (SPNETs). All samples were reviewed to confirm the diagnosis. Each specimen had at least 50% tumor. RESULTS: Six of the 43 cases of IPNET had no copy number aberrations. In contrast, each case of SPNET had copy number aberrations detected by CGH. Statistically significant differences in copy number aberrations of chromosomes 14, 17, and 19 were detected in the two groups. The most common copy number aberration in the IPNETs was gain of chromosome 17q, which was observed in 16 of 43 cases (37%). However, no case of SPNET had gain of 17q. Loss of 14q was detected in four of ten SPNETs but was not detected in any of the IPNET cases. Loss of 19q was detected in 4 of 10 SPNETs and in only 1 of 43 IPNETs. CONCLUSIONS: These results indicate that the genetic aberrations of IPNETs differ from the genetic aberrations of SPNETs. Although they are similar histologically, SPNETs and IPNETs appear to be biologically distinct entities.     

Different chromosomal imbalances in metastasized and nonmetastasized tongue carcinomas identified by comparative genomic hybridization

Tumors of different metastatic behavior possibly differ in genomic constitution. We identified molecular cytogenetic differences between a group of metastasized and nonmetastasized primary tongue tumors by comparative genomic hybridization. Most frequent chromosome copy number changes for metastasized and nonmetastasized tumors were +8q (100% and 71%, respectively) and +3q (56% and 43%, respectively). Metastasized tumors showed significantly more chromosome copy number changes than nonmetastasized tumors. High copy number gains were exclusively found in metastasized tumors for 3q23-qter, 5p, 12p and 13q21-q22. Genomic imbalances occurring in metastasized tumors but not in nonmetastasized tumours were +7q21 (44%), +14q (33%), and -15q (33%). The genetic constitution of primary tongue tumors that metastasize differs from tongue tumors that do not metastasize. Our data, although obtained from a relative small group of tumors, spotlights copy number gain of chromosome region 7q21 as a potential marker for metastatic behavior.     

DNA copy number gains at loci of growth factors and their receptors in salivary gland adenoid cystic carcinoma.

PURPOSE: Adenoid cystic carcinoma (ACC) is a malignant salivary gland tumor with a high mortality rate due to late, distant metastases. This study aimed at unraveling common genetic abnormalities associated with ACC. Additionally, chromosomal changes were correlated with patient characteristics and survival. EXPERIMENTAL DESIGN: Microarray-based comparative genomic hybridization was done to a series of 18 paraffin-embedded primary ACCs using a genome-wide scanning BAC array. RESULTS: A total of 238 aberrations were detected, representing more gains than losses (205 versus 33, respectively). Most frequent gains (>60%) were observed at 9q33.3-q34.3, 11q13.3, 11q23.3, 19p13.3-p13.11, 19q12-q13.43, 21q22.3, and 22q13.33. These loci harbor numerous growth factor [fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF)] and growth factors receptor (FGFR3 and PDGFRbeta) genes. Gains at the FGF(R) regions occurred significantly more frequently in the recurred/metastasized ACCs compared with indolent ACCs. Furthermore, patients with 17 or more chromosomal aberrations had a significantly less favorable outcome than patients with fewer chromosomal aberrations (log-rank = 5.2; P = 0.02). CONCLUSIONS: Frequent DNA copy number gains at loci of growth factors and their receptors suggest their involvement in ACC initiation and progression. Additionally, the presence of FGFR3 and PDGFRbeta in increased chromosomal regions suggests a possible role for autocrine stimulation in ACC tumorigenesis.