Originally published as JCO Early Release 10.1200/JCO.2006.05.9238 on September 11 2006

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Loss of Heterozygosity 1p36 and 19q13 Is a Prognostic Factor for Overall Survival in Patients With Diffuse WHO Grade 2 Gliomas Treated Without Chemotherapy

Luigi Mariani, Gianluca Deiana, Erik Vassella, Ali-Reza Fathi, Christine Murtin, Marlène Arnold, Istvan Vajtai, Joachim Weis, Peter Siegenthaler, Martina Schobesberger, Michael M. Reinert

From the Department of Neurosurgery, Inselspital; Division of Neuropathology, Institute of Pathology, University of Bern, Switzerland; Institute of Neuropathology, RWTH University Hospital, Aachen, Germany

Address reprint requests to Luigi Mariani, MD, Leitender Arzt und Chefarzt-Stv., Klinik für Neurochirurgie, Universitätsspital Inselspital, CH-3010 Bern, Switzerland; e-mail: luigi.mariani{at}insel.ch

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions GLOSSARY REFERENCES

 
PURPOSE: This study was conducted to elucidate the impact of loss of heterozygosity (LOH) for chromosomes 1p36 and 19q13 on the overall survival of patients with diffusely infiltrating WHO grade 2 gliomas treated without chemotherapy.

PATIENTS AND METHODS: We assessed the LOH status of tumors from patients harboring WHO grade 2 gliomas diagnosed between 1991 and 2000. Patients were either followed after initial biopsy or treated by surgery and/or radiation therapy (RT). Overall survival, time to malignant transformation, and progression-free survival were last updated as of March 2005.

RESULTS: Of a total of 79 patients, LOH 1p36 and LOH 19q13 could be assessed in 67 and 66 patients, respectively. The median follow-up after diagnosis was 6 years. Loss of either 1p or 19q, in particular codeletion(s) at both loci, was found to positively impact on both overall survival (log-rank P < .01), progression-free survival, and survival without malignant transformation (P < .05). Tumor volume (P < .0001), neurologic deficits at diagnosis (P < .01), involvement of more than one lobe (P < .01), and absence of an oligodendroglial component (P < .05) were also predictors of shorter overall survival. The extent of surgery was similar in patients with or without LOH 1p and/or 19q; RT was more frequently resorted to for patients without than for patients with LOH 1p/19q (30% v 60%).

CONCLUSION: The presence of LOH on either 1p36 or 19q13, and in particular codeletion of both loci is a strong, nontreatment-related, prognostic factor for overall survival in patients with diffusely infiltrating WHO grade 2 gliomas.

	INTRODUCTION

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Low-grade cerebral gliomas of diffusely infiltrating type (WHO grade 2) represent a heterogeneous group of tumors with astrocytoma, oligodendroglioma (OD), and mixed oligoastrocytoma (OA) being the most common and clinically significant neoplastic entities.^1-3 Median overall survival times of 6 years^4-6 are nothing less than discouraging, given the relatively young age and good clinical condition of this patient population at the time of diagnosis. The clinical course of the disease may be highly variable and ultimately contingent on the occurrence of malignant progression. The potential impact of any therapeutic intervention on long-term survival is unclear because the prognosis of affected patients seems to depend mainly on factors that can not be influenced.⁷ Age over 40 years, presence of neurologic deficits at diagnosis, larger tumor size, bihemispheric involvement, purely astrocytic composition, and high proliferating cell fraction have been perceived as the most reliable, independent prognostic factors identifying patients at high risk for earlier progression and shorter overall survival.^4,8-10 The catalog of genetic events underlying the disease is expanding, and the prognostic sequelae of individual molecular alterations are being increasingly appreciated.^1,6,11-17 Loss of heterozygosity (LOH) on chromosomal arms 1p and 19q has been found to occur in the majority of oligodendrogliomas^14,16,18-20 and in a significant proportion of astrocytomas.^14,21 Patients with tumors harboring this genetic constellation have been shown both to respond to chemotherapy and to have longer progression-free survival.^19,22,23 It is, however, unclear whether LOH 1p and/or 19q is also a prognostic factor for overall survival. In this study, we report on the impact of LOH 1p36/19q13 on survival of a cohort of patients with WHO grade 2 gliomas,⁹ in whom chemotherapy was not part of the treatment.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions GLOSSARY REFERENCES

 
Patient Selection and Management Policy
We followed since 2001 a cohort of 79 patients with WHO grade 2 glioma diagnosed at the University Hospital of Bern (Bern, Switzerland) between January 1991 and December 2000. After surgery or biopsies, patients were typically observed without adjuvant treatment. The policy of our institution was to recommend early radiation therapy (RT) to patients with two or more of the following risk factors for early tumor progression: age older than 45 years, preoperative neurologic deficits, large residual tumor volume after surgery (> 5 cm in cross-sectional diameter or more than 60 mL in volume), bilateral involvement (infiltration of the corpus callosum), mass effect with midline shift, and a gemistocytic component. At tumor progression, the patients were typically offered repeat surgery whenever possible or RT. None of the patients was treated by chemotherapy as of March 2005.

Data Collection, Histopathologic Reassessment, Definition of End Points
The following parameters were retrieved from the existing databank and updated (when applicable): age, sex, Karnofsky performance status (KPS), neurologic signs and symptoms, history of symptomatic epilepsy, timing and type of diagnostics procedures, extent of tumor removal, histopathologic diagnosis of primary and relapsing tumors (including MIB1 labeling index), and evolution of tumor volume over time based on magnetic resonance imaging (MRI). The pathologic reassessment was performed before the LOH analysis. The tumor was called OA if a fibrillary, gemistocytic or protoplasmatic component was well-developed and if at least one high-power field was found in the specimen that, if considered alone, would have warranted the diagnosis of an OD.²⁴ This approach is thought to result in a good interobserver concordance.^24,25 The tumor was considered OD if this component was exclusive or largely predominant and no astroglial differentiation was present except for the minigemistocytes and gliofibrillary oligodendrocytes frequently present in typical ODs.²⁴ The following survival end points were updated: progression-free survival, interval until malignant transformation, and overall survival after initial tissue diagnosis. Tumor progression was defined as an increase by more than 25% (and at least 5 mL) of the residual tumor volume after surgery or early RT using a postoperative MRI as a baseline. Malignant transformation to a higher grade (WHO grade 3 or 4) was determined after neuropathologic evaluation of tissue samples and sometimes based solely on a new contrast-enhancement in patients not having received RT before that MRI exam. Overall survival was calculated from the time of first tissue diagnosis and updated for all patients either at the last follow-up visit or by calling the municipality of the city of origin being the ultimate depositary of the survival status in March 2005.

Measurement of Tumor Volume
MRI scans and follow-up exams were stored digitally. Tumor volume at diagnosis and on follow-up scans was measured after interactive analysis with a dedicated software, as described previously.⁹ Briefly, the tumor volume at diagnosis was defined as the volume of hyperintensity on T2-weighted or (when available) on fluid attentuated inversion recovery (FLAIR) sequences before surgery. The tumor volume on follow-up scans was calculated with the same technique. When applicable, the volume of the resection cavity (based on T1-weighted images) was subtracted.

LOH on Chromosomal loci 1p36 and 19q13
Representative areas of tumor were excised from formalin-fixed paraffin-embedded tissue and DNA was extracted using the QIAamp DNA mini kit (Qiagen, Hombrechtikon, Switzerland) according the manufacturer's protocol. Reference DNA was extracted from the patient's EDTA peripheral blood using the PURGENE kit (Gentra Systems, Minneapolis, MN). Written informed consent for the use of frozen material for genetic analyses on tumor and blood was obtained from patients. Genotypes for multiple loci were determined by polymerase chain reaction (PCR) using fluorescent primers tagged with HEX or FAM (Microsynth, Balgach, Switzerland) for microsatellite markers on chromosome 1p36 (D1S468, D1S1612, D1S228, D1S214) and chromosome 19q13 (D19S219, D19S412, D19-HRC). The microsatellite markers spanned over the regions 1p36.21 to 1p36.33 and 19q13.31 to 19q13.41 (Fig 1) and were selected according to Smith et al.²⁶ PCR amplification was performed in separate reactions. Analysis of PCR products was performed by capillary electrophoresis using a genetic analyser (ABI Prism 3100-Avant; Applied Biosystems, Rotkreuz, Switzerland) and the GeneMapper software 3.5. LOH was determined by measuring the peak area from each of the alleles produced from the tumor and corresponding normal DNA, respectively. Diagnostic criteria for LOH required the calculated ratio of the peak areas to be less than 0.5.¹³

View larger version (17K): [in this window] [in a new window]   Fig 1. Markers of microsatellite polymorphism used to detect loss of heterozygosity for 1p and 19q.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions GLOSSARY REFERENCES

 
Descriptive Statistics
Clinical data, MRI, and histopathologic results. The mean age of the cohort of 79 patients at diagnosis was 41 years (range, 20 to 76 years; median 38.3 years); 43 patients were 40 years old or younger, 36 were older; the male:female ratio was 1.55 (48:31). The preoperative KPS was 90 or 100 in 72 patients (91.1%; range, 70% to 100%). Epilepsy was the first manifestation in 57 patients (76%), and neurologic deficits were present at diagnosis in 26 patients (33%). The tumor was located on the left in 51% of patients and on the right in 44%. Bilateral involvement was found in 5% of patients. Tumor location was in one lobe in 41% and in more than one lobe in 59% of the cases; the majority of tumors had frontoinsular involvement (59%). Mean tumor volume at diagnosis was 90 ± 72 cm³. Fifty-six percent of tumors were larger than 60 cm³. Twelve patients (15%) had a biopsy, and 67 (85%) had surgical resection at diagnosis. All tumors were WHO grade 2. Fifty-nine tumors (75%) were classified as astrocytoma, 14 (17.5%) as oligodendroglial, and 6 (7.5%) as OD. A significant gemistocytic component was found in 14 astrocytomas. A tumor resection of more than 50%, more than 75%, and more than 90% was achieved in 60%, 20%, and 4.4% of the patients, respectively. Overall, 47 patients (59.5%) were treated with RT; among them, 15 (19%) had early RT (within 6 months from diagnosis) because of the presence of two or more risk factors as listed herein (12 patients) or because of their choice (three patients); 32 patients (40.5%) had delayed RT at tumor progression.

The mean follow-up for overall survival of the 79 patients was 80 ± 43 months (6 years and 8 months; range, 1 to 165 months, median, 71 months). Thirty-nine patients (49.5%) died during the observation period. Thirty-one (50%) of 62 assessable patients had suffered malignant transformation by the last follow-up.

LOH for 1p and 19q
Assessment of LOH for one or more microsatellite loci of the chromosomal regions 1p36.21-1p36.33 and 19q13.31-19q13.41 was possible in 67 (85%) and 64 patients (81%), respectively. LOH 1p was found in 21 cases (31%), and LOH 19q in 22 cases (34%). LOH of both 1p and 19q was found in 17 patients (21.5%; ie, in approximately 80% of patients with any LOH of either 1p or 19q). The single microsatellite loci D1S468, D1S214, D1S1612, and D1S228 of 1p were informative in 54%, 56%, 70%, and 53% of the patients, respectively. The markers D19S219, D19S412, and D19-HRC of 19q were informative in 61%, 65%, and 37% of the patients, respectively. The frequency of a combined LOH 1p/19q was 83% in OD (five of six cases), 50% in OAs (six of 12 informative cases), and 13.3% in astrocytomas (6 out of 45 informative cases). All six OD (100%) had LOH 1p (three for one locus, two for three loci, and one for all loci); five of those six tumors also had LOH 19q (three for one locus, two for two loci). Eight (16.7%) of 48 informative astrocytoma patients had LOH 1p; 10 (21.7%) of 46 had LOH 19q. LOH 1p was found in seven (54%) of 13 informative OA cases; LOH 19q in seven (58%) of 12.

By the time of follow-up, 66% of the patients without any evidence of LOH 1p or 19q had been treated by RT, whereas only 31% with LOH 1p and/or 19q needed that treatment. None of the 15 patients who had received early RT had LOH 1p or 19q.

The mean overall survival of the 68 patients in whom the 1p or 19q status could be assessed for at least one chromosomal locus was 81.48 ± 44.3 months (median, 72 months).

Correlation With Survival End Points
Kaplan-Meier analysis of overall survival with the log-rank test revealed a survival advantage for patients with codeletions of 1p36 and 19q13 (P < .01), any LOH 1p36 (P = .01), LOH 1p36-468 (P < .05), any LOH 19q13 (P < .01), and loss of the microsatellite D19-HRC on 19q13 (P < .05; Figs 2A, 2B, and 2C). In the subgroup of astrocytomas, there was a survival advantage for patients with combined LOH 1p/19q compared with patients without LOH. The difference in overall survival was statistically significant according to the Mann-Whitney U test (P = .01) but not with the Kaplan-Meier method (P = .09; Fig 2F). Larger tumors, especially before surgery but also after surgery showed the strongest association with a shorter overall survival (log-rank P < .0001 for < or > than 60 mL preoperatively, < .001 for volumes < or > than 30 mL postoperatively; Table 1 and Figs 2G, 2H, and 2I). The presence of neurologic deficits at diagnosis was also negatively associated with overall survival (P = .004; Fig 2D). Analysis of correlations between LOH and the other predictors of overall survival showed a significant association between codeletions of 1p/19q and the presence of an oligodendroglial component (P < .01, Fisher's exact test), and between codeletions of 1p/19q and smaller tumor volumes (P < .05) but not between codeletions of 1p/19q and a monolobar involvement or the presence of neurologic deficits at diagnosis. The association with oligodendroglial phenotype was stronger for LOH 1p than for LOH 19q. On the other hand, LOH 19q was associated with a monolobar involvement (P = .047).

View larger version (29K): [in this window] [in a new window]   Fig 2. Kaplan-Meier survival curves for patients with WHO grade 2 glioma grouped according to genetic, clinical, and radiologic factors associated with the overall survival; univariate analysis. Survival estimates according to the following variables are shown: (A) loss of heterozygosity (LOH) 1p/19q; (B) LOH 19q; (C) presence or absence of neurologic deficits at diagnosis; (D) oligodendroglioma versus other subtypes; (E) astrocytoma and LOH 1p/19q; (F) monolobar versus multiobar tumor involvement; (G) preoperative tumor volume < or > 60 mL; (H) postoperative tumor volume < or > 30 mL.

Tumor volume (P < .001) pre- and postoperatively, the involvement of more than one cerebral lobe (P < .01) and an intact 19q (P < .05) were predictors of an earlier tumor progression. Absence of LOH 1p showed a similar tendency (P = .08) but did not reach statistical significance.

The multivariate, stepwise Cox regression model indicated preoperative tumor volume followed by the presence of allelic codeletions of 1p and 19q as the best predictors of overall survival, time to malignant transformation, and progression-free survival.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions GLOSSARY REFERENCES

 
Our data demonstrate that LOH 1p36.21-33, especially in combination with LOH 19q13.31-41, is a favorable true prognostic factor for overall survival in patients with diffusely infiltrating, WHO grade 2 gliomas. LOH 1p/19q was also significantly associated with a longer survival without malignant transformation and without tumor progression in these patients. Although this is a retrospective study, it has significant strengths: first, the length of follow-up: 30 (44%) of 68 patients in whom the LOH status could be assessed were dead after a median follow-up of 6 years; second, none of the patients was treated by chemotherapy, which is an effective therapy and therefore a potentially confounding factor for survival analysis in tumors with 1p loss²²; third, the extent of surgery was comparable for patients with and without LOH; and fourth, RT was performed more often in patients without than in patients with LOH, meaning that the survival advantage of patients with LOH can not be attributed to RT. Tumor volume and involvement of more cerebral lobes, presence of neurologic deficits at diagnosis, and absence of an oligodendroglial component were also associated with shorter overall survival, as has been reported previously.^4,9 After multivariate analysis, tumor volume and LOH 1p/19q were the strongest independent predictors of overall survival.

The relative proportions of the histologic subtypes (75% astrocytomas, 17.5% OAs, and 7.5% ODs) and the frequency of combined LOH 1p/19q (13% in astrocytomas, 50% in OAs, and 83% in ODs) found in this study are in the range of what has been reported previously.^{6,17,20,24,26,27} The relatively high percentage of oligodendroglial tumors in this series reflects a trend over the last years, whereby an even small but typical oligodendroglial component is considered important and leads to the diagnosis of a mixed glioma (OA),²⁴ in accordance with the WHO guidelines. These diagnostic criteria lead to a strict definition of astrocytomas. In this series, patients with LOH 1p/19q–positive astrocytomas had a longer overall survival than patients with LOH 1p/19q–negative astrocytomas; this finding stresses the importance of LOH analysis also in this subgroup of patients and not only in patients with oligodendroglial tumors.

That LOH 1p/19q is a prognostic factor in patients with diffusely infiltrating gliomas is not surprising and has been anticipated by others.^19-22,28 However, the available series are not conclusive for the association between this genetic signature and overall survival in WHO grade 2 tumors. Felsberg et al²¹ reported on 38 patients with WHO grade 2 oligodendroglial tumors and showed a trend for a longer overall survival in the 29 patients with a combined LOH 1p and 19q compared with the nine patients without LOH; however, the difference did not reach statistical significance. Whether the patients were treated by chemotherapy or not is not reported in the paper. Kujas et al²⁰ reported longer progression-free survival in low-grade glioma patients with LOH 1p compared with those with intact 1p. There was a high proportion of ODs (53%) in that series and the large majority of the patients had received chemotherapy. The follow-up for overall survival, with only 30 patients (23%) having died, was probably too short to reveal a significant survival advantage for patients with LOH. Idbaih et al²⁸ reported a positive effect of complete loss of 1p on the overall survival of patients with gliomas, all grades confounded (WHO II-IV); only 39 of 108 patients had a WHO grade 2 glioma, and the results for that subgroup of patients were not shown in the paper. We assume that the size of the sample (21 patients with LOH 1p versus 16 without LOH 1p) and the short follow-up did not allow for a conclusive statement concerning a potential association with overall survival. The majority of the patients in that series were also treated by chemotherapy.

Our findings support routine LOH 1p/19q testing to better identify good risk WHO grade 2 glioma patients. Because tumors with LOH 1p/19q are likely to respond to chemotherapy,²² this treatment option may be preferred to RT⁵ in this subgroup of patients. However, the dilemma in the management of patients with a WHO grade 2 glioma is still unsolved, and the role of LOH 1p/19q testing in the decision process needs to be clarified in appropriately designed studies.

The presence of LOH on either 1p36 or 19q13, and in particular codeletion of both loci is a strong, nontreatment-related prognostic factor for overall survival in patients with diffusely infiltrating WHO grade 2 gliomas.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions GLOSSARY REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions GLOSSARY REFERENCES

 

Conception and design: Luigi Mariani, Erik Vassella, Christine Murtin, Joachim Weis, Michael M. Reinert Provision of study materials or patients: Luigi Mariani, Gianluca Deiana, Ali-Reza Fathi, Christine Murtin, Istvan Vajtai, Joachim Weis, Peter Siegenthaler, Michael M. Reinert Collection and assembly of data: Luigi Mariani, Gianluca Deiana, Erik Vassella, Ali-Reza Fathi, Christine Murtin, Marlène Arnold, Istvan Vajtai, Joachim Weis, Peter Siegenthaler, Martina Schobesberger Data analysis and interpretation: Luigi Mariani, Gianluca Deiana, Erik Vassella, Ali-Reza Fathi, Marlène Arnold Manuscript writing: Luigi Mariani, Gianluca Deiana, Erik Vassella Final approval of manuscript: Luigi Mariani, Gianluca Deiana, Erik Vassella, Ali-Reza Fathi, Christine Murtin, Marlène Arnold, Istvan Vajtai, Joachim Weis, Peter Siegenthaler, Martina Schobesberger, Michael M. Reinert

 

	GLOSSARY

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions GLOSSARY REFERENCES

 

LOH (loss of heterozygosity) :

A situation where one chromosome has a normal allele of a gene and one chromosome has a mutant or deleted allele.

Microsatellite markers:

Microsatellites are short, tandemly repeated DNA sequences scattered throughout the genome. Thelength of a repeat unit is different in the two (paternal and maternal) alleles and is highly specific for every individual. Microsatellite sequences are therefore often used as markers for genetic fingerprinting and to detect the loss of one of the two alleles of one or more genes.

	ACKNOWLEDGMENTS

 
We thank Pietro Ballinari of the Department of Statistics of the University of Berne for his assistance in the analysis of the data and Andreas Kappeler, PhD, Institute of Pathology, University of Bern, for support with the molecular genetic analysis.

	NOTES

 
published online ahead of print at www.jco.org on September 11, 2006.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions GLOSSARY REFERENCES

 
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2. Kleihues P, Davis RL, Ohgaki H, et al: Diffuse astrocytoma, in Kleihues P, Cavenee WK (eds): Pathology and Genetics of Tumours of the Nervous System. Lyon, France, IARC Press, 2000, pp 22-26

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22. Hoang-Xuan K, Capelle L, Kujas M, et al: Temozolomide as initial treatment for adults with low-grade oligodendrogliomas or oligoastrocytomas and correlation with chromosome 1p deletions. J Clin Oncol 22:3133-3138, 2004[Abstract/Free Full Text]

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Submitted February 14, 2006; accepted June 23, 2006.

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