Point Mutations and Deletions of the Bcl10 Gene in Solid Tumors and Malignant Lymphomas1

[CANCER RESEARCH 59, 5674–5677, November 15, 1999] Advances in Brief

Sug Hyung Lee,2 Min Sun Shin,2 Hong Sug Kim, Won Sang Park, Su Young Kim, Hun Kyung Lee, Jik Young Park, Ro Ra Oh, Ja June Jang, Kyung Mi Park, Ji Youn Han, Chang Suk Kang, Jung Young Lee, and Nam Jin Yoo3 Departments of Pathology [S. H. L., M. S. S., H. S. K., W. S. P., S. Y. K., H. K. L., J. Y. P., R. R. O., J. Y. L., N. J. Y.], Internal Medicine [J. Y. H.], Clinical Pathology [C. S. K.], and Cancer Research Institute [S. H. L., J. Y. L., W. S. P., N. J. Y.], College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea; Department of Pathology and Cancer Research Center, Seoul National University College of Medicine, Seoul 110-799, Korea [J. J. J.]; Department of Pathology, Sanggye Paik Hospital, College of Medicine, Inje University, Seoul 139-707, Korea [K. M. P.]

Abstract and effector molecules, including Apaf-1, caspase-1, caspase-2, caspase-9, RAIDD, RICK/RIP/CARDIAK, and ARC (9–15). The Bcl10 gene, which encodes a protein with proapoptotic activity, Bcl10 expressed in a MALT lymphoma exhibited a frameshift recently has been identified on chromosome 1p22. In this study, we mutation resulting in truncation beyond the CARD (9, 10). Unlike the analyzed somatic mutations and deletions of the Bcl10 gene in a series of 439 tumor tissues from various histological origins that are known to have wild-type Bcl10 protein, the truncated mutants failed to induce apop- ␬ frequent loss of heterozygosity at chromosome 1p22. According to the tosis but retained nuclear factor- B activation (9–12). Some proteins LOH study at intragenic polymorphic sites, deletion of Bcl10 in inform- that induce apoptosis function as suppressors of transformation, and ative cases was detected in 50% of malignant mesotheliomas, 33% of such transformation is suppressed efficiently by some human tumor gastric carcinomas, 23% of breast carcinomas, 20% of hepatocellular suppressor proteins, such as wild-type p53 (16). Cotransfection of carcinomas, 17% of lymphomas, 15% of colorectal carcinomas, 13% of wild-type Bcl10 reduced the numbers of transformed colonies gener- laryngeal carcinomas, and 10% of male germ cell tumors (GCTs). In ated by oncogenes such as ras, HPVE7, E1a, and mutant p53, whereas contrast, we detected Bcl10 mutations in 4 of 120 lymphomas (3.3%) and cotransfection with mutant Bcl10 markedly enhanced the number of 2 of 78 GCTs (2.6%), respectively, but no mutation was found in the colonies and caused the transformed colonies to appear earlier (9). remaining solid tumors analyzed. Taken together, these data imply that These data indicate that failure of Bcl10-mediated apoptosis caused by Bcl10 may occasionally be involved in the pathogenesis of lymphoma and GCTs. However, the absence or low frequency of the mutation suggests gene mutation may contribute to the development of human tumors. that either Bcl10 is inactivated by other mechanisms or it is not the only To date, there have been contradictory reports on Bcl10 gene target of chromosome 1p22 deletion in human tumors. mutations in human tumors. Two research groups reported frequent Bcl10 mutations in primary lymphomas and/or cell lines from MMs, Introduction GCTs, and colon carcinoma (9, 10), whereas the other two groups reported the absence of Bcl10 mutation in tumor tissues of lymphoma The development of human tumors results from clonal expansion of and GCTs, and cell lines from MM and GCTs (17, 18). To charac- genetically modified cells that acquired selective growth advantage terize the Bcl10 mutation in human tumors, the following questions through accumulated alterations of proto-oncogenes and tumor sup- were investigated in this study: (a) whether human tumor tissues from pressor genes (1). Inactivation of a tumor suppressor gene frequently various histological origins that are known to have frequent LOH at is accompanied by loss of portions of the chromosome on which the chromosome 1p22 have somatic mutations of Bcl10 gene; and (b) if tumor suppressor gene resides (2). Deletions and rearrangements of so, whether the Bcl10 somatic mutation is relevant to the frequent chromosome 1p22 have been reported in many types of human LOH at chromosome 1p22 in human tumors. tumors, raising the possibility that tumor suppressor genes are present in this region (3–7). Materials and Methods Cytogenetic studies of MALT4 lymphoma have identified abnor- malities of chromosome 1p22, in particular translocation t(1;14)(p22; Tissue Samples. A series of 439 paraffin-embedded tissues of 120 malig- q32), as uncommon but recurrent events (8). Recently, Willis et al. (9) nant lymphomas (88 B-cell-lineage tumors and 32 T-cell-lineage tumors), 78 cloned a t(1;14)(p22;q32) translocation breakpoint from a low-grade GCTs, 15 MMs, 41 colorectal adenocarcinomas, 60 invasive ductal carcinomas MALT lymphoma and identified a recurrent breakpoint upstream of of breast, 43 advanced gastric adenocarcinomas, 50 HCCs, and 32 laryngeal the promoter of a novel gene, Bcl10. The Bcl10 gene is a cellular squamous cell carcinomas were selected for SSCP and LOH analysis of the homologue of the herpesvirus-2 E10 gene; both contain amino-termi- Bcl10 gene. The malignant lymphomas tested consisted of 68 diffuse large B-cell lymphomas, 13 MALT lymphomas, 10 angiocentric lymphomas, 2 nal CARD homologues to that found in several apoptotic regulatory mantle cell lymphomas, 5 follicular lymphomas, 8 anaplastic large cell lymphomas, 12 peripheral T-cell lymphomas, unclassified, and 2 angioimmuno- Received 6/22/99; accepted 10/1/99. blastic T-cell lymphomas. The GCTs comprised 35 mature teratomas, 4 The costs of publication of this article were defrayed in part by the payment of page immature teratomas, 16 yolk sac tumors, 1 embryonal carcinoma, 16 semino- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. mas, and 6 tumors with mixed histology. The tumor samples of laryngeal 1 This work was supported by funding from the Molecular Medicine Research Group carcinoma and breast carcinoma included 20 and 28 cases of lymph node program of the Ministry of Science and Technology of Korea (98-J03-02-01-A-01), and metastases, respectively. from the Catholic Medical Center of Korea (the special project of 1999). Microdissection. Malignant cells were selectively procured from H&E- 2 Sug Hyung Lee and Min Sun Shin contributed equally to this work. 3 To whom requests for reprints should be addressed, at Department of Pathology, stained sections using a 30G1/2 hypodermic needle (Becton Dickinson, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Franklin Lakes, NJ) affixed to a micromanipulator, as described previously Seoul 137-701, Korea. Phone: 82-2-590-1191; Fax: 82-2-537-6586. (19). We also microdissected infiltrating lymphocytes for corresponding nor- 4 The abbreviations used are: MALT, mucosa-associated lymphoid tissue; CARD, mal DNA from the same slide in all cases. This microdissection technique used caspase recruit domain; MM, malignant mesothelioma; GCT, male germ cell tumor; LOH, loss of heterozygosity; HCC, hepatocellular carcinoma; SSCP, single-strand conforma- in this study has been proven to be precise and effective for procurement of tional polymorphism. tumor cells without contamination by normal cells (19). DNA extraction was 5674

Table 1 Polymorphisms and LOH data of Bcl10 gene in human tumors Allele LOH of each tumor type (no. of LOH cases/no. of informative cases) DNA Amino acid frequencya Exon alteration alteration (%) Lymphoma GCT MM HCC Breast cancer Stomach cancer Colorectal cancer Laryngeal cancer 1 13G Ala 5 Ser 2 NDb ND ND ND ND ND ND ND 1 24G Leu 8 Leu 20 2/15 2/25 2/6 2/10 2/13 2/8 1/7 1/7 3 485C Thr 162 Met 3 ND ND ND ND ND ND ND ND 3 638G Gly 213 Glu 39 3/19 3/31 5/10 4/20 5/26 6/19 2/15 1/12 Total 5/29 (17) 4/40 (10) 6/12 (50) 5/25 (20) 7/31 (23) 8/24 (33) 3/20 (15) 2/15 (13) a Percentage shown represents allele frequency in 50 healthy individuals. b ND, not determined.

performed by a modified single-step DNA extraction method, as described Complete or nearly complete absence of one allele in the tumor DNA of previously (19). informative cases, as defined by direct visualization, was considered as LOH. SSCP Analysis. Genomic DNA from normal lymphocytes or tumor cells was amplified by PCR using seven primer pairs covering the entire coding region of the Results Bcl10 gene. The primer pairs were as follows: exon 1, 5Ј-GGACCCGGAA- GAAGCGCCATCTCC-3Ј and 5Ј-GATCCTCCTTGTCCTCGGACTC-3Ј (prod- Bcl10 Mutations. Genomic DNA was isolated and analyzed for uct size, 187 bp); exon 2-1, 5Ј-AAGACTGCCAACTAATAGTCACGT-3Ј and potential mutations in all three exons of the Bcl10 gene by PCR-SSCP 5Ј-AAGTAGTCTAACAATTTTCCAGCCC-3Ј (200 bp); exon 2-2, 5Ј-CACT- analysis. Enrichment and direct sequence analysis of aberrantly mi- GAAGAAATTTCTTGTCGAACA-3Ј and 5Ј-AGACCTTTTGGGTTTTCCTG- grating bands led to the identification of mutations in 6 of the 439 TAAGTA-3Ј (184 bp); exon 2-3, 5Ј-AAGGGCTGGAAAATTGTTAGA-3Ј and samples (1.4%): 4 of 120 malignant lymphomas (3.3%), and 2 of 78 5Ј-AAAGCATTATTACATTTAAATTAGCTCC-3Ј (231 bp); exon 3-1, 5Ј- GCTs (2.6%; Table 2; Fig. 1, A and B). Of the six mutations identi- TTAACAAGTCACAAGATGGACAGTG-3Ј and 5Ј-CGTGCTGGATTCTCCT- fied, five were observed in exon 3, and one was observed in exon 2. TCTG-3Ј (217 bp); exon 3-2, 5Ј-AACTGAGGGCATCCACTGTCA-3Ј and Fifteen MMs, 41 colorectal adenocarcinomas, 60 invasive ductal Ј Ј Ј 5 -CAGGTCTGGGAAGTGTAGTTGAAGA-3 (150 bp); exon 3-3, 5 -AG- carcinomas of breast, 43 advanced gastric adenocarcinomas, 50 GCAGAACTGAAAATACCAT-3Ј and 5Ј-TTAAAAATTAAAAGGCAATA- HCCs, and 32 laryngeal squamous cell carcinomas did not show any AAGTG-3Ј (191 bp). The oligonucleotide primers for exons 2-2, 2-3, 3-1, 3-2, and 3-3 were designed with the program Oligo (National Biosciences, Plymouth, MN) Bcl10 gene mutations in the SSCP analysis. The four lymphomas with using sequences obtained from GenBank (accession no. AF097732), and primers the mutations consisted of one angiocentric T-cell lymphoma of the for exons 1 and 2-1 were the same primers described by Willis et al. (9). Each PCR nasal cavity (case ML 21), one B-cell-origin diffuse large cell lym- reaction was performed under standard conditions in a 10-␮l reaction mixture phoma of the spleen (case ML 15), one B-cell-origin diffuse large cell containing 1 ␮l of template DNA, 0.5 mM of each primer, 0.2 ␮M of each lymphoma of the mesenteric lymph node (case ML 23), and one deoxynucleotide triphosphate, 1.5 mM MgCl2, 0.4 units of AmpliTaq Gold po- high-grade MALT lymphoma (case GL 13). Both of the two GCTs lymerase (Perkin-Elmer, Foster City, CA), 0.5 ␮Ci of [32P]dCTP (Amersham, with Bcl10 mutations were mature teratomas (cases GT 37 and GT Buckinghamshire, United Kingdom), and 1 ␮lof10ϫ buffer. The reaction 53). None of the corresponding normal samples showed evidence of mixture was denatured for 12 min at 94°C and incubated for 35 cycles (denaturing mutations by SSCP (Fig. 1, A and B), indicating that the mutations for 30 s at 94°C, annealing for 30 s at 50–60°C, and extension for 30 s at 72°C). detected in these specimens had risen somatically. Final extension was continued for 5 min at 72°C. After amplification, PCR products were denatured for 5 min at 95°C at a 1:1 dilution of sample buffer All six mutations identified were caused by single-nucleotide sub- containing 98% formamide-5 mM NaOH and were loaded onto a SSCP gel (FMC stitution. Among these, four were missense mutations that affect Mutation Detection Enhancement system; Intermountain Scientific, Kaysville, codons 80, 161, 175, and 200 of Bcl10, and would result in amino acid UT) with 10% glycerol. After electrophoresis, the gels were transferred to 3-mm substitutions (Table 2). The remaining two mutations included one Whatman paper and dried, and autoradiography was performed with Kodak nonsense mutation (GL 13) and one silent mutation (GT 37). The X-OMAT film (Eastman Kodak, Rochester, NY). For the detection of mutations, nonsense mutation showed a T-to-A transversion at bp 521, causing a DNAs showing mobility shifts were cut out from the dried gel and reamplified for premature stop at codon 174. The detection of Bcl10 gene mutations 35 cycles using the same primer set. Sequencing of the PCR products was carried was reproducible through triplicate experiments that included tissue out using the cyclic sequencing kit (Perkin-Elmer) according to the manufacturer’s microdissection, PCR, SSCP, and sequencing analysis, ensuring the recommendation. specificity of the results. LOH Analysis. It has been known that three polymorphisms at positions 13, 24, and 638 are located in the Bcl10 gene (17, 18). In addition, during the Allelic Status. In the course of the SSCP analysis of the Bcl10 current study, we found a novel biallelic polymorphisms at bp 485 (Table 1). gene, we identified four patterns of aberrant bandshift (two in exon 1 Therefore, SSCP analysis at these polymorphic sites was used for the detection and two in exon 3), which were detected in both the tumor tissues and of LOH as well as for the detection of mutations. The PCR and SSCP the corresponding normal tissues (Fig. 1E). These patterns were also conditions of the LOH study were the same as the condition described above. observed in DNAs from the lymphocytes of healthy individuals (Ta-

Table 2 Data summary of the cases with Bcl10 mutations LOH

Case Histologic type Exon Nucleotide change Codon Predictive effect P1a P3b ML 15 B-cell lymphoma, diffuse-large cell 2 240 C to A 80 Asp to Glu NIc LOH ML 21 Angiocentric T-cell lymphoma 3 524 C to T 175 Pro to Leu LOH LOH ML 23 B-cell lymphoma, diffuse-large cell 3 539 G to A 200 Gly to Asp NI Het GL 13 MALT lymphoma, high grade 3 521 T to A 174 Stop at codon 174 NI NI GT 37 Mature teratoma 3 468 A to T 156 Pro to Pro NI NI GT 53 Mature teratoma 3 588 C to T 161 Thr to Met Het Het a Polymorphism at bp 24. b Polymorphism at bp 638. c NI, not informative (homozygosity); Het, retention of heterozygosity. 5675

Fig. 1. Representative results showing SSCP analysis for mutations (A and B), sequencing analysis (C and D), and SSCP analysis for LOH (E)oftheBcl10 gene. A and B, SSCPs of DNA from tumors (T) of case GL 13 (A) and GT 53 (B) show wild-type bands and additional aberrant bands when compared with SSCPs from corresponding normal lymphocytes (N). C and D, cyclic sequencing analysis using DNA template from aberrant bands from case GL 13 (C) and case GT 53 (D). The arrows indicate the nucleotide substitutions in tumor tissues. E, detection of allelic loss by amplification of a region encompassing the biallelic polymorphism at bp 638 in exon 3. Left panel, SSCP showing a noninformative case. Middle panel, SSCP showing retention of heterozygosity. Right panel, a pattern of LOH. Loss of two bands was observed in DNA from tumor cells (T) compared with the SSCP from normal cells (N). ble 1). Thus, we considered these alteration patterns as polymor- boxyl terminus complexes with caspase-9 and promotes its processing phisms. On the DNA sequencing, these polymorphisms exhibited T to the active protease (11). Mutational analysis of these CARD and instead of G at bp 13, C instead of G at bp 24, T instead of A at bp non-CARD regions demonstrated that both regions are required for 485, and A instead of G at bp 638. Because the heterozygosity rates inducing apoptosis (11). In the current study, one missense mutation of the polymorphisms at bp 13 and bp 485 were too low for LOH (80 Asp to Gly) was identified in the CARD domain. Therefore, in study (Table 1), only the polymorphisms at bp 24 and bp 638 were this case, the mutated CARD might not mediate oligomerization of used for the LOH study of the Bcl10 gene. Overall, 196 of 392 cases Bcl10 protein. The other four mutations identified in the non-CARD analyzed (50%) were informative for one or two polymorphic mark- carboxyl terminus (161 Thr to Met, 174 Leu to stop, 175 Pro to Leu, ers, and 40 of 196 (20%) informative cases showed LOH. The LOH and 200 Gly to Asp), might impair death signaling through poor data of each type of tumors are summarized in Table 1. interaction of the mutant proteins with caspase-9. In the six cases with Bcl10 mutations, two (ML 15 and ML 21) In MALT lymphoma, Zhang et al. (10) identified a Bcl10 point showed LOH for one or two polymorphic marker(s). Another two mutation that generates an amino acid substitution at position 174. In mutation cases (GL 13 and GT 37) were not informative for the addition, the mutation of codon 175 of Bcl10 was identified in polymorphic markers. The remaining two cases (ML 23 and GT 53) follicular lymphoma (9). Of the six Bcl10 gene mutations identified in were heterozygous for at least one of these markers but did not show the present study, two mutations generated amino acid changes at LOH (Table 2). residues 174 and 175 of exon 3. In exon 2, the mutations involving amino acid substitutions at residue 80 were observed in our study and Discussion the previous study (9). These observations suggest that these areas in To extend the previous findings on the Bcl10 gene mutations in exon 2 (codon 80) and in exon 3 (codons 174 and 175) might be some some human tumors and cell lines (9, 10) to a wider range of primary of the common mutation sites of the Bcl10 gene in human tumors. human tumors, we investigated somatic mutations and deletions of the The previous study by Zhang et al. (10) found one nucleotide Bcl10 gene in a series of 439 tumor tissues from various histological change at bp 638 (G to A) of Bcl10 gene and described it as a origins that are known to have frequent LOH at chromosome 1p22. missense mutation. However, in this study, we observed this nu- We detected four and two Bcl10 mutations in lymphomas and GCTs, cleotide change in both tumors and their corresponding normal respectively, but no mutation was found in the remaining solid tumors tissues (Table 1; Fig. 1E). Moreover, the change was found in analyzed, which suggests that Bcl10 mutations are involved in the lymphocytes of healthy individuals, which indicates that it is a pathogenesis of human tumors. polymorphism of the Bcl10 gene. Using this and another intragenic Although functional studies have not yet been performed, some of polymorphism, we have found LOHs with a range from 10 to 50% the mutations identified in the present study are likely to disrupt or according to the tumor types, which is comparable to the LOH data alter the normal function of the Bcl10 protein. One of the mutations using microsatellite markers at chromosome 1p22 (3–7). However, (case GL 13) identified is a nonsense variant (174 Leu to stop; Table unexpectedly, we found only six Bcl10 mutations in lymphomas 2), which is predicted to cause premature termination of the protein and GCTs. These findings could be explained in several ways. synthesis, and hence resemble typical loss-of-function mutations. An- First, it is possible that other tumor suppressor genes in addition to other of the mutations (case ML 21) would result in an amino acid Bcl10 reside at chromosome 1p22 or that some of the LOHs substitution from Pro to Leu. Proline differs from the other common represent evidence of genomic instability affecting this area with- amino acids in having a secondary amino group, and the resulting out targeting specific genes. Second, the second allele could be cyclic structure would markedly influences protein architecture (20). inactivated by Bcl10 gene silencing through promoter methylation, Therefore, it is possible that Bcl10 mutant protein with an amino acid but this possibility remains unknown at this stage. Third, the substitution from 175 Pro to Leu might have a change in its structure discrepancy might be partially explained by the ongoing mutation and might lose its function, which remains to be confirmed by of the Bcl10 gene in MALT lymphomas. In the course of searching functional and structural analysis. for Bcl10 mutations, Willis et al. (9) observed that different To date, the somatic mutations of the Bcl10 gene in tumor patients sections from different histological blocks from the same tumor have been identified in exons 2 and 3 (9, 10). Exon 2 encodes the showed different SSCP bands; they considered this phenomenon as evolutionarily conserved CARD domain at the amino terminus, and ongoing mutation. Because we did not sequence individual exon 3 encodes most of the non-CARD carboxyl terminus of the genomic clones, the frequency of Bcl10 mutations might be sig- Bcl10 protein (9–14). The CARD motif within Bcl10 induces the nificantly underestimated in the present study. Finally, it is also self-oligomerization of this protein (11–13), and the non-CARD car- possible that the primers we used were not suitable to detect all of 5676

Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1999 American Association for Cancer Research. Bcl10 MUTATIONS IN HUMAN TUMORS the Bcl10 mutations present on the tumors analyzed in this study. 8. Wotherspoon, A. C., Pan, L., Diss, T. C., and Isaacson, P. G. Cytogenetic study of However, this possibility is unlikely because we have also tried B-cell lymphoma of mucosa-associated lymphoma tissue. Cancer Genet. Cytogenet., 58: 35–38, 1992. SSCP analysis with the same primer sets described in the previous 9. Willis, T. G., Jadayel, D. M., Du, M-Q., Peng, H., Perry, A. R., Abdul-Rauf, M., studies (9) and found that the primer sets had the same mutation Price, H., Karran, L., Majekodunmi, O., Wlodarska, I., Pan, L., Crook, T., Hamoudi, detection efficiency (data not shown). R., Isaacson, P. G., and Dyer, M. J. S. Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types. Cell, 96: 35–45, 1999. In summary, we searched for Bcl10 gene mutations in a wide range 10. Zhang, Q., Siebert, R., Yan, M., Hinzmann, B., Cui, X., Xue, L., Rakestraw, K. M., of human tumors with frequent LOH at chromosome 1p22, where Naeve, C. W., Beckmann, G., Weisenburger, D. D., Sanger, W. G., Nowotny, H., Bcl10 resides, and found that this gene is somatically mutated in some Vesely, M., Callet-Bauchu, E., Salles, G., Dixit, V. M., Rosenthal, A., Schlegelberger, B., and Morris, S. W. Inactivating mutations and overexpression of BCL10, a caspase lymphomas and GCTs. Because wild-type Bcl10 is proapoptotic and recruitment domain-containing gene, in MALT lymphoma with t(1;14)(p22;q32). behaves as a tumor suppressor gene, the Bcl10 mutations identified in Nat. Genet., 22: 63–68, 1999. this study might lead to a longer survival of affected tumor cells and 11. Yan, M., Lee, J., Schilbach, S., Goddard, A., and Dixit, V. mE10, a novel caspase recruitment domain-containing proapoptotic molecule. J. Biol. Chem., 274: 10287– might contribute to tumorigenesis of some lymphomas and GCTs. 10292, 1999. And, because deletion of chromosome 1p22 has been considered as an 12. Koseki, T., Inohara, N., Chen, S., Carrio, R., Merino, J., Hottiger, M. O., Nabel, G. J., important event in the pathogenesis of many human tumors (3–7), and Nunez, G. CIPER, a novel NF ␬B-activating protein containing a caspase studies are now needed to locate any other possible tumor suppressor recruitment domain with homology to herpesvirus-2 protein E10. J. Biol. Chem., 274: 9955–9961, 1999. genes in this region. 13. Srinivasula, S. M., Ahmad, M., Lin, J., Poyet, J. L., Fernandes-Alnemri, T., Tsichlis, P. N., and Alnemri, E. S. CLAP, a novel caspase recruitment domain-containing References protein in the tumor necrosis factor receptor pathway, regulates NF-␬B activation and apoptosis. J. Biol. Chem., 274: 17946–17954, 1999. 1. Reed, J. C. Double identity for proteins of Bcl-2 family. Nature (Lond.), 14: 773–776, 14. Thome, M., Martinon, F., Hofmann, K., Rubio, V., Steiner, V., Schneider, P., 1997. Mattmann, C., and Tschopp, J. Equine herpesvirus-2 E10 gene product, but not its 2. Knudson, A. G. Antioncogenes and human cancer. Proc. Natl. Acad. Sci. USA, 90: cellular homologue, activates NF-␬B transcription factor and c-Jun N-terminal kinase. 10914–10921, 1993. J. Biol. Chem., 274: 9962–9968, 1999. 3. Offit, K., Jhanwar, S. C., Ladanyi, M., Filippa, D. A., and Chaganti, R. S. Cytogenetic 15. Hofmann, K., Bucher, P., and Tschopp, J. The CARD domain: a new apoptotic analysis of 434 consecutively ascertained specimens of non-Hodgkin’s lymphoma: signaling motif. Trends Biochem. Sci., 22: 155–156, 1997. correlations between recurrent aberrations, histology, and exposure to cytotoxic 16. Crook, T., Marston, N. J., Sara, E. A., and Vousden, K. H. Transcriptional activation treatment. Genes Chromosomes Cancer, 3: 189–201, 1991. by p53 correlates with suppression of growth but not transformation. Cell, 79: 4. Mathew, S., Murty, V. V., Bosl, G. J., and Chaganti, R. S. K. Loss of heterozygosity identifies multiple sites of allelic deletions on chromosome 1 in human male germ cell 817–827, 1994. tumors. Cancer Res., 54: 6265–6269, 1994. 17. Fakruddin, J. M., Chaganti, R. S. K., and Murty, V. V. V. S. Lack of BCL10 5. Lee, W. C., Balsara, B., Liu, Z., Jhanwar, S. C., and Testa, J. R. Loss of heterozy- mutations in germ cell tumors and B cell lymphomas. Cell, 97: 683–684, 1999. gosity analysis defines a critical region in chromosome 1p22 commonly deleted in 18. Apostolou, S., De Rienzo, A., Murthy, S. S., Jhanwar, S. C., and Testa, J. R. human malignant mesothelioma. Cancer Res., 56: 4297–4301, 1996. Absence of BCL10 mutations in human malignant mesothelioma. Cell, 97: 6. Nagai, H., Pineau, P., Tiollais, P., Buendia, M. A., and Dejean, A. Comprehensive 684–686, 1999. allelotyping of human hepatocellular carcinoma. Oncogene, 14: 2927–2933, 1997. 19. Lee, J. Y., Dong, S. M., Kim, S. Y., Yoo, N. J., Lee, S. H., and Park, W. S. A simple, 7. Mertens, F., Johansson, B., Hoglund, M., and Mitelman, F. Chromosomal imbalance precise and economical microdissection technique for analysis of genomic DNA from maps of malignant solid tumors: a cytogenetic survey of 3185 neoplasms. Cancer archival tissue sections. Virchows Arch., 433: 305–309, 1998. Res., 57: 2765–2780, 1997. 20. Stryer, L. Biochemistry. New York: Freeman, 1988.

5677

Sug Hyung Lee, Min Sun Shin, Hong Sug Kim, et al.

Cancer Res 1999;59:5674-5677.

Updated version Access the most recent version of this article at: http://cancerres.aacrjournals.org/content/59/22/5674

Cited articles This article cites 19 articles, 8 of which you can access for free at: http://cancerres.aacrjournals.org/content/59/22/5674.full#ref-list-1

Citing articles This article has been cited by 2 HighWire-hosted articles. Access the articles at: http://cancerres.aacrjournals.org/content/59/22/5674.full#related-urls

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://cancerres.aacrjournals.org/content/59/22/5674. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.