Biomedical subjects

O Monni

Publications and source records attributed to O Monni.

At least 19 recordsLinked to original sources

PubMed2006

Identification of target genes in laryngeal squamous cell carcinoma by high-resolution copy number and gene expression microarray analyses.

Molecular mechanisms contributing to initiation and progression of head and neck squamous cell carcinoma are still poorly known. Numerous genetic alterations have been described, but molecular consequences of such alterations in most cases remain unclear. Here, we performed an integrated high-resolution microarray analysis of gene copy number and expression in 20 laryngeal cancer cell lines and primary tumors. Our aim was to identify genetic alterations that play a key role in disease pathogenesis and pinpoint genes whose expression is directly impacted by these events. Integration of DNA level data from array-based comparative genomic hybridization with RNA level information from oligonucleotide microarrays was achieved with custom-developed bioinformatic methods. High-level amplifications had a clear impact on gene expression. Across the genome, overexpression of 739 genes could be attributed to gene amplification events in cell lines, with 325 genes showing the same phenomenon in primary tumors including FADD and PPFIA1 at 11q13. The analysis of gene ontology and pathway distributions further pinpointed genes that may identify potential targets of therapeutic intervention. Our data highlight genes that may be critically important to laryngeal cancer progression and offer potential therapeutic targets.

Carcinoma, Squamous Cell↗

PubMed2001

New amplified and highly expressed genes discovered in the ERBB2 amplicon in breast cancer by cDNA microarrays.

Amplification of the ERBB2 oncogene at 17q12 has been well documented in breast cancer and has been shown to contribute to a poor clinical outcome. However, systematic surveys of copy number and expression levels of all genes within the 17q12 region have not been performed. Here, we used cDNA and comparative genomic hybridization microarray technologies to undertake a broad survey of genes involved in the 17q12 amplification in breast cancer. A chromosomal region-specific cDNA microarray containing 217 expressed sequence tag (EST) clones from 17q12 was constructed and used for parallel analysis of gene copy numbers and expression levels in seven breast cancer cell lines allowing direct identification of genes whose expression is elevated because of an increase in copy number in this chromosomal region. The copy number and expression survey identified 12 transcripts that showed a consistent pattern of increased copy number and expression in three or more of the 17q12-amplified cell lines. As expected, these included ERBB2 as well as the GRB7 and MLN64 genes previously shown to be coamplified with ERBB2. In addition, five other known genes and four uncharacterized ESTs were also found to be consistently activated by amplification in these breast cancer cell lines. Amplicon mapping by fluorescence in situ hybridization revealed a minimal common region of amplification containing four highly expressed genes, ERBB2, GRB7, MLN64, and an uncharacterized EST 48582. Furthermore, several other genes, although not located in the minimal common region of amplification, showed a correlated pattern of amplification and expression indicating that they might play a role in breast cancers with the 17q12 amplification. In conclusion, parallel analysis of gene copy number and expression levels by cDNA microarray can be used to directly identify candidate target genes involved in amplifications. Our results show that the 17q12 amplification in breast cancer leads to the simultaneous elevation of expression levels of several genes.

Breast Neoplasms↗

PubMed2001

Comprehensive copy number and gene expression profiling of the 17q23 amplicon in human breast cancer.

The biological significance of DNA amplification in cancer is thought to be due to the selection of increased expression of a single or few important genes. However, systematic surveys of the copy number and expression of all genes within an amplified region of the genome have not been performed. Here we have used a combination of molecular, genomic, and microarray technologies to identify target genes for 17q23, a common region of amplification in breast cancers with poor prognosis. Construction of a 4-Mb genomic contig made it possible to define two common regions of amplification in breast cancer cell lines. Analysis of 184 primary breast tumors by fluorescence in situ hybridization on tissue microarrays validated these results with the highest amplification frequency (12.5%) observed for the distal region. Based on GeneMap'99 information, 17 known genes and 26 expressed sequence tags were localized to the contig. Analysis of genomic sequence identified 77 additional transcripts. A comprehensive analysis of expression levels of these transcripts in six breast cancer cell lines was carried out by using complementary DNA microarrays. The expression patterns varied from one cell line to another, and several overexpressed genes were identified. Of these, RPS6KB1, MUL, APPBP2, and TRAP240 as well as one uncharacterized expressed sequence tag were located in the two common amplified regions. In summary, comprehensive analysis of the 17q23 amplicon revealed a limited number of highly expressed genes that may contribute to the more aggressive clinical course observed in breast cancer patients with 17q23-amplified tumors.

Breast Neoplasms↗

PubMed2001

From chromosomal alterations to target genes for therapy: integrating cytogenetic and functional genomic views of the breast cancer genome.

A vast number of recurrent chromosomal alterations have been implicated in cancer development and progression. However, most of the genes involved in recurrent chromosomal alterations in solid tumors remain unknown, despite the recent substantial progress in genomic research and availability of high-throughput technologies. For example, it is now possible to quickly identify large numbers of differentially expressed genes in cancer specimens using cDNA microarrays. Integration of this "functional genomic view" of the cancer genome with the "cytogenetic view" could lead to the identification of genes playing a critical role in cancer development and progression. In this review, we illustrate how the combination of three different microarray technologies, cDNA, CGH, and tissue microarrays, makes it possible to directly identify genes involved in chromosomal rearrangements in cell line model systems and then rapidly explore their significance as potential diagnostic and therapeutic targets in human primary breast cancer progression.

Breast Neoplasms↗

PubMed2001

11q deletions in hematological malignancies.

Structural aberrations involving 11q are among the most common aberrations in a number of hematological malignancies. Most of the aberrations, such as translocations and deletions, often harbor a breakpoint at 11q23, which suggests that this region might contain a tumor suppressor gene important for the genesis of lymphoproliferative disorders. Interestingly, deletions are concentrated only in some subtypes of hematological malignancies, where they are detected at a relatively high frequency. In B-cell chronic lymphocytic leukemia (B-CLL), deletions have been detected in 20-30% of the cases, whereas almost half of the mantle cell lymphomas (MCL) show deletion at 11q23 in fluorescence in situ hybridization analysis. In T-cell prolymphocytic leukemia (T-PLL), deletions involving the region 11q23.3-23.1 have also been detected to be frequent. In B-cell chronic lymphocytic leukemia, 11q deletion is associated with more rapid disease progression and poor survival in a younger subgroup of patients. The putative tumor suppressor genes have remained unrevealed until recently, when the ATM gene was found to carry mutations in cases with deletion in B-CLL, MCL and T-PLL. These data suggest that 11q deletions and dysfunction of the ATM gene might have significance in the tumorigenesis of certain subsets of hematological malignancies. Importance of 11q deletion as a diagnostic marker needs to be further studied in a larger series of patients. Another issue that remains to be investigated is the involvement of other target genes in the deletion.

Chromosome Aberrations↗

PubMed2001

PPP2R1B gene in chronic lymphocytic leukemias and mantle cell lymphomas.

Deletion of chromosome bands 11q22-q23 is one of the most common structural chromosome alterations in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). The PPP2R1B gene is located very close to the minimal common deletion region of 11q22-q23 in CLL and MCL. Recently, the PPP2R1B gene was found to be mutated in human lung and colon cancers. To evaluate the role of the PPP2R1B gene in the pathogenesis of CLL and MCL, we performed RT-PCR analysis and cDNA sequencing on 10 CLL RNA samples and SSCP analysis on 26 CLL and 37 MCL genomic DNA samples. A deletion of exon 3 was found in one CLL sample. No mutation was detected in the SSCP analysis. To exclude the possibility of large genomic deletions we performed Southern blotting analysis. One MCL sample showed abnormal bands. Our results do not suggest that the PPP2R1B gene has a major pathogenic role in CLL and MCL.

Base Sequence↗

PubMed2000

Multiple genes at 17q23 undergo amplification and overexpression in breast cancer.

Studies by comparative genomic hybridization imply that amplification of the chromosomal region 17q22-q24 is common in breast cancer. Here, amplification and expression levels of six known genes located at 17q23 were examined in breast cancer cell lines. Four of them (RAD51C, S6K, PAT1, and TBX2) were found to be highly amplified and overexpressed. To investigate the involvement of these genes in vivo, fluorescence in situ hybridization analysis of a tissue microarray containing 372 primary breast cancers was used. S6K, PAT1, and TBX2 were coamplified in about 10% of tumors, whereas RADS1C amplification was seen in only 3% of tumors. Expression analysis in 12 primary tumors showed that RAD51C and S6K were consistently expressed in all cases in which they were amplified and also in some tumors without amplification. These data suggest that 17q23 amplification results in simultaneous up-regulation of several genes, whose increased biological activity may jointly contribute to the more aggressive clinical course observed in patients with 17q23-amplified tumors.

Adult↗

PubMed2000

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.

Breast Neoplasms↗

PubMed2000

Deletions at 11q23 in different lymphoma subtypes.

BACKGROUND AND OBJECTIVES: Chromosome band 11q23 is frequently deleted in various types of neoplasm. The region represented by yeast artificial chromosome (YAC) clone 755b11 at 11q23 has been shown to be the minimal common region of deletion in mantle cell lymphoma (MCL) and B-cell chronic lymphocytic leukemia (B-CLL). The aim of the study was to determine the frequencies of 11q23 deletion in different lymphoma subtypes. DESIGN AND METHODS: We performed fluorescence in situ hybridization (FISH) analysis with YAC755b11 on either peripheral blood or lymph node biopsy (LN) specimens of patients diagnosed as having MCL (47), CLL/small lymphocytic lymphoma (SLL) (62), diffuse large cell lymphoma (DLCL) (17), follicular lymphoma (FL) (9), and Hodgkin's disease (HD) (11). Fifteen cases of reactive or normal lymph node biopsies were studied as controls. RESULTS: Forty of the 161 (25%) samples exhibited deletions in the region represented by YAC755b11. The 11q23 deletion was found only in MCL (23, 49%), CLL / SLL (13, 21%) and DLCL (4, 24%). Three cases were classified as Richter's syndrome and they all exhibited the deletion at 11q23. The deletion frequencies in the blood specimens of typical CLL (30%) and lymph node specimens of CLL/SLL (13%) were remarkably different. INTERPRETATION AND CONCLUSIONS: Our study demonstrated that the 11q23 deletion is not common in lymphomas other than MCL, CLL and DLCL. It also showed the possible correlation of the 11q23 deletion with the transformation of localized lymphoma to CLL, and with the development of Richter's syndrome.

Adolescent↗

PubMed1999

Concomitant gastrin and ERBB2 gene amplifications at 17q12-q21 in the intestinal type of gastric cancer.

Our recent studies using comparative genomic hybridization showed that gain or amplification at the 17q12-q21 region is very common in the intestinal type of gastric cancer. Here, we describe a fluorescence in situ hybridization study with gastrin (GAS)-specific and ERBB2-specific probes on ten specimens of gastric carcinoma that, by using comparative genomic hybridization, showed 1) DNA copy number gain or amplification at 17q12-q21, a region known to harbor the GAS and ERBB2 genes (four cases); 2) gain of the entire chromosome 17 (three cases); or 3) normal copy number of chromosome 17 (three cases). GAS and ERBB2 protein expression was studied by Western immunoblotting from gastric cancer cell lines with or without gain at 17q12-q21 as well as a breast cancer cell line with ERBB2 amplification. Our results showed that simultaneous amplification of both GAS and ERBB2 was four- to ninefold in the tumors with the 17q12-q21 amplification. Both genes were amplified in the same nuclei, and the hybridization signals were localized to the same region of the nucleus. Overexpression of GAS and ERBB2 was observed by Western immunoblotting only in the gastric cancer cell line with gain at 17q12-q21. The ERBB2 amplification is also a recurrent change in breast cancer. To investigate whether the GAS amplification is unique in gastric cancer, fluorescence in situ hybridization analysis was performed on 40 breast cancer cell lines. The ERBB2 amplification was observed in 11 cell lines, but none of the lines showed the GAS amplification. This indicates that the formation of an amplicon, in which both the GAS and the ERBB2 genes are amplified, might be unique in gastric cancer, especially in its intestinal type, and that simultaneous amplification of both genes is important to the tumorigenesis of intestinal gastric cancer. We demonstrate here for the first time that a gene of a physiological hormone is amplified in tumors that originate from cells that normally secrete the hormone.

Breast Neoplasms↗

PubMed1999

DNA copy number losses in human neoplasms.

This review summarizes reports of recurrent DNA sequence copy number losses in human neoplasms detected by comparative genomic hybridization. Recurrent losses that affect each of the chromosome arms in 73 tumor types are tabulated from 169 reports. The tables are available online at http://www.amjpathol.org and http://www. helsinki.fi/ approximately lglvwww/CMG.html. The genes relevant to the lost regions are discussed for each of the chromosomes. The review is supplemented also by a list of known and putative tumor suppressor genes and DNA repair genes (see Table 1, online). Losses are found in all chromosome arms, but they seem to be relatively rare at 1q, 2p, 3q, 5p, 6p, 7p, 7q, 8q, 12p, and 20q. Losses and their minimal common overlapping areas that were present in a great proportion of the 73 tumor entities reported in Table 2 (see online) are (in descending order of frequency): 9p23-p24 (48%), 13q21 (47%), 6q16 (44%), 6q26-q27 (44%), 8p23 (37%), 18q22-q23 (37%), 17p12-p13 (34%), 1p36.1 (34%), 11q23 (33%), 1p22 (32%), 4q32-qter (31%), 14q22-q23 (25%), 10q23 (25%), 10q25-qter (25%),15q21 (23%), 16q22 (23%), 5q21 (23%), 3p12-p14 (22%), 22q12 (22%), Xp21 (21%), Xq21 (21%), and 10p12 (20%). The frequency of losses at chromosomes 7 and 20 was less than 10% in all tumors. The chromosomal regions in which the most frequent losses are found implicate locations of essential tumor suppressor genes and DNA repair genes that may be involved in the pathogenesis of several tumor types.

Chromosomes, Human↗

PubMed1999

Discontinuous deletions at 11q23 in B cell chronic lymphocytic leukemia.

Loss of genomic material in 11q is one of the most common structural chromosome aberrations in B cell chronic lymphocytic leukemia (B-CLL). In order to characterize the deletions of 11q23 in B-CLL, we performed fluorescence in situ hybridization (FISH) with eight YAC (yeast artificial chromosome) probes on peripheral leukocytes of 30 patients. These YACs form a contig spanning 7.8 Mb at 11q23.1-q23.3. We found deletions in nine out of 30 cases (30%) and five of them had discontinuous deletions in this region. The region represented by YAC 755b11 (1.6 Mb in size) was involved in all cases with deletions, supporting the hypothesis that this region might contain a novel gene of pathogenic importance to B-CLL. A more distal region represented by YAC 785e12 (760 kb in size) was deleted frequently and specifically. Whether there is another novel gene of pathogenic importance to B-CLL and what is its potential relationship to the deletions in the region represented by YAC 755b11, are issues that require further studies.

Aged↗

PubMed1999

Molecular characterization of deletion at 11q22.1-23.3 in mantle cell lymphoma.

Chromosomal deletions at 11q21-23 have recently been reported to be common aberrations in mantle cell lymphoma (MCL). To characterize the structure of the deletion, we studied 41 cases of MCL by fluorescence in situ hybridization using a YAC contig, which spans the region at 11q22.1-23.3. 17 MCLs were studied using a set of 20 yeast artificial chromosomes (YACs) in a contig, and nine of these cases showed deletion of 11q22-23. The deletion spanned several megabases in all but one case, where only YAC 755b11 at 11q23.1, covering approximately a 1.6 Mb of DNA, was deleted. Analysis of additional 24 MCLs with YAC 755b11 revealed the deletion in 49% of all cases (20/41). The deleted region at 11q22.1-23.3 was discontinuous in five lymphomas and in the majority of the cases the distal breakpoint occurred between YACs 785e12 and 911f2 at 11q23.3. We conclude that the deletion of 11q22-23 and particularly the deletion of YAC 755b11 are very common in MCL and may be important in the genesis or progression of the disease.

Adult↗

PubMed1999

BCL2 overexpression in diffuse large B-cell lymphoma.

Translocation (14;18)(q32;q21), which is detected in 20-30% of diffuse large B-cell lymphomas (DLBCL), is regarded as a major mechanism for BCL2 protein overexpression. Nevertheless, BCL2 overexpression is not always caused by t(14;18), because it is often detected in lymphomas without BCL2 rearrangement. Recent studies have shown that increased expression of BCL2 may also result from BCL2 gene amplification in DLBCL. Similarly, it has been speculated that the mutations of the open reading frame might cause increased expression of BCL2 by affecting the interactions of BCL2 with other proteins. The results obtained from studies on the association of BCL2 protein overexpression with survival of DLBCL are controversial, although a correlation with decreased overall survival seems to exist. However, BCL2 rearrangement does not seem to have any major association with poor prognosis, but it is difficult to assess its true impact on prognosis due to differences in treatment and follow-up, and methodologies applied to study the BCL2 rearrangement. This review summarizes the BCL2 expression studies in DLBCL and discusses the prognostic relevance of BCL2 overexpression and its mechanisms.

Animals↗

PubMed1998

Comparative genomic hybridization reveals differences in DNA copy number changes between sporadic gastric carcinomas and gastric carcinomas from patients with hereditary nonpolyposis colorectal cancer.

Comparative genomic hybridization was used to search for DNA copy number changes in samples of gastric cancer from 12 hereditary nonpolyposis colon cancer (HNPCC) patients and in samples of sporadic gastric carcinoma from 13 patients. The gastric cancer samples from HNPCC patients showed gains affecting 19q, Xp, and whole chromosome 22, each in a single patient. Neither high-level amplifications nor losses of DNA copy number were detected. On the other hand, 10 of the 13 (77%) sporadic gastric carcinoma samples had multiple DNA copy number changes. The most frequent gains occurred with minimal common overlapping regions at 1q22-q31, 8q23-qter, 17p11.2-q22, and 20q, all at a frequency of 31%. High-level amplifications were also seen at 17q21 in three cases (23%). Losses were rare, and the most frequent loss was with a minimal common overlapping region at 4q32 (23%). This suggests that multiple DNA copy number changes are needed for the development of sporadic gastric carcinoma but not for gastric carcinoma in HNPCC patients.

Chromosome Aberrations↗

PubMed1998

Identification and characterization of a new latent transforming growth factor-beta-binding protein, LTBP-4.

Transforming growth factor betas (TGF-betas) are secreted by most cell types as latent high molecular weight complexes consisting of TGF-beta and its latency associated peptide (LAP) propeptide dimers, covalently linked to latent TGF-beta-binding proteins (LTBPs). Currently, three different LTBPs are known (LTBPs 1, 2, and 3), all with highly similar protein domain structure consisting of epidermal growth factor-like and 8-Cys repeats. The 3rd 8-Cys repeat of LTBP-1 mediates its association with TGF-beta1.LAP. By using an expressed sequence tag homologous to the 3rd 8-Cys repeat of human LTBP-1 as a probe, a novel cDNA similar to known LTBPs was cloned from human heart cDNA library. This cDNA was named LTBP-4 and found to exist in at least four different forms, generated by alternative splicing at the amino terminus and at the central epidermal growth factor repeat domain. One of the alternative amino-terminal forms contained an RGD sequence, indicating possible cell-surface interactions with integrins. LTBP-4 gene was localized to chromosomal position 19q13. 1-19q13.2. The major LTBP-4 mRNA form is about 5.1 kilobase pairs in size and is predominantly expressed in the heart, aorta, uterus, and small intestine. Immunoblotting analysis indicated that LTBP-4 was secreted from cultured human lung fibroblasts both in a free form and in a disulfide bound complex with a TGF-beta. LAP-like protein. Both LTBP-4 forms were also found to be deposited in the extracellular matrix. The matrix-associated LTBP-4 was susceptible to proteolytic release with plasmin. LTBP-4 is a new member of the growing LTBP-fibrillin family of proteins and offers an alternative means for the secretion and targeted matrix deposition of TGF-betas or related proteins.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Comparative genomic hybridization study on pooled DNAs from tumors of one clinical-pathological entity.

Comparative genomic hybridization (CGH) was performed using DNAs pooled from numerous specimens from tumor categories studied case-by-case. The series of six DNA pools consisted of 28 diffuse centroblastic lymphomas (DCL), 28 gastrointestinal stromal tumors (GIST), 21 primary chondrosarcomas (CS), 17 samples from the Ewing family of tumors (ET), 14 liposarcomas (LS), and 14 mesotheliomas (MS). Losses and gains present in at least 50% of the individual specimens were always detected in the pooled DNAs. The loss of the whole p-arm of chromosome 1 was observed even when the affected proportion of individual specimens was only 25%. Gains were also detected at frequencies lower than 50%, but with a high-level amplification in one or more specimens. In conclusion, the present pooled DNA study revealed the following changes: DCL had a gain at 18q22-qter; GIST had losses at 14 and 22q12, and gains at 5p, 8q22-24, 17q22-qter, and 19q13; ET had gains at 1q and 8q13-qter; LS had gains at 1q21-25 and 12q; and MS had a loss at 9p22-pter. No changes were observed in the CS DNA pool. The results from individual specimens also stressed the importance of these chromosomal regions to the tumorigenesis in the corresponding malignancies. This pooled DNA approach can thus be used for fast screening of recurrent DNA copy number in a specific tumor entity.

DNA, Neoplasm↗

PubMed1998

Gain of 3q and deletion of 11q22 are frequent aberrations in mantle cell lymphoma.

We used comparative genomic hybridization (CGH) to screen for DNA copy number changes in 34 specimens from 27 cases of mantle cell lymphoma (MCL). The most common gains were detected at 3q (52%), 8q (30%), and 15q (26%), whereas the most frequent losses involved 13q (41%), 1p (33%), 6q (30%), 9p (30%), and 11q (30%). The gain of 3q, with a minimal common region at 3q26.1-27, appeared in more than half of the lymphomas, suggesting the location of an important oncogene here. A common deleted region at 11q22 was found in one-third of the patients, which suggests that this region may harbor a tumor suppressor gene important in the tumorigenesis of MCL. The mean number of changes was higher in more aggressive blastoid variants of MCL than in lymphomas with typical morphology. Our results show that the chromosomal regions affected in MCL are highly consistent and are different from those seen in other types of non-Hodgkin's lymphoma.

Aged↗