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Molecular Biology, Pathobiology, and Genetics |
1 Mayo Clinic, Rochester, Minnesota; 2 Merit Care Community Clinical Oncology Program, Fargo, North Dakota; and 3 Wake Forest University School of Medicine, Winston-Salem, North Carolina
Requests for reprints: Robert B. Jenkins, Division of Laboratory Genetics, Mayo College of Medicine, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-284-9617; Fax: 507-284-0043; E-mail: rjenkins{at}mayo.edu.
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Abstract |
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2 test). The median overall survival (OS) for all patients was 8.1 years without fusion and 11.9 years with fusion (P = 0.003). The median OS for patients with low-grade oligodendroglioma was 9.1 years without fusion and 13.0 years with fusion (P = 0.01). Similar significant median OS differences were observed for patients with combined 1p/19q deletions. The absence of alterations was associated with a significantly shorter OS for patients who received higher doses of radiotherapy. Our results strongly suggest that a t(1;19)(q10;p10) mediates the combined 1p/19q deletion in human gliomas. Like combined 1p/19q deletion, the 1;19 translocation is associated with superior OS and progression-free survival in low-grade glioma patients. (Cancer Res 2006; 66(20): 9852-61) |
Introduction |
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Whereas the prognostic relevance of 1p and 19q deletions is well established for anaplastic oligodendrogliomas and mixed oligoastrocytomas, the prognostic relevance of the deletions for low-grade gliomas is more controversial. In this report, using patients enrolled on two NCCTG trials for newly diagnosed low-grade gliomas, we show that combined deletion of 1p and 19q independently predicts a prolonged survival for patients with these tumors.
The majority of 1p and 19q deletions have appeared to involve the entire 1p and 19q arms (1, 2, 4, 6). Based on this observation, we hypothesized that an unbalanced translocation might be the etiology of both deletions. In this report, we show that an unbalanced t(1;19)(q10;p10) likely mediates the combined 1p and 19q deletion in gliomas. Furthermore, we show that the translocation is associated with a significantly better prognosis as well as response [as measured by overall survival (OS) and progression-free survival (PFS)] to radiation in patients with low-grade gliomas, especially gliomas with oligodendroglial components.
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Materials and Methods |
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Fluorescence in situ hybridization. Fluorescence in situ hybridization (FISH) analyses of fixed cytogenetic preparations from the fresh oligodendroglioma followed standard methods.
1p and 19q deletion analysis of formalin-fixed paraffin-embedded gliomas by FISH was done as described previously (9).
The prehybridization, hybridization, and posthybridization procedures for the t(1;19) translocation analysis of formalin-fixed paraffin-embedded tissues were similar to the above method.
FISH probes: for 1p and 19q deletion analysis of metaphase and interphase nuclei (for both fresh and paraffin-embedded tumor specimens), nick-translated bacterial artificial chromosome (BAC) contig probes for the target region 1p36 (Spectrum Orange, Vysis, Downers Grove, IL) with a control region at 1q24 (Spectrum Green, Vysis) and the control region 19p13 (Spectrum Green) with the target region 19q13 (Spectrum Orange) were used as described previously (9). Whole chromosome painting (WCP) probes (Vysis) for 1 and 19 were used in the analysis of metaphase spreads from the primary tumor. For the t(1;19) translocation (fusion) analysis, a chromosome 1 
satellite probe CEP1 in Spectrum Orange (Vysis) was cohybridized with a BAC contig probe for 19p12 that was nick translated and labeled in Spectrum Green. The BAC clones included in the 19p12 probe were the following: RP11-771C12, RP11-587H3, RP11-460G17, CTD-3173A10, CTD-3074B13, and RP11-677G1. All BAC clones were supplied by Invitrogen (Carlsbad, CA).
Scoring criteria. For the deletion portion of the study, 100 nuclei were scored per specimen for number of red and green signals per nuclei. The specimen was considered deleted if the red/green ratio was <0.85 and aneusomy if there were >30% of the nuclei with three green signals.
For the translocation portion of the study, the definition of fusion required that the red and green signals be within two signal widths of each other (16). This less strict fusion requirement was due to the potential 4.0 to 6.5 Mb gap between the probes when the hypothesized translocation was present. The range in estimated gap size is based on the distance from the position of BAC RP11-587H3 (the 19p BAC closest to the centromere that did not show cross-hybridization) to the center and q-arm end of the chromosome 19 centromere (17). The two-signal width definition was selected after measurement of the interphase distance in paraffin-embedded nuclei from the tumor with the known t(1;19) (see Results). Fifty nuclei were scored by each of two independent scorers. Diploid nuclei were classified as abnormal if one or more fusion signals were identified. Aneuploid nuclei were classified as abnormal if apparently triploid cells had one or more fusion signals and apparently tetraploid cells had two or more fusion signals. The criteria for translocation was established by scoring 12 normal glial specimens and 5 abnormal astrocytoma and glioblastoma multiforme specimens known not to contain combined 1p and 19q deletion. For a case to be classified as containing the t(1;19), 60% or greater of the nuclei were required to have fusion of the red and green signals. This relatively high criteria is necessary because the two-signal width definition for fusion results in a large random colocalization volume.
Statistical methods. Counts were summarized as frequencies and relative frequencies. Distributions of counts were compared among groups with a 2 test. Time-to-event data (survival and PFS) were summarized by Kaplan-Meier estimation. Differences in time-to-event experiences between groups (i.e., those with deletion versus those without deletion, those with fusion and those without fusion) were compared with a Wilcoxon test. Univariable and multivariable analyses of time-to-event data were conducted using Cox proportional hazards modeling. The following variables were included in the modeling: age, gender, histologic type, mini-mental status exam (MMSE) status, 1p/19q deletion status, and CEP1/19p12 fusion status. The intent of the multivariable models was to ascertain whether the univariable association between deletion status and fusion and the time-to-event end points (survival and PFS) remained after adjusting for known prognostic factors.
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Results |
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1p and 19q deletion as well as CEP1 and 19p12 fusion predict PFS and OS in patients with low-grade gliomas. Of 125 patients enrolled in NCCTG 94-72-53, paraffin blocks were available for 98 patients, and FISH studies for 1p/19q deletion were successful for 91 (93%) patients. FISH studies for CEP1 and 19p12 fusion were successful for 84 (86%) patients. The reasons for unsuccessful FISH studies were block depletion (two patients, deletion; three patients, fusion) and hybridization failure (5 patients, deletion; 11 patients, translocation). Table 1 compares characteristics of all eligible patients enrolled on the NCCTG trials to those of patients for whom FISH studies were successful. There were no significant differences in age, gender, MMSE, performance scores, treatment, and histologic type among groups. Supplementary Table S1 summarizes the 1p and 19q deletion and the CEP1/19p12 fusion results for each patient enrolled on 94-72-53.
Table 2A summarizes the 1p and 19q deletion results. Of 91 patients with low-grade glioma, 37 (41%) showed 1p and 19q codeletion, 6 (6%) showed 19q deletion alone, and 48 (53%) showed neither. In this group of patients, no case showed 1p deletion alone.
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2 test). Patients with 1p and 19q deletion had a median OS time of 11.9 years and a 5-year OS rate of 95% versus 8.1 years and 59%, respectively, for those without deletion (Wilcoxon P = 0.004). The median PFS time and 5-year PFS rate for patients with 1p and 19q deletion were 8.2 years and 84% versus 3.3 years and 48%, respectively, for those without deletion (Wilcoxon P = 0.002).
In oligodendroglioma patients, median OS time and 5-year OS rate were 13 years and 96%, respectively, in patients with 1p/19q–codeleted tumors versus 10.8 years and 70% in those without deletion (Wilcoxon P = 0.06). Median PFS time and 5-year PFS rate were 8.2 years and 85%, respectively, in patients with 1p/19q–codeleted tumors versus 7.0 years and 70% in those without deletion (Wilcoxon P = 0.26).
We also did an analysis of the combined set of 78 oligodendrogliomas and mixed oligoastrocytomas. Patients with oligodendrogliomas or mixed oligoastrocytomas with 1p and 19q deletion had a median OS time of 11.9 years and a 5-year OS rate of 95% versus 10.3 years and 66%, respectively, for those without deletion (Wilcoxon P = 0.02). The median PFS rate and 5-year PFS rate for patients with 1p and 19q deletion was 8.2 years and 84% versus 5.6 and 59%, respectively, for those without deletion (Wilcoxon P = 0.04).
Table 2B summarizes the CEP1 and 19p12 fusion results. Of the 84 patients, 37 (44%) had CEP1/19p12 fusion, whereas 47 (56%) did not. The prevalence of fusion was 55% among 42 oligodendrogliomas, 47% among 30 mixed oligoastrocytomas, and 0% among 12 astrocytomas. The prevalence of fusion was significantly different between all three histologic groups (P < 0.001, 2 test).
1p and 19q deletion results were available for 81 of the 84 patients. Supplementary Table S2 summarizes the association of CEP1/19p12 fusion with chromosome 1p and 19q deletion data. Briefly, of 33 gliomas with combined 1p and 19q deletion, 91% had CEP1/19p12 fusion. Of 48 gliomas without combined 1p and 19q deletion, 13% had CEP1/19p12 fusion. This difference in proportion was significant (P < 0.001, 2 test).
Figure 2A and B shows the Kaplan-Meier survival curves for median OS and PFS time for patients with grade II gliomas with and without CEP1/19p12 fusion. Patients with fusion had a median OS time of 11.9 years and 5-year OS rate of 95% versus 8.1 years and 60%, respectively, for those without fusion (Wilcoxon P = 0.003). The median PFS time and 5-year PFS rate for patients with fusion was 8.1 years and 78%, versus 3.3 years and 51%, respectively, for those without the translocation (Wilcoxon P = 0.006).
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We also did an analysis of the combined set of 72 oligodendrogliomas and mixed oligoastrocytomas. Patients with oligodendrogliomas or mixed oligoastrocytomas with CEP1/19p12 fusion had a median OS time of 11.9 years and a 5-year OS rate of 95% versus 8.7 years and 60%, respectively, for those without fusion (Wilcoxon P = 0.005). The median PFS time and 5-year PFS rate for patients with CEP1/19p12 fusion was 8.1 years and 78%, versus 4.4 years and 57%, respectively, for those without fusion (Wilcoxon P = 0.05).
The t(1;19) or combined 1p and 19q deletion status is associated with treatment response. One of the trial components of NCCTG 94-72-53, NCCTG 86-72-51, compared two doses of RT for low-grade gliomas: 50.4 Gy versus 64.8 Gy (12). Table 3 summarizes the survival associations of combined 1p and 19q deletion or CEP1/19p12 fusion with these two radiation doses. Although no difference in OS between the two treatment arms was observed (12), there was evidence that patients without fusion had a significantly shorter OS when treated with higher doses of radiation (Fig. 3A ; Table 3). The hazard ratio (HR) for death after 64.8 Gy of radiation, comparing patients with and without fusion, was 2.75 [95% confidence interval (95% CI), 1.14-6.65; likelihood ratio P = 0.03; median OS, 11.6 years versus 5.0 years]. Conversely, there was no significant difference in OS whether the patients with fusion received either a lower or higher dose of radiation (Fig. 3A; Table 3). The HR for death after 64.8 Gy versus 50.4 Gy of radiation for patients with fusion was 1.59 (95% CI, 0.57-4.42; likelihood ratio P = 0.37; median OS, 11.6 years versus not reached years). Similar results were observed for the association of PFS after RT with fusion status (Fig. 3B; Table 3) and associations of OS and PFS after RT with combined 1p and 19q deletion status (Table 3; data not shown).
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Multivariable modeling. We did multivariable modeling to assess whether the tumor deletion and fusion status remained associated with survival among the patients enrolled on 94-72-53 after adjusting for known prognostic factors (see Statistical Methods). Supplementary Table S3 summarizes the univariable and multivariable Cox modeling. Briefly, in multivariable modeling, the HRs for 1p and 19q deletion status did not change considerably from those in the univariable model, indicating that the association still remained after adjustment. The Ps did not achieve significance at the 0.05 level, likely due to the number of variables in the model and the relatively small sample size. However, after adjustment for known prognostic variables, the association between CEP1/19p12 fusion status and OS remained significant in the whole cohort of low-grade gliomas and in the subset of mixed oligoastrocytomas plus oligodendrogliomas (P = 0.04 and 0.03, respectively). This indicates that there is likely an independent association between fusion status and OS.
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Discussion |
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The FISH method used for detection of the t(1;19) within interphase nuclei was somewhat different from prior interphase translocation strategies. The abnormal chromosome has the cytogenetic appearance of being the result of a whole-arm (centrosomic or pericentrosomic) translocation. The initial probe choice to detect such alterations would be to use centromere-specific probes for chromosomes 1 and 19 (e.g., using a CEP1 and CEP19 in two different colors). However, there is significant sequence homology between the centromeres of chromosomes 1 and 19 (and 5; ref. 25). Much of 19p12 and the entire 19cen (including the satellite region) band is homologous to both 5cen and 1cen (25). Although it has been possible to develop centromere 1 probes that do not cross-hybridize with chromosome 19, it has been difficult to develop centromere 19 probes that do not cross-hybridize with chromosome 1. Thus, we developed a FISH probe for proximal 19p12, using BACs that mapped close to the 19 centromere, but which lacked cross-hybridization with other genomic sequences, including chromosomes 1 and 5. Given the hypothesized size of most human centromeres (17), the CEP1 probe and the 19p12 probe would be separated by at least 4.0 Mb (and at most 6.5 Mb) by the translocation. Thus, we did not expect to observe actual fusion of the red and green signals (e.g., a merged yellow signal) within interphase nuclei that contained the translocation. We empirically set the criteria for signal fusion to require that at least one red and one green signal be within two signal diameters of each other. The resulting potential colocalization volume is large enough to result in random fusion events. The rate of random fusion is also increased by tumor aneuploidy and polyploidy. For example, trisomy 19 is a common alteration in glioblastomas (18, 23). Our final criteria for fusion, which minimized the false-positive and false-negative rates, required at least 60% of nuclei show colocalization of the red and green signals. Because the two-signal width definition will be relatively difficult to implement into clinical practice, we are currently developing a three-color probe strategy to simultaneously detect 1p or 19q deletion and the t(1;19).
The strong homology of the chromosome 1 and 19 centromeric regions suggests a mechanism, centromeric or pericentromeric fusion, for the translocation. Similar whole-arm translocations have been observed in several congenital and neoplastic disorders [e.g., translocation Down syndrome (trisomy 21) and translocation Patau syndrome (trisomy 13)] in the t(1;7)(p10;q10) observed in secondary myelodysplastic syndromes (26) and in many carcinomas (reviewed in ref. 27). Abnormalities of the chromosome 1, 9, and 16 centromeres (containing satellite DNA) and qh regions (containing satellite 2 and 3 sequences) are also common in ICF syndrome (28), a disorder with immunodeficiency, centromere region instability, and abnormal facies. Breakage and rejoining of homologous satellite sequences appear to mediate these centromeric alterations (29). Similar centromeric instability has been hypothesized to underlie many of the whole-arm translocations observed in solid tumors (27). Recent evidence suggests that chromosomes (including chromosomal centromeres) are organized into a specific intranuclear anatomy that is cell type and developmental stage specific (30, 31). Because the t(1;19) seems to be relatively specific for gliomas, and especially oligodendrogliomas, it is reasonable to speculate that regions of chromosomes 1 and 19 are colocalized, within early or more mature glial precursor cells and/or within mature oligodendroglial cells. We observed seven gliomas (two retrospective and five NCCTG tumors) with evidence of fusion but without deletion. Although the discordant cases could be measurement errors, these gliomas may be evidence that colocalization precedes translocation or deletion.
The cancer-specific nature of the translocation may also be facilitated by alterations of DNA methylation and/or histone modification. Whereas the promoters of many genes are hypermethylated in cancer (32), several DNA repeat sequences, including centromeric and pericentromeric repeats, are usually hypomethylated in cancer (33). These epigenetic alterations may underlie the centromeric instability in cancer. It has been reported recently that mutations in the DNMT3B gene are associated with the development of chromosome 1qh region alterations in hepatocellular carcinoma (34, 35). Similarly, hypomethylation of the chromosome 9qh region is associated with abnormalities of chromosome 9 in urothelial cancers (36). A relevant observation supporting our proposed mechanism is that combined deletions of 1p and 19q are highly correlated with hypermethylation of a large number of genes (and putatively with centromeric hypomethylation; ref. 37).
Molecular cytogenetic deletion mapping studies have suggested that the minimal regions of deletion and, by implication, the putative candidate genes reside within 1p36 and 19q13.3 (4, 6, 23, 38). Isolated deletions of 19q are relatively common in astrocytic and oligodendroglial tumors (6, 9, 10, 23). We observed six such cases in the low-grade NCCTG cohort described in this report; one of these had evidence of CEP1/19q12 fusion. Isolated deletions of 1p are rarer in gliomas and are associated with a poorer prognosis (4, 8–10, 23). It should be noted that the smaller deletions have usually been described in high-grade gliomas, especially glioblastomas (6, 21). The prevalence of the translocation strongly suggests that the combined loss of two or more genes on 1p and 19q are required for the development of oligodendrogliomas. Our results do not exclude the possibility that small single-copy regions of DNA within the pericentromeric repeats might be involved in the translocation. Because of their location, such regions would be difficult to clone and would likely be underrepresented in the current versions of the human genome map.
In 1998, using retrospectively collected material, Cairncross et al. (7) showed that 1p and 19q deletions were associated with anaplastic oligodendrogliomas that had better prognosis. Cairncross et al. also suggested that the deletions were associated with responsiveness to adjuvant chemotherapy and RT. Recently, using prospectively collected anaplastic oligodendrogliomas and mixed oligoastrocytomas from patients enrolled on RTOG trial 9402, Cairncross et al. (10) have confirmed that combined 1p and 19q deletions are associated with significantly better prognosis (median survival of 7 years versus 2.8 years, comparing patients whose tumors contained or did not contain combined 1p and 19q deletion). The prospective trial data also suggest that patients with combined 1p and 19q deletion may have a better initial response to PCV chemotherapy and radiotherapy. Similar prognostic but not predictive conclusions were drawn by the simultaneous EORTC trial of PCV and radiation in patients with anaplastic oligodendrogliomas (11).
The prognostic relevance of combined 1p and 19q deletion of low-grade gliomas is somewhat more controversial. However, the majority of reports suggest that patients whose low-grade glioma, especially oligodendroglioma, with combined 1p and 19q deletion have a better prognosis than those patients whose tumor lack the deletions (4–6). Two recent reports also suggest that low-grade oligodendrogliomas with 1p deletions may be associated with response to temozolomide chemotherapy (39, 40). In this report, using prospectively collected patients enrolled on cooperative group trials, we confirm that combined deletion of 1p and 19q is associated with significantly prolonged OS and PFS in patients with low-grade oligodendrogliomas. In the parent trials, there was no significant difference in the response of the patients by different radiotherapeutic arm (12, 13). However, like the response of anaplastic oligodendrogliomas to PCV (10), the presence of combined 1p and 19q deletion seemed to be associated with responsiveness to RT. The RT results suggest that higher doses (64.8 Gy) of radiation are associated with shorter survival in patients who lack combined 1p and 19q deletion. Patients with combined deletion fare equally with both 50.4 and 64.8 Gy. It should be noted that these observations may be an artifact of subset analysis.
In this report, we also show that the t(1;19) that underlies the majority of the combined deletions is also associated with a prolonged OS and PFS and response to radiation (as measured by survival). Multivariable analysis suggested that, in this group of patients, the t(1;19) is independently associated with OS (compared with combined deletion). Although the multivariable results may be due to differences in FISH assay performance, they may also mean that the mechanism of combined deletion is of clinical and biological relevance (e.g., that loss of 1p and 19q by translocation has different consequences compared with loss of 1p and 19q by other mechanisms). It is likely that the t(1;19) will also predict the prognosis of patients with anaplastic oligodendrogliomas and perhaps predict the initial response to chemotherapy in such patients.
In summary, we report that the majority of combined 1p and 19q deletions associated with oligodendrogliomas are mediated by a single genetic event, a t(1;19)(q10;p10). The prevalence of this translocation in low-grade oligodendrogliomas is 44%. Combined with the recent observation that ERG1:TMPRSS2 and ETV1:TMPRSS2 translocations are highly specific for and prevalent in prostate cancer (41), the results suggest that recurrent translocations are more common in solid tumors than previously appreciated. Finally, our results confirm that combined 1p and 19q deletions as well as the t(1;19) that mediates these translocations are independently associated with a significantly better prognosis in patients with low-grade gliomas, especially oligodendrogliomas.
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Acknowledgments |
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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.
We thank the Cytogenetics Shared Resource of the Mayo Clinic Cancer Center for the equipment and laboratory support of the molecular cytogenetic studies and Heidi Durland for secretarial support.
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Footnotes |
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Received 5/16/06. Revised 7/26/06. Accepted 8/ 9/06.
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 C. Hong, K. S. Moorefield, P. Jun, K. D. Aldape, S. Kharbanda, H. S. Phillips, and J. F. Costello Epigenome scans and cancer genome sequencing converge on WNK2, a kinase-independent suppressor of cell growth PNAS, June 26, 2007; 104(26): 10974 - 10979. [Abstract] [Full Text] [PDF]
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P. Y. Wen and L. M. DeAngelis Chemotherapy for low-grade gliomas: Emerging consensus on its benefits Neurology, May 22, 2007; 68(21): 1762 - 1763. [Full Text] [PDF]
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