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1 Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan; 2 Department of Hematology, Cambridge University, Medical Research Council Center, Cambridge, United Kingdom; and 3 Geneshot Project, R&D Center, NGK Insulators, Ltd., Nagoya, Japan
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The high-level amplification seen at 13q21-qter has been observed in hematological and other solid neoplasms. Amplification at 13q21-qter has been reported in diffuse large B-cell lymphoma (DLBCL; Ref. 5 ), mantle cell lymphoma (6) , follicular lymphoma (7) , primary cutaneous B-cell lymphoma (8) , and nasal-type natural killer/T-cell lymphoma (9) . Additional cases of amplification at 13q21-qter have also been reported in solid tumors: glioma (10) , non-small cell lung cancer (10) , bladder cancer (10) , squamous-cell carcinoma of the head and neck (10) , peripheral nerve sheath tumor (11) , malignant fibrous histiocytoma (12) , and alveolar rhabdomyosarcoma (13) . We also reported the results of cytogenetic analysis of 70 DLBCL patients (14) using conventional comparative genomic hybridization (CGH), which found amplification of 13q, including the 13q31-q32 region, in 18 of 70 DLBCL cases.
Glypican 5 (GPC5) has been reported recently as a possible target gene for amplification at 13q31-q32 in a study using fluorescent in situ hybridization (FISH) in lymphoma cell lines (15) . However, the mRNA expressions of GPC5 and expression sequence tags (ESTs) located in the amplification region of 13q31-q32 were not dealt with in their study.
In the study presented here, we identified the common region of amplification at 13q31-q32 in DLBCL patients and lymphoma cell lines by CGH, FISH, and array CGH, which allows for rapid screening and more detailed analysis of genomic imbalance in tumor genomes (16, 17, 18) . This report describes the fine mapping of the 13q31-q32 amplification and identification of a novel gene, designated C13orf25 (Chromosome 13 open reading frame 25) that showed parallel expression to that of genomic amplification of 13q31-q32 in lymphoma cell lines and DLBCL patients. We also provided evidence that GPC5 is not a likely target for 13q31-q32 amplification.
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MATERIALS AND METHODS |
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Array CGH.
The array fabrication and hybridization was performed according to the method described by Hodgson et al. (23)
and Pinkel et al. (17)
, respectively. The array consisted of 2,088 bacterial artificial chromosome (BAC) and P-1 derived artificial chromosome (PAC) clones, covering the human genome at roughly a 1.5-Mb resolution, from library RP11 and 13 for BAC clones and RP1, 3, 4, and 5 for PAC clones. Information on clone names and their location on chromosomes is available on request. These clones were obtained from the BACPAC Resource Center at the Children’s Hospital Oakland Research Institute (Oakland, CA).4
Each clone was cultured in Terrific Broth medium with the chloramphenicol (25 µg/ml), and BAC and PAC DNA was extracted with a plasmid Mini-kit (Qiagen, Germantown, MD). The location of each clone was also confirmed by FISH analysis. Roughly 10% of these clones could not be assigned to their expected region and excluded from this study, whereas the confirmed clones were used for array CGH. We used 10 ng of BAC and PAC DNA as the template for degenerate oligonucleotide primed PCR with the primer 5'-CCGACTCGAGNNNNNNATGTGG-3', where n = A, C, G, or T (24)
. Amplifications were performed on a TaKaRa PCR Thermal Cycler MP (TaKaRa, Tokyo, Japan) using ExTaq polymerase (TaKaRa). Degenerate oligonucleotide primed-PCR products were enriched by ethanol precipitation and dissolved in distilled water, and then equal volume of DNA spotting solution DSP0050 (MATSUNAMI, Osaka, Japan) was added (
1 µg/µl). DNA was robotically spotted (NGK Insulators, Ltd., Nagoya, Japan) in duplicate onto CodeLink activated slides (Amersham Biosciences, Piscataway, NJ). Tested and reference DNA (1 µg each) was digested with DpnII and labeled with the Bio prime DNA labeling system (Invitrogen Life Technologies, Inc., Tokyo, Japan) using cyanine3-dUTP and cyanine5-dUTP (Amersham Pharmacia Biotech, Piscataway, NJ), respectively. Unincorporated fluorescent nucleotides were removed with the aid of Sephadex G-50 spin columns (Amersham Biosciences). Labeled 1 µg of tested and reference DNA samples was mixed with 100 µg of Human Cot-1 DNA (Invitrogen Life Technologies, Inc.) and precipitated, after which the pellet was resuspended in the 45-µl hybridization mixture, which consisted of 50% formamide, 10% dextran sulfate, 2x SSC, 4% SDS, and 10 µg/µl yeast tRNA (Invitrogen Life Technologies, Inc.). The hybridization solution was heated to 73°C for 5 min to denature the DNA and then incubated for 45 min at 37°C to allow blocking of the repetitive sequences. The slides spotted with DNA were denatured in a solution consisting of 70% formamide/2x SSC at 73°C for 4 min, then dehydrated in cold 70%, 85%, and 100% ethanol for 5 min each and air-dried. Hybridization was performed for 48 h in a container placed on a slowly rocking table containing 200 µl of 50% formamide and 2x SSC to control moisture. It was followed by 15 min posthybridization washing in 50% formamide/2x SSC at 50°C, 30 min in 2x SSC/0.1% SDS at 50°C, 15 min in PN buffer consisting of 0.1 M NaH2PO4, 0.1 M Na2HPO4 at (pH 8.0), and 0.1% NP40 at room temperature, rinsing in 2x SSC at room temperature, and finally dehydration in 70%, 85%, 100% ethanol at room temperature for 2 min each and air-drying. Scanning analysis was basically carried out with the Agilent Micro Array Scanner (Agilent Technologies, Palo Alto, CA). Thus, acquired array images were analyzed using Genepix Pro 4.1 (Axon Instruments, Inc., Foster City, CA). DNA spots were automatically segmented, the local background was subtracted, and the total intensities and fluorescence intensity ratio of the two dyes for each spot were calculated. Fluorescence intensity ratio of the two dyes (Cy3 intensity/Cy5 intensity) were converted into log2 intensity ratios (log2 ratio).
For the array used in this study, six simultaneous hybridizations of normal male versus normal male were performed to define the normal variation for log2 ratio. In this experiment, 122 clones showed less than one-tenth the fluorescence intensity of the mean value for all of the clones, and were excluded from array CGH analysis. The remaining 1,966 clones were used for the array CGH analysis. More than 95% of the measured fluorescence log2 ratio values of each spot (2 x 1966 clones) ranged from +0.2 to –0.2. The thresholds for the log2 ratio of gains and losses were set at the log2 ratio of +0.2 and –0.2, respectively. We also normalized the log2 ratio of each sample according to the following method.
The medium log2 ratio value for all of the clones was computed, and the clones were selected with a log2 ratio more than "the median + SD x A " or less than " the median – SD x A." "A" was visually defined as the normal region by referring to the log2 ratio plots of all clones for each experiment. "A" was also assigned an approximate ranged from 0.3 to 0.7. We then computed the mean log2 ratio value for the selected clones, and designated this mean log2 ratio value as "X." Finally, we obtained the "Y" value by subtracting "X" from the log2 ratio for each clone. In this study, each log2 ratio was analyzed on the basis of the "Y" value. We visually selected the clones, computed the SD for each experiment, and confirmed that the SD did not exceed 0.15. If it did, the value was considered unreliable for CGH analyses.
Array-hybridization of normal male versus normal female was performed to check any change in one copy number of the X chromosome. To confirm linearity associated with a change in the copy number, we also performed array hybridization of normal versus each cell line with different number of the X chromosome (GM04626: 47XXX; GM01415D: 48XXXX; and GM05009C: 49XXXXX). These cell lines were obtained from the National Institute of General Medical Sciences Human Genetics Cell Repository Coriell Institute for Medical Research. Fifty seven BAC or PAC clones of the X chromosome were used for the analysis. We computed the mean log2 ratio value of those clones on each hybridization.
FISH Analysis.
We confirmed the location of BAC clones on 13q31-q32 from information archived by the Ensembl Genome Data Resources.5
FISH analysis using 19 BAC clones located around the region of high-level amplification of 13q31-q32 demonstrated by array CGH, covering 15 Mb, was used for three cell lines (Karpas 1718, OCI-Ly4, and Rec1). Each interphase chromosome slide of cell lines was prepared according to a standard method. FISH was carried out according to the method described elsewhere (25)
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Location of ESTs and Genes.
ESTs and genes located on the region of chromosome 13q31.3 were referenced by the National Center for Biotechnology Information,6
the Ensembl genome data resource,5
and the University of California at Santa Cruz Biotechnology.7
Array CGH and FISH analysis demonstrated that the common region of amplification at 13q31-q32 extended from BAC, RP11–360A9 to BAC, RP11–93M14. This region contained 65 independent ESTs that do not overlap each other and GPC5 (Table 1)
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. Each primer was also designed so that the Tm value would be between 55°C and 60°C. Amplifications were performed on a Thermal Cycler (Perkin-Elmer Corporation, Norwalk, CT). RT-PCR was conducted with the touchdown PCR method described elsewhere (26)
. Briefly, the reactions were comprised of 10 cycles of denaturation (94°C, 0.5 min), annealing (63°C, 0.5 min, 1°C decrease per 2 cycles), and extension (72°C, 2.5 min), followed by 35 cycles of denaturation (94°C, 0.5 min), annealing (58°C, 0.5 min), and extension (72°C, 2.5 min), and a final extension of 5 min at 72°C. Basically, the annealing temperature of the reaction was from 63 to 58°C. Additionally, RT-PCR was also performed under different conditions by changing the annealing temperature from 65 to 60°C or 60°C to 55°C. If no PCR products were obtained, we designed new primer sets to confirm their true negativity. All of the PCR products were separated by electrophoresis and purified using the QIA Quick Gel Extraction kit (Qiagen). TA cloning to purified PCR products was performed by using pBluescriptII SK (–), and sequenced by using ABI PRISM 310 Genetic Analyzer (Applied Biosystems, Foster City, CA).
Northern Blot Analysis.
Northern blotting was performed with 30 ESTs and GPC5 cDNA against five cell lines (Rec1, Karpas 1718, OCI-Ly4, Jurkat, and ATN-1) and human placenta. Additional analysis used the candidate genes BC040320 and GPC5, which was included because it has been reported to be a candidate gene for this region (15)
. We analyzed and compared the expression of each of the ESTs and GPC5 in the cell lines with high-level amplification at 13q31-q32 (Rec1, Karpas 1718, and OCI-Ly4) and in the cell lines without (Jurkat and ATN-1). To examine the expression of BC040320 and GPC5 in detail, Northern blot analysis was also performed for several cell lines and patients. Northern blot hybridization was performed with a standard method (21)
. Each RT-PCR product was used as a specific probe labeled by PCR. Briefly, 10 ng of the RT-PCR products were labeled with [
-32P]dCTP by PCR. The reactions were carried out with 25 cycles of denaturation (94°C, 0.5 min), annealing (55°C, 0.5 min), and extension (72°C, 2.5 min), and a final extension of 5 min at 72°C. Total cellular RNA (5 µg) was size-fractioned on 1% agarose/0.66 M formaldehyde gel, transferred onto a Hybond-N+ nylon membrane (Amersham Pharmacia Biotech, Tokyo, Japan). The membranes were then hybridized overnight at 42°C with [-32P]dCTP-labeled probes, washed, and then exposed to BIOMAX MS films (EKC, Rochester, NY).
Candidate Gene Analysis.
BC040320, a candidate gene in the 13q31-q32 amplification region, was additionally analyzed. To confirm the sequence of the candidate gene, RT-PCR was performed between exon 1 and exon 4 of BC040320 using the primers 5'-TCCGGTCGTAGTAAAGCGCAGGCG-3', designed on the side of exon1 and 5'-CTGAAGTCTCAAGTGGGCAT-3', designed on the side of exon4 of BC040320. The PCR reaction was the same as the one described in the RT-PCR section.
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RESULTS |
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. The linearity of copy number changes was studied with cell lines having a different number of X chromosomes. As shown in Fig. 1B
, the result of the plot of each calculated mean fluorescence ratio demonstrated that the fluorescence ratio was proportional to the change of one copy number. The array CGH used for four cell lines (Karpas 1718, Rec1, OCI-Ly4, and OCI-Ly7) and one DLBCL patient (D778) demonstrated high-level gains in copy number changes at 13q31-q32. Fig. 2A
shows a representative result for Karpas 1718 of the array CGH. Detailed results of chromosome 13 from three cell lines (Karpas 1718, Rec1, and OCI-Ly7) and one DLBCL patient (D778) are shown in Fig. 2B
. Conventional CGH and FISH analyses clearly confirmed these array CGH data (Fig. 3)
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were conducted, and it was found that the common amplified region at 13q31-q32 was located between RP11–29C8 and RP11–93M14. The high-resolution array CGH data are shown in Fig. 4B
. Karpas 1718 and D778 (DLBCL patient sample) showed a wide area of amplification extending over >50 Mb of chromosome 13q. A small genomic region showing high-level amplification (defined as log2 ratio >1) extended from 13q22.2 to 13q31.3, with the region of 13q31.3 in particular showing a higher log2 ratio of >2. In the same manner, OCI-Ly7 and Rec1 also showed high-level amplification, which confined to 13q31.3. These results identified the common region of high-level amplification to extend from RP11–360A9 to RP11–481A22. On the basis of the FISH and array CGH results, we defined the genomic region between RP11–360A9 and RP11–93M14 as the common and smallest region of amplification in four cell lines and one DLBCL patient.
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. Thirty ESTs and GPC5, which showed the expected size of band, were found to be positive in all of the three cell lines with amplification of 13q31.3, and they were confirmed by their nucleotide sequence. Fifteen ESTs also showed the expected size, but RT-PCR analysis demonstrated only one or two cell lines so that they were excluded as candidate ESTs associated with amplification at 13q31.3. The remaining 21 ESTs did not show any bands in either OCI-Ly4 or fetal brain. They were also examined with another set of primers, but again no bands were detected (data not shown) so that they were also excluded as the candidate ESTs. A total of 35 of 65 ESTs were thus excluded and not additionally analyzed.
Northern Blotting.
To identify the expression patterns of 30 ESTs and GPC5, Northern blot was used for six kinds of RNAs, which were human placenta, three B-cell lymphoma cell lines (Rec1, Karpas 1718, and OCI-Ly4) with 13q31.3 amplification, and two T-cell lymphoma cell lines (Jurkat and ATN-1) without 13q31.3 amplification. Twenty-two of the ESTs showed hardly any detectable bands in any of the cell lines (Table 2)
. Fig. 5
shows representative expression patterns of the ESTs. AF339828 and BC040320 showed the similar expression pattern of a transcript of 6 kb and a smeary band >6 kb. The signals were observed in only three B-cell lymphoma cell lines, but not in human placenta or the T-cell lines. GPC5, a gene incompletely included in the common region of amplification at 13q31-q32, showed weak expression of 5-kb transcript in all of the cell lines and the human placenta at similar intensity. The signals for the other ESTs did not reflect any difference in copy number at 13q31.3 between cell lines and human placenta. Therefore, we regarded AF339828 and BC040320 as the most possible target gene for amplification at 13q31.3. Additional study against various samples including patient samples and normal tissues was performed with these two ESTs, and GPC5, reportedly a target gene for 13q31.3 amplification, was also examined.
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. High-level expression of BC040320 was seen in five cell lines with amplification at 13q31-q32 (Rec1, Karpas 1718, OCI-Ly4, OCI-Ly7, and OCI-Ly8). Lower level of expression than that of the five cell lines was seen in three cell lines without amplification (Karpas 422, SP49, and SUDHL6). Furthermore, two patients with amplification showed higher expression than the other two patients without amplification. These results indicated that the expression of BC040320 paralleled the gain in copy number shown by both conventional and array CGH. On the same membrane, expression of GPC5 in five cell lines with amplification at 13q31-q32 was not significantly different from that of the other cell lines without amplification, suggesting that GPC5 is not a likely candidate gene. The expression pattern of BC040320 was examined against various hematopoietic cell lines (T-cell lymphoma, multiple myeloma, myeloid leukemia, and natural killer/T-cell lymphoma; Fig. 6B
). Some cell lines showed weak signals when compared with the two cell lines with high-level amplification. GPC5 cDNA again yielded very weak signals without significant differences but with some variation. When normal tissues were examined, the BC040320 signal was hardly observable except for lung, thymus, and lymph node (Fig. 6C)
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Full Length, Genomic Location, and Characterization of the Candidate Gene.
We focused on AF339828 and BC040320 as the most likely candidate gene on the basis of the results of FISH, array CGH, and Northern blot analysis. We named this candidate gene C13orf25 (Chromosome 13 open reading frame 25) according to the recommendation of HUGO Gene Nomenclature Committee.8
To additionally characterize this gene and cDNA structures, we performed RT-PCR on exon 1 to exon 4 of BC040320. Two transcripts were obtained and sequence analysis found the shorter one to be transcript-A and the longer one transcript-B (Fig. 7)
. Database search with the Vega Genome Browser showed that bA121J7.2 (Vega_gene ID) is also located in this region.9
The peptides of 32-amino acids (AA) were predicted as bA121J7.2. The peptides of 32-AA predicted in bA121J7.2 were also predicted transcript-A. Furthermore, the same initiation codon predicted the 70-AA polypeptide in the transcript-B. It should be noted that five kinds of precursor micro-RNAs (miRNAs; miR91-precursor-13 micro RNA, miR18- precursor-13 micro RNA, miR19a-precursor-13 micro RNA, miR19b-precursor-13 micro RNA, and miR92-precursor-13 micro RNA), including seven kinds of miRNA (microRNA miR-17, miR-91, miR-18, miR-19a, miR-20, miR-19b, and miR-92) were also recognized in the sequence of transcript-B (Fig. 7)
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Northern blotting also showed that expression of GPC5 in cell lines with amplification at 13q31-q32 was not significantly different from that of the other cell lines without amplification. On the other hand, both BC040320 and AF339828 were expressed only in B-cell lymphoma cell lines with 13q31-q32 amplification but not in T-cell lymphoma or human placenta without 13q31-q32 amplification. Their ESTs were fully included in the common region of amplification at 13q31-q32. Detailed analysis using Northern blot showed that the expression of BC040320 almost paralleled the gains in copy number shown by both conventional and array CGH. Northern blot analysis showed that BC040320 was especially overexpressed in B-cell lymphoma cell lines with amplification at 13q31-q32 and hardly expressed in normal tissues, including lymphoid tissues. Although we also found minor mRNA expression of BC040320 in SP49 (mantle cell lymphoma cell line) and SUDHL6 (B-cell lymphoma cell line) without amplification at 13q31-q32 (Fig. 6B)
, this expression may well have been caused not by the gain in copy number but other reasons that are not yet fully understood. These results suggested that BC040320 was the most likely a candidate gene for the amplification at 13q31-q32. We named this candidate gene C13orf25 (Chromosome 13 open reading frame 25).
To confirm the validity of C13orf25 cDNA, RT-PCR was performed, and two transcripts (Transcript-A and -B) were obtained. The Vega genome browser9
predicted the presence of a gene, bA121J7.2, encoding 32-AA polypeptides in the Transcript-A cDNA. A possible open reading frame in Transcript-B was also predicted, encoding 70-AA polypeptides starting from the same ATG (Fig. 7)
. The genomic structure of C13orf25 might be incomplete on the 3' side because AF339828, which showed the same pattern of hybridization as BC040320, was observed near C13orf25 and was located at 300-bp downstream of C13orf25. Because of the presence of multiple bands in Northern blot analysis with BC040320, various transcripts might also be produced, but RT-PCR demonstrated major transcripts. The result of computer analysis using National Center for Biotechnology Information BLAST10
showed that the predicted proteins of C13orf25 contained no putative domains in those transcripts. Further study is needed, however, to characterize the proteins.
Five precursor miRNAs (miR91-precursor-13 miRNA, miR18-precursor-13 miRNA, miR19a-precursor-13 miRNA, miR19b-precursor-13 miRNA, and miR92-precursor-13 miRNA), including seven mature miRNAs (miRNA miR-17, miR-91, miR-18, miR-19a, miR-20, miR-19b, and miR-92), were obtained from the transcript-B sequence. The function of miRNA reportedly is to regulate the expression of target genes in both humans (27) and Caenorhabditis elegans (28, 29, 30, 31) . miRNAs also mediate a cleavage of mRNA in Arabidopsis thaliana (32 , 33) . Calin et al. (34) reported recently an association between chronic lymphocytic leukemia and deletion of a section of chromosome 13 that contains the genes for miR-15 and miR-16. The presence of these miRNAs on the C13orf25 gene may provide an insight into the processes of tumorigenesis.
In the study presented here, we were able to demonstrate that C13orf25 but not GPC5 is the most likely candidate gene for amplification. C13orf25 gene was expressed in association with genomic amplification, and may play an important role in tumorigenesis and resulting poor prognosis.
Additional investigation into the function of C13orf25, including the seven miRNAs, can be expected to provide an insight into the role of the C13orf25 in tumorigenesis.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Note: A. Ota and H. Tagawa contributed equally to this work.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Requests for reprints: Masao Seto, Division of Molecular Medicine, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. Phone: 81-52-762-6111, extension 7080/7082; Fax: 81-52-764-2982; E-mail: mseto{at}aichi-ml.jp
4 Internet address: http://bacpac.chori.org/. 
5 Internet address: http://www.ensembl.org/.
6 Internet address: http://www.ncbi.nlm.nih.gov/.
7 Internet address: http://genome.ucsc.edu/.
8 Internet address: http://www.gene.ucl.ac.uk/nomenclature/.
9 Internet address: http://vega.sanger.ac.uk/.
10 Internet address: http://www.ncbi.nlm.nih.gov/BLAST/.
Received 12/ 3/03. Revised 2/ 5/04. Accepted 2/23/04.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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6.8 Mb region of 13q32–33. Genes Chromosomes Cancer, 32: 236-43, 2001.[CrossRef][Medline]
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G. A. Calin and C. M. Croce MicroRNA-Cancer Connection: The Beginning of a New Tale. Cancer Res., August 1, 2006; 66(15): 7390 - 7394. [Abstract] [Full Text] [PDF]
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A. Oshiro, H. Tagawa, K. Ohshima, K. Karube, N. Uike, Y. Tashiro, A. Utsunomiya, M. Masuda, N. Takasu, S. Nakamura, et al. Identification of subtype-specific genomic alterations in aggressive adult T-cell leukemia/lymphoma Blood, June 1, 2006; 107(11): 4500 - 4507. [Abstract] [Full Text] [PDF]
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W. Chen, J. Houldsworth, A. B. Olshen, G. Nanjangud, S. Chaganti, E. S. Venkatraman, J. Halaas, J. Teruya-Feldstein, A. D. Zelenetz, and R. S. K. Chaganti Array comparative genomic hybridization reveals genomic copy number changes associated with outcome in diffuse large B-cell lymphomas Blood, March 15, 2006; 107(6): 2477 - 2485. [Abstract] [Full Text] [PDF]
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K. K.-H. Farh, A. Grimson, C. Jan, B. P. Lewis, W. K. Johnston, L. P. Lim, C. B. Burge, and D. P. Bartel The Widespread Impact of Mammalian MicroRNAs on mRNA Repression and Evolution Science, December 16, 2005; 310(5755): 1817 - 1821. [Abstract] [Full Text] [PDF]
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Y. Kasugai, H. Tagawa, Y. Kameoka, Y. Morishima, S. Nakamura, and M. Seto Identification of CCND3 and BYSL as Candidate Targets for the 6p21 Amplification in Diffuse Large B-Cell Lymphoma Clin. Cancer Res., December 1, 2005; 11(23): 8265 - 8272. [Abstract] [Full Text] [PDF]
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Y. Hayashita, H. Osada, Y. Tatematsu, H. Yamada, K. Yanagisawa, S. Tomida, Y. Yatabe, K. Kawahara, Y. Sekido, and T. Takahashi A Polycistronic MicroRNA Cluster, miR-17-92, Is Overexpressed in Human Lung Cancers and Enhances Cell Proliferation Cancer Res., November 1, 2005; 65(21): 9628 - 9632. [Abstract] [Full Text] [PDF]
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 G. A. Calin, M. Ferracin, A. Cimmino, G. Di Leva, M. Shimizu, S. E. Wojcik, M. V. Iorio, R. Visone, N. I. Sever, M. Fabbri, et al. A MicroRNA Signature Associated with Prognosis and Progression in Chronic Lymphocytic Leukemia N. Engl. J. Med., October 27, 2005; 353(17): 1793 - 1801. [Abstract] [Full Text] [PDF]
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H. Tagawa, M. Suguro, S. Tsuzuki, K. Matsuo, S. Karnan, K. Ohshima, M. Okamoto, Y. Morishima, S. Nakamura, and M. Seto Comparison of genome profiles for identification of distinct subgroups of diffuse large B-cell lymphoma Blood, September 1, 2005; 106(5): 1770 - 1777. [Abstract] [Full Text] [PDF]
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H. Tagawa, S. Tsuzuki, R. Suzuki, S. Karnan, A. Ota, Y. Kameoka, M. Suguro, K. Matsuo, M. Yamaguchi, M. Okamoto, et al. Genome-Wide Array-Based Comparative Genomic Hybridization of Diffuse Large B-Cell Lymphoma: Comparison between CD5-Positive and CD5-Negative Cases Cancer Res., September 1, 2004; 64(17): 5948 - 5955. [Abstract] [Full Text] [PDF]
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G. A. Calin, C.-G. Liu, C. Sevignani, M. Ferracin, N. Felli, C. D. Dumitru, M. Shimizu, A. Cimmino, S. Zupo, M. Dono, et al. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias PNAS, August 10, 2004; 101(32): 11755 - 11760. [Abstract] [Full Text] [PDF]
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shows the common region of gain in copy number, which extended fromRP11–29C8 to RP11–93M14. The positions of STS markers and all BAC clones were confirmed from information archived by Ensembl Genome Data Resource.
in Transcript-B. C, polypeptides sequences are also shown below the structure. The polypeptides of 13 amino acids (AA) are shared by Transcript-A and Transcript-B, and are indicated by underlining.