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© 2000 American Society for Clinical Oncology Alterations of Chromosome Arms 1p and 19q as Predictors of Survival in Oligodendrogliomas, Astrocytomas, and Mixed OligoastrocytomasFrom the Division of Laboratory Genetics, Division of Anatomic Pathology, Department of Neurology, and Section of Biostatistics, Mayo Clinic and Foundation, Rochester, MN; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD; Division of Neuropathology, Ohio State University, Columbus, OH; and Washington University School of Medicine, St Louis, MO. Address reprint requests to Robert B. Jenkins, MD, PhD, Department of Cytogenetics, Mayo Clinic, 200 First St, Southwest, Rochester, MN 55905; email rjenkins{at}mayo.edu
PURPOSE: A recent report suggests that alterations of chromosome arms 1p and 19q are associated with chemotherapeutic response and overall survival in anaplastic oligodendroglioma patients treated with procarbazine, lomustine, and vincristine chemotherapy. We set out to further clarify the diagnostic and prognostic implications of these alterations in a broader set of diffuse gliomas, including astrocytic neoplasms and low-grade oligodendrogliomas. PATIENTS AND METHODS: Fluorescence in situ hybridization (FISH) signals from DNA probes mapping to 1p and 19q common deletion regions were enumerated in 162 diffuse gliomas (79 astrocytomas, 52 oligodendrogliomas, and 31 mixed oligoastrocytomas), collected as part of an ongoing prospective investigation of CNS tumors. RESULTS: The oligodendroglial phenotype was highly associated with loss of 1p (P = .0002), loss of 19q (P < .0001), and combined loss of 1p and 19q (P < .0001). Combined loss of 1p and 19q was identified as a univariate predictor of prolonged overall survival among patients with pure oligodendroglioma (log-rank, P = .03) and remained a significant predictor after adjusting for the effects of patient age and tumor grade (P < .01). This favorable association was not evident in patients with astrocytoma or mixed oligoastrocytoma. CONCLUSION: Combined loss of 1p and 19q is a statistically significant predictor of prolonged survival in patients with pure oligodendroglioma, independent of tumor grade. Given the lack of this association in patients with astrocytic neoplasms and the previously demonstrated chemosensitivity of oligodendrogliomas, a combined approach of histologic and genotypic assessment could potentially improve existing strategies for patient stratification and management.
DIFFUSE GLIOMAS are the most common primary malignancies of the CNS and are comprised of astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas. Though all glioma subtypes are often grouped together, differences in clinical behavior and response to therapy warrant separation. Furthermore, within each subtype there is a wide spectrum of clinical behavior among individual patients. However, distinguishing glial subtypes based on nuclear and cellular morphology alone is subjective, with significant interobserver variability, even among highly experienced neuropathologists.1-4 The importance of further stratifying patient populations is exemplified by the often remarkable chemosensitivity of a subset of oligodendrogliomas and mixed oligoastrocytomas.5-9 As many as two thirds of oligodendrogliomas have been shown to be chemosensitive, particularly to the combination of procarbazine, lomustine (1-[chloroethyl]-3-cyclohexyl-1-nitrosourea), and vincristine (PCV). A recent report by Cairncross et al10 suggests that alterations of chromosome arms 1p and 19q are associated with both chemotherapeutic response and prolonged overall survival in anaplastic (grade 3) oligodendrogliomas treated with PCV chemotherapy. Though combined loss of 1p and 19q is associated with the oligodendroglial phenotype, these alterations are occasionally encountered in other glioma subtypes, both individually and in combination.11-17 Recently, we studied chromosomes 1 and 19 in a large collection of gliomas, finding loss of 1p, 19q, and combined loss of 1p and 19q in 18%, 38%, and 11% of astrocytomas (n = 55), respectively.3 In the present study, we set out to further understand the potential diagnostic and prognostic significance of 1p and 19q alterations in the three diffuse glioma subtypes: oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas. The prognostic significance of these alterations has not been previously reported for the latter two subtypes, and, in contrast to Cairncross et al,10 our oligodendrogliomas were predominantly low-grade (World Health Organization grade 2).
Tumor Selection and Pathology Review A set of 162 surgically resected diffuse gliomas was selected, based on the availability of tissue for analysis, from cases collected as part of the Glioma Markers Network, an ongoing multi-institutional prospective investigation of CNS tumors. Specimens used for the present analysis were surgically resected at the Mayo Clinic in Rochester, MN (142 cases), or at the Johns Hopkins Hospital in Baltimore, MD (20 cases). Tumors were classified morphologically and graded according to the World Health Organization system1 by three independent neuropathologists. Consensus morphology and grade were established for each glioma, as previously described.3 Specimens derived from initial surgical resection were classified as primary (n = 116, 72%), whereas those from subsequent resections were classified as recurrent (n = 46, 28%).
Clinical Parameters Typical treatment for patients with astrocytoma, either low-grade (grade 2) or high-grade (grades 3 and 4), included surgical resection followed by radiation (approximately 50 to 60 Gy). Most patients with high-grade astrocytoma also received adjuvant chemotherapy that included a nitrosourea compound. At present, however, there is no conclusive evidence that differences in chemotherapy regimens affect the survival of patients with high-grade astrocytomas.18 Approximately half of the patients with low-grade oligodendroglioma or low-grade mixed oligoastrocytoma (grade 2) were treated by radiation (approximately 50 to 60 Gy); the remaining patients were observed. High-grade oligodendrogliomas and high-grade oligoastrocytomas (grades 3 and 4) were typically treated with radiation and adjuvant chemotherapy, consisting of either PCV or a different regimen including a nitrosourea compound.
Flourescence In Situ Hybridization (FISH) Probe Selection and Analysis For each case, a paraffin-embedded tumor block was selected based on tumor content, including the highest grade component and representation of the predominant morphology of the individual case. Approximately 20 5-µm sections were prepared for various studies from each selected tumor block. The first and last sections were hematoxylin and eosin stained, regions representing tumor and normal tissue were delineated, and the first section was examined to ensure that it met the standards by which the block was selected. Importantly, for the present study, FISH analyses were performed using the sections immediately adjacent to the first hematoxylin and eosin stained slide to minimize the effects of tumor heterogeneity. FISH analysis was performed, as previously described.21 Briefly, tumor sections were deparaffinized, dehydrated, microwave treated in citrate buffer (pH 6.0) for 10 minutes, digested in pepsin solution (4 mg/mL in 0.9% NaCl, pH 1.5) for 15 minutes at 37°C, rinsed in two times standard saline citrate (SSC) at room temperature for 5 minutes, and air dried. Dual-probe hybridization was performed using a digoxigenin-labeled locus-specific 1p or 19q probe and a SpectrumGreen-labeled probe (Vysis, Downers Grove, IL) mapping to 1q and 19p, respectively. Probes and target DNA were denatured simultaneously in an 80°C oven for 5 minutes, followed by overnight incubation at 37°C. Slides were then washed in 1.5 mol urea/0.1 times SSC at 45°C for 10 minutes (three times) and in two times SSC at room temperature for 2 minutes. After washing, the digoxigenin-labeled probes were detected using a rhodamine detection kit (Oncor, Gaithersburg, MD). Nuclei were counterstained with 4,6-diamidino-2-phenylindole and the antifade compound p-phenylenediamine. A Zeiss (Thornwood, NY) Axioplan microscope equipped with a triple-pass filter (DAPI/Green/Orange; Vysis, Downers Grove, IL) was used to assess the number of FISH signals for each locus-specific FISH probe. Approximately 300 nonoverlapping nuclei were enumerated per hybridization. Ranges for normal FISH probe copy number were established by hybridizing and enumerating gliosis specimens (data not shown) and through extensive comparisons of FISH, LOH, and CGH data.3 These ranges are delineated in Fig 2.
Statistical Analysis Data for both primary and recurrent tumors were used to evaluate the association between molecular alterations and histologic subtype. These associations were assessed using  2 tests. Pearson’s and Fisher’s exact tests were used to calculate P values for comparison of these binomial proportions. Survival analyses were performed using the 116 specimens from initial surgical resection, with survival defined as the time between tissue acquisition and patient death. Survival distributions were estimated with Kaplan-Meier curves22 and compared among patient subsets with log-rank tests.23 Multivariate analyses were performed by generating Cox models using maximum likelihood methodology.24
Glioma Pathology Review and Clinical Parameters Table 1 lists the distributions of consensus histologic subtype and grade of the gliomas that were evaluated by FISH. Unanimous agreement among the three pathologists for histologic subtype classification was observed for 69% (36 of 52) of oligodendrogliomas, 13% (four of 31) of mixed oligoastrocytomas, and 76% (60 of 79) of astrocytomas. These findings are similar to those previously report by Smith et al.3 Notably, when compared with primary examples, recurrent oligodendrogliomas and oligoastrocytomas were less often grade 2, and recurrent astrocytomas were less often grade 4. Grade 2 astrocytomas were rare with one primary and one recurrent case each. The clinical parameters for the 116 patients with primary glioma are listed in Table 2.
FISH Analysis of Chromosomes 1 and 19 Figure 1 illustrates representative histology for case number 62, a primary grade 2 oligodendroglioma. Also shown are FISH images and corresponding probe enumeration data demonstrating loss of the 1p and 19q common deletion regions for this case.
Figure 2 summarizes the FISH data for all gliomas analyzed and defines four distinct groups of gliomas based on alterations of chromosomes 1 and 19 (blue, green, brown, and red diamonds). Of the 162 gliomas analyzed, 75 (46%) had no apparent alterations of either chromosome 1 or chromosome 19, 11 (7%) had loss of 1p without loss of 19q, 32 (20%) had loss of 19q without loss of 1p, and 37 (23%) had loss of both 1p and 19q. Primary tumors with apparent loss of an entire copy of chromosome 1 or 19 were classified as having loss of 1p or loss of 19q, respectively, for comparisons of genotype with survival.
Associations of 1p and 19q Alterations With Histologic Subtype
Survival Analyses Combined loss of 1p and 19q is a statistically significant positive predictor of overall survival in oligodendroglioma patients. Table 4 lists the molecular and clinical data for each of the 36 primary oligodendroglioma patients. The incidence of recurrence did not differ significantly between those with combined alteration of 1p and 19q and those without this combined alteration (three of 14 v 11 of 22, respectively; P = .16). Notably, all of the patients with combined 1p and 19q loss were alive at last follow-up (median follow-up, 67.5 months), whereas six (27%) of those without these combined alterations have died. Figure 3 shows the Kaplan-Meier curves for these two subsets of oligodendroglioma patients, those with combined loss of 1p and 19q (n = 14) and those without combined loss of 1p and 19q (n = 22). As listed in Table 5, when all grades are analyzed together, the oligodendroglioma patients with combined loss of 1p and 19q demonstrate a significantly better probability of survival than do those without this combined alteration (P = .03).
Cox multivariate models were generated using all 36 primary oligodendroglioma patients analyzed. After adjusting for the effects of patient age and tumor grade, combined loss of 1p and 19q remained a statistically significant positive predictor of overall survival (P < .01). Combined loss of 1p and 19q is not a statistically significant predictor of overall survival in grade 4 astrocytoma or in mixed oligoastrocytoma patients. Of the 53 grade 4 primary astrocytomas, five demonstrated combined loss of 1p and 19q. Though not statistically significant, these five patients exhibited a modest trend toward shorter overall survival (Table 6), with a median survival of 5.6 months compared with the 12-month median survival of the 48 patients without the combined alterations (P = .17). Combined alteration of 1p and 19q was not a statistically significant predictor of survival in mixed oligoastrocytoma patients (P = .98, Table 6).
Loss of 1p or 19q, in isolation, was not a statistically significant predictor of overall survival in any of the glioma subtypes examined (Tables 5 and 6). Patients with oligodendroglioma did, however, demonstrate a trend toward better survival if their tumors exhibited loss of 1p (P = .15) or loss of 19q (P = .15). In contrast, grade 4 astrocytoma patients exhibited a trend toward shorter overall survival if their tumors demonstrated loss of 1p (P = .12) and a trend toward prolonged survival if their tumors had loss of 19q (P = .18).
Diffuse gliomas demonstrate considerable heterogeneity with regard to prognosis, both among and within the histologic subtypes. However, our current capacity to effectively stratify these lesions by histology is primarily limited to subjective differences in cellular morphology. Because no specific immunohistochemical markers are available, other diagnostic and prognostic aids are clearly needed. Tumor genotyping offers the potential for further treatment stratification that minimizes patient morbidity and mortality and may also provide important clues to the underlying mechanisms of glioma tumorigenesis and malignant progression. Allelic alterations of chromosomes 1 and 19 are frequent events in human gliomas, and in the present study we have used FISH analysis to examine the capacity of these alterations to serve as predictors of overall survival. Further, we have confirmed the strong association of these alterations with oligodendroglial morphology in a considerably larger collection of gliomas than has been previously reported. FISH was selected for the present studies because of its considerably higher resolution compared with CGH analysis and its higher sensitivity compared with LOH analysis. In general, FISH can detect a deletion when it is present in as few as 20% to 30% of the cells, whereas molecular techniques require much purer samples.25 In this regard, FISH would be expected to have a considerably higher sensitivity for tumors with clonal heterogeneity or mixed populations. Combined loss of 1p and 19q has been shown to be a statistically significant multivariate predictor of overall survival in anaplastic oligodendrogliomas.10 Our results complement and extend these findings. We demonstrate that combined loss of the 1p and 19q common deletion regions is a statistically significant univariate and multivariate predictor of overall survival for patients with oligodendroglioma, independent of tumor grade. However, demonstrating this association using predominantly low-grade lesions is inherently more difficult because of the longer survival of these patients. Thus, it is important to appreciate these findings in light of the relatively few cases analyzed and the relatively few deaths among these patients. As opposed to those with combined loss, patients with oligodendrogliomas exhibiting loss of 1p or 19q, in isolation, show a trend toward better survival, but these alterations, independently, do not reach statistical significance as predictors of overall survival. Previous reports regarding oligodendrogliomas have suggested that loss of 1p without concomitant loss of 19q is uncommon.16,26 Indeed, the present study identified only two oligodendrogliomas (4%) with loss of 1p that lacked apparent alteration of 19q. There were, however, 10 oligodendrogliomas (19%) with loss of 19q that did not exhibit alteration of 1p, suggesting that loss of 19q precedes loss of 1p in oligodendroglioma development. Perhaps, loss of 19q predisposes these neoplasms to further loss of 1p, which, in turn, commits the tumor to a less aggressive biologic behavior. Alternatively, those tumors without deletion may have other alterations of 1p. Consistent with previous reports,27,28 the incidence of combined 1p and 19q loss in this set of astrocytic tumors was significantly low (six of 79 cases, 8%). Five of these cases were primary tumors, and the patients with these tumors demonstrated a trend toward shorter survival. This may hint of a rare alteration associated with poor prognosis or, more likely, may simply reflect overall genomic instability in a high-grade lesion. In contrast to the associations of combined 1p and 19q losses with the oligodendroglial phenotype, our prior FISH study demonstrated a strong association of p16-RB-CDK4 alterations with the astrocytic phenotype.29 Therefore, a FISH battery using combinations of these oligodendroglial and astrocytic markers could potentially provide diagnostically useful information for diffuse gliomas with equivocal morphologic features. Loss of 1p or 19q, in isolation, was not a statistically significant predictor of overall survival in our astrocytomas. Further, the frequent association of 1p loss with 19q loss seen in oligodendrogliomas was not observed for astrocytomas, suggesting that these alterations are not interrelated in astrocytic tumors as they are in oligodendroglial tumors. There was no association of 1p and 19q alterations, either separately or in combination, with overall survival of the patients with mixed oligoastrocytoma analyzed in this study. It should be noted, however, that this category of tumors is notoriously difficult to define, even among the most experienced neuropathologists, and consists of tumors with varying degrees of oligodendroglial and astrocytic differentiation. Although we did use consensus among three neuropathologists to define this category, in the present study there were no set percentages or criteria for the diagnosis of mixed oligoastrocytomas, and cases ranged from those with separate regions resembling oligodendroglial and astrocytic differentiation to those with intermediate nuclear and cellular features throughout the tumor. Although this represents the state of the art for mixed glioma diagnosis, these ambiguities complicate further histologic stratification of these lesions. Thus, further studies are needed to address whether the degree of oligodendroglial differentiation is prognostically relevant for these cases. Furthermore, only 19 primary mixed gliomas were studied in this series. Maintz et al30 have demonstrated subsets of mixed gliomas with genotypes resembling either those of pure astrocytomas or oligodendrogliomas. Appropriately, our mixed gliomas demonstrated frequencies of 1p and 19q losses intermediate to the two pure subtypes. Likewise, our prior FISH study of p16-RB-CDK4 alterations also demonstrated intermediate frequencies in this group of tumors.29 The high frequency of 1p and 19q loss in diffuse gliomas strongly suggests that these chromosome arms harbor tumor suppressor genes. Refined mapping and subsequent cloning of the putative 1p and 19q glioma tumor suppressor genes are important steps to further understand the significance of these alterations and to effectively translate this tool to the clinical setting. The importance of the 1p glioma tumor suppressor is underscored by the strong association between 1p loss and chemosensitivity in anaplastic oligodendrogliomas.10 Furthermore, virtually all human malignancies, from solid cancers to leukemias and myeloproliferative disorders have demonstrated nonrandom involvement of chromosome 1, particularly the telomeric end of 1p.31-34 p73, a recently identified homologue of p53, maps to the glioma 1p common deletion region35 but has been eliminated as a candidate for the 1p glioma tumor suppressor gene based on mutational analysis of oligodendrogliomas with 1p loss.36 Alterations of 19q in human gliomas are of particular interest because they are the only known alterations shared by all three major glioma subtypes.11,13-15 Furthermore, most other common malignancies rarely demonstrate loss of 19q,37 suggesting the presence of a glial-specific tumor suppressor gene. Considerable efforts have been made to map the deletions on this chromosome arm,3,19,20 and several genes have been eliminated as candidate 19q glioma tumor suppressor genes based on mutational analysis.38-40 In summary, we have reaffirmed by FISH in a large set of gliomas that alterations of the 1p and 19q common deletion regions, both independently and in combination, are associated with the oligodendroglial phenotype. Further, we have shown that combined loss of 1p and 19q is a statistically significant predictor of longer overall survival in patients with oligodendroglioma, including low-grade examples. Our data suggests that FISH analysis could potentially provide useful diagnostic and prognostic information in selected patients with diffuse gliomas.
Supported by National Institutes of Health grants no. CA50905, CA64928, and CA50910, the American Brain Tumor Association, and the Sydney Luckman Endowed Physician Scientist Scholarship.
The first two authors contributed equally to this study.
1. Kleihues P, Burger PC, Scheithauer BW: Histological Typing of Tumours of the Central Nervous System. Berlin, Germany,Springer-Verlag, 1992 2. Lopes MBS, VandenBerg SR, Scheithauer BW: The World Health Organization classification of nervous system tumors in experimental neuro-oncology, in Levin AJ, Schmidek HH (eds): Molecular Genetics of Nervous System Tumors. New York, NY,Wiley-Liss, 1993, pp 1-36 3. Smith JS, Alderete B, Minn Y, et al: Localization of common deletion regions on 1p and 19q in human gliomas and their association with histological subtype. Oncogene 18:4144-4152, 1999[Medline] 4. Rorke LB: Pathologic diagnosis as the gold standard. Cancer 7:665-667, 1997 (editorial) 5. Cairncross JG, Macdonald DR: Successful chemotherapy for recurrent malignant oligodendroglioma. Neurol 23:350-364, 1988 6. Glass J, Hochberg FH, Gruber ML, et al: The treatment of oligodendrogliomas and mixed oligodendroglioma-astrocytomas with PCV chemotherapy. J Neurosurg 76:741-745, 1992[Medline]
7.
Cairncross G, Macdonald D, Ludwin S, et al: Chemotherapy for anaplastic oligodendroglioma. J Clin Oncol 12:2013-2021, 1994 8. Kim L, Hochberg FH, Thornton AF, et al: Procarbazine, lomustine, and vincristine (PCV) chemotherapy for grade III and grade IV oligoastrocytomas. J Neurosurg 85:602-607, 1996[Medline]
9.
Mason WP, Krol GS, DeAngelis LM: Low-grade oligodendroglioma responds to chemotherapy. Neurology 46:203-207, 1996
10.
Cairncross JG, Ueki K, Zlatescu C, et al: Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendroglioma. J Natl Cancer Inst 90:1473-1479, 1998
11.
von Deimling A, Louis DN, von Ammon K, et al: Evidence for a tumor suppressor gene on chromosome 19q associated with human astrocytomas, oligodendrogliomas, and mixed gliomas. Cancer Res 52:4277-4279, 1992 12. von Deimling A, Nagel J, Bender B, et al: Deletion mapping of chromosome 19 in human gliomas. Int J Cancer 57:676-680, 1994[Medline]
13.
von Deimling A, Bender B, Jahnke R, et al: Loci associated with malignant progression in astrocytomas: A candidate on chromosome 19q. Cancer Res 54:1397-1401, 1994 14. Reifenberger J, Reifenberger G, Liu L, et al: Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol 145:1175-1190, 1994[Abstract] 15. Ritland SR, Ganju V, Jenkins RB: Region-specific loss of heterozygosity on chromosome 19 is related to the morphologic type of human glioma. Genes Chrom Cancer 12:277-282, 1995[Medline] 16. Kraus JA, Koopman J, Kaskel P, et al: Shared allelic losses on chromosomes 1p and 19q suggest a common origin of oligodendrogli-oma and oligoastrocytoma. J Neuropathol Exp Neurol 54:91-95, 1995[Medline] 17. Bello MJ, Leone E, Vaquer J, et al: Allelic loss at 1p and 19q frequently occurs in association and may represent early oncogenic events in oligodendroglial tumors. Int J Cancer 64:207-210, 1995[Medline]
18.
Dinapoli RP, Brown LD, Arusell RM, et al: Phase III comparative evaluation of PCNU and carmustine combined with radiation therapy for high-grade glioma. J Clin Oncol 11:1316-1321, 1993 19. Rosenberg JE, Lisle DK, Burwick JA, et al: Refined deletion mapping of the chromosome 19q glioma tumor suppressor gene to the D19S412-STD interval. Oncogene 13:2483-2485, 1996[Medline] 20. Smith JS, Jenkins RB: Loss of heterozygosity mapping of the chromosome 19q-arm in human gliomas. FASEB Lett 11:3131, 1997 (abstr 451)
21.
Jenkins RB, Qian J, Lee HK, et al: A molecular cytogenetic analysis of 7q31 in prostate cancer. Cancer Res 58:759-766, 1998 22. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 23. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966[Medline] 24. Cox DR: Regression models and life tables. J R Stat Soc B 34:187-220, 1972 25. Perry A, Nobori T, Ru N, et al: Detection of p16 gene deletions in gliomas: A comparison of fluorescence in situ hybridization (FISH) versus quantitative PCR. J Neuropathol Exp Neurol 56:999-1008, 1997[Medline] 26. Louis DN, Gusella JF: A tiger behind many doors: Multiple genetic pathways to malignant glioma. Trends Genet 11:412-415, 1995[Medline] 27. Kim DH, Mohapatra G, Bollen A, et al: Chromosomal abnormalities in glioblastoma multiforme tumors and glioma cell lines detected by comparative genomic hybridization. Int J Cancer 60:812-819, 1995[Medline] 28. Ransom DT, Ritland SR, Moertel CA, et al: Correlation of cytogenetic analysis and loss of heterozygosity studies in human diffuse astrocytomas and mixed oligoastrocytomas. Genes Chrom Cancer 5:357-374, 1992[Medline] 29. Perry A, Anderl K, Borell TJ, et al: Detection of p16, RB, CDK4, and p53 gene deletion/amplification by fluorescence in situ hybridization (FISH) in 96 gliomas. Am J Clin Pathol 112:801-809, 1999[Medline] 30. Maintz D, Fiedler K, Koopman J, et al: Molecular genetic evidence for subtypes of oligoastrocytomas. J Neuropathol Exp Neurol 56:1098-1104, 1997 [Medline] 31. Schwab M, Praml C, Amler LC: Genomic instability in 1p and human malignancies. Genes Chrom Cancer 16:211-229, 1996[Medline] 32. Atkin NB: Chromosome 1 aberrations in cancer. Cancer Genet Cytogenet 21:279-285, 1986[Medline] 33. Heim S, Mitelman F: Cancer Cytogenetics. New York, NY,Alan R. Liss Inc, 1987 34. Oláh E, Balogh E, Kovács I, et al: Abnormalities of chromosome 1 in relation to human malignant diseases. Cytogenet 43:179-194, 1989 35. Kaghad M, Bonnet H, Yang A, et al: Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 90:809-819, 1997[Medline] 36. Mai M, Huang H, Reed C, et al: Genomic organization and mutation analysis of p73 in oligodendrogliomas with chromosome 1 p-arm deletions. Genomics 51:359-363, 1998[Medline] 37. Seizinger B, Klinger HP, Junien C, et al: Report of the committee on chromosome and gene loss in human neoplasia. Genet 58:1080-1096, 1991 38. Yong WH, Ueki K, Chou D, et al: Cloning of a highly conserved human protein serine-threonine phosphatase gene from the glioma candidate region on chromosome 19q13.3. Genomics 29:533-536, 1995[Medline] 39. Chou D, Miyashita T, Mohrenweiser HW, et al: The BAX gene maps to the glioma candidate region at 19q13.3, but is not altered in human gliomas. Cancer Genet Cytogenet 88:136-140, 1996[Medline]
40.
Peters N, Smith JS, Tachibana I, et al: The human glia maturation factor-gamma (hGMF- Submitted March 5, 1999; accepted September 15, 1999. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
) gene: Genomic structure and mutation analysis in gliomas with chromosome 19q loss. Neurogenetics 2:163-166, 1999
