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Clinicopathologic Correlations of Genomic Gains and Losses in Follicular Lymphoma

From the Abteilung Innere Medizin III, Pathologie, and Biometrie und Medizinische Dokumentation, Universität Ulm,Ulm; Pathologisches Institut and Med. Klinik und Poliklinik V, Universität Heidelberg, Heidelberg; Pathologisches Institut, Universität Würzburg, Würzburg; Institut für Humangenetik, Universitätsklinikum Kiel, Kiel; and Institut für Zell- und Molekularpathologie, Medizinische Hochschule Hannover, Hannover, Germany.

Address reprint requests to Martin Bentz, MD, Med Klinik III, University of Ulm, Robert-Koch-Str 8, 89081 Ulm, Germany; email: martin.bentz{at}medizin.uni-ulm.de

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To evaluate the clinical relevance of genomic aberrations in follicular lymphomas (FLs).

PATIENTS AND METHODS: In this study, we analyzed 124 biopsy samples of patients with FL using comparative genomic hybridization.

RESULTS: In 87 cases (70%), genomic imbalances were detectable. The most frequent aberrations were gains of chromosome arms 7p (21 patients), 7q (21 patients), Xp (16 patients), 12q (15 patients), and 18q (14 patients) as well as losses on 6q (21 patients). Grades 2 and 3 according to the World Health Organization classification correlated with a more complex karyotype (P < .0001). In a subset of 82 patients, a comprehensive clinical data set was available. In a multivariate analysis including all clinical risk factors of the International Prognostic Index as well as genomic aberrations, the loss of material on chromosomal bands 6q25q27 was the strongest predictor of a shorter survival (P = .0001; hazard ratio, 6.5), followed by elevated serum lactate dehydrogenase level (P = .0009; hazard ratio, 4.9), the presence of more than one extranodal manifestation (P = .017; hazard ratio, 4.2), and age greater than 60 years (P = .022; hazard ratio, 2.6).

CONCLUSION: These data indicate that genomic aberrations may contribute significantly to risk assessment in patients with FL, the majority of whom are included in low-risk groups using established clinical prognostic scores.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
FOLLICULAR LYMPHOMA (FL) is one of the most frequently occurring lymphoma entities in Europe and North America. It is characterized by a typical histomorphology and a specific chromosomal translocation, t(14;18)(q32;q21), which is present in approximately 80% of cases.¹ The clinical course varies from cases with long indolent phases to cases with rapid transformation. Therapeutic strategies range from watchful waiting to myeloablation followed by autologous stem-cell transplantation.² For improved treatment strategies in FL, the identification of risk factors is clearly required. Several clinical parameters, such as age, stage, bone marrow involvement, B symptoms, performance status, serum lactate dehydrogenase (LDH) levels, and anemia, have been associated with the clinical course.^3-7 The International Prognostic Index⁸ also proved to be of value in FL.⁹ Recently, another prognostic score based on data of 987 patients was proposed; it included age, sex, number of extranodal sites, serum LDH level, B symptoms, and erythrocyte sedimentation rate.¹⁰

When applying these clinical prognostic scores, there is still a considerable proportion of low-risk patients with an unfavorable course and also a proportion of high-risk patients with an indolent course. In acute and chronic leukemias, specific chromosomal aberrations are the most important risk factors.^11-13 In contrast, the prognostic impact of genomic aberrations in FL has not been extensively investigated. Because of the poor availability of fresh tumor tissue, which is required for chromosomal banding analysis, there is only one study in which the prognostic impact of chromosome aberrations was analyzed using multivariate analysis.¹⁴ In this study of 66 patients, the complexity of the karyotype and specific chromosomal aberrations (deletions on chromosome arms 17p and 6q) were identified as independent prognostic parameters in FL.

With molecular cytogenetic techniques, especially comparative genomic hybridization (CGH),¹⁵ a comprehensive analysis of the tumor genome can be performed on archival material.¹⁶ In this study, we analyzed lymph node samples from 124 patients with histologically confirmed FL. In 82 cases, a comprehensive clinical data set was available for multivariate analysis.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
One hundred seven fresh frozen lymph node samples and 17 paraffin-embedded lymph node samples of 124 patients with histologically confirmed FL were analyzed by CGH. Histopathologic evaluation was performed based on morphologic and immunohistochemical criteria according to the World Health Organization (WHO) classification of malignant lymphomas^17,18 by the German lymph node registries. Fifty-two patients were male and 72 patients were female. Their median age was 53 years (range, 25 to 80 years). All patients were treated in tertiary referral centers, which is the most likely explanation for the young median age of our cohort. In 78 of these cases, biopsy specimens were obtained at primary diagnosis. Twenty-seven cases were biopsied at relapse 11 to 224 months after initial diagnosis (median, 42 months). In 19 cases, no information was available. In a retrospective review of 91 of 124 FL cases, a histopathologic grading according to the definition of the WHO classification of malignant lymphomas^17,18 was performed by two expert hematopathologists (P.M. and G.O.). FL grade 1 (International Classification of Diseases [ICD]-0 code 9691/3) was present in 68 cases, FL grade 2 (ICD-0 code 9695/3) was present in 16 cases, and FL grade 3 (ICD-0 code 9697/3) was present in seven cases.

In 82 cases, a comprehensive clinical data set was available. In 72 of these patients, material was obtained at initial diagnosis.

Detection of a t(14;18) Translocation or an Immunoglobulin H–BCL2 Fusion
A total of 117 of the 124 cases were analyzed for the presence of a t(14;18) translocation. In 42 cases, suitable tumor tissue for chromosomal banding analysis was available. Harvesting, slide preparation, and R banding were performed as described.¹⁹ In four cases, the presence of a t(14;18) translocation was diagnosed using fluorescence in situ hybridization (for details, see Taniwaki et al²⁰). In 75 cases, a nested polymerase chain reaction (PCR) approach was used for the detection of the immunoglobulin H (IgH)–BCL2 fusion. Analyses of the major breakpoint region and the minor cluster region were performed as reported previously.²¹

CGH
DNA isolation, labeling, and hybridization were performed as described previously.²² Normal human genomic DNA (control DNA) was labeled with digoxigenin-11-deoxyuridine triphosphate (Roche, Mannheim, Germany), and tumor DNA was labeled with biotin-16-deoxyuridine triphosphate (Roche) by a standard nick translation reaction. One microgram of labeled tumor DNA, 1 µg of differentially labeled control DNA, and 70 µg of human Cot1-DNA (BRL Life Sciences, Gaithersburg, MD) were cohybridized to metaphase cells prepared from blood of a healthy donor. After hybridization for 2 to 3 days and posthybridization washes, control and test DNAs were detected via rhodamine and fluorescein isothiocyanate staining, respectively. Chromosomes were counterstained with 4,6-diamidino-2-phenylindole, which resulted in a Q-banding-like pattern that was used for chromosome identification.

Digital Image Analysis
Image analysis was performed as described previously.²² Images were acquired using an epifluorescence microscope (Axioplan; Zeiss, Jena, Germany) and the commercially available image analysis system ISIS (MetaSystems, Altlußheim, Germany). The first 28 patients were analyzed using dedicated software as described previously.²³ Ratio profiles of the fluorescence intensities of tumor DNAs and control DNAs were calculated for each individual chromosome. For each patient, the mean ratio profiles of between four and 20 metaphase cells (median, 13) were computed. Heterochromatin blocks including the centromeric regions are known to be critical in CGH analysis.²³ Accordingly, these regions were not considered. Moreover, chromosome 19 and the distal part of chromosome 1p were excluded from CGH evaluation because of the risk of false-positive CGH results.

Statistical Analyses
The Kaplan-Meier method was used to estimate the distribution of overall survival.²⁴ Differences between Kaplan-Meier curves were assessed using the log-rank test.²⁵ Multivariate analysis of survival was performed using the Cox proportional hazards model.²⁶ Overall survival end points measured from date of lymph node biopsy were death (failure) and alive at last follow-up (censored observation). The following variables were examined to identify risk factors in a univariate analysis for overall survival using the log-rank test: age (< 60 years v 60 years), sex, stage (I, II v III, IV), presence of B symptoms, serum LDH level (< 240 U/L v 240 U/L), presence of more than one extranodal involvement, performance status according to the Eastern Cooperative Oncology Group (ECOG) classification (0 v 1, 2, and 3), number of chromosomal imbalances (zero or one v two or more imbalances), and presence of recurrent chromosomal aberrations (> 5% of cases) with gains and losses of chromosomal material defined by CGH. In previous studies,^8,10 the patients were dichotomized by performance status to a group with ECOG scores of 0 and 1 versus a group with ECOG scores of 2 or more. Since in our series only two of 82 patients had a performance status of 2 or more, we dichotomized with ECOG 0 and ECOG 1, 2, and 3 for reasonable statistical modeling. In the multivariate analysis, all clinical and cytogenetic parameters, which showed some association with survival in univariate testing (P < .2), were included. However, in cases in which aberrations were found frequently in both the short and long arms of a specific chromosome, only the chromosome arm with the more frequent involvement was included (eg, 7p, 12q, or 18q). Instead of all patients with 6q deletions, only those with deletions of chromosomal bands 6q25q27 were entered into the Cox model.

Binary variables were analyzed with Fisher’s exact test. Statistical computations were performed using the SAS statistical software package, version 6.12 (SAS Institute, Inc, Cary, NC). Results of statistical tests were labeled significant if P < .05; otherwise, they were not significant. Because of the exploratory character of this study, no adjustment for multiple testing was done.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Clinical Data
The median observation time of the 82 patients with comprehensive clinical data sets was 45 months (range, 2 to 119 months). Twenty-seven of 82 patients died. All these patients had progressive disease. Clinical data were assessed at the time of biopsy. The clinical characteristics of these 82 patients are listed in Table 1.

CGH
CGH results were obtained for 124 patients. For a proportion of these cases, CGH data have been published.^27,28 Imbalanced chromosomal aberrations were found in 87 cases (70.2%; range, zero to eight aberrations per case; average number of aberrations per case, 1.9). The most frequent findings (present in > 5% of cases) were gains on chromosome arms 1q (12 patients), 2p (12 patients), 7p (21 patients), 7q (21 patients), 8q (10 patients), 12p (eight patients), 12q (15 patients), 16p (seven patients), 17q (nine patients), 18p (10 patients), 18q (14 patients), Xp (16 patients), and Xq (11 patients), as well as deletions on 6q (21 patients) and 13q (eight patients). In six cases, eight high-level DNA amplifications were found that mapped to chromosome bands 1q23 to 1q25, 2p14 to 2p16 (three cases), 6p21, 8q24 (two cases), and 12q13. Details of the CGH data are listed in Table 2, and the complete data are illustrated in Fig 1.

View larger version (37K): [in this window] [in a new window]   Fig 1. Summary of chromosomal imbalances detected in 124 patients with FL: lines on the left side of the ideograms indicate losses; lines on the right side indicate gains; and black squares indicate high-level amplifications.

Characteristic Pattern of Chromosomal Imbalances
The most frequent single chromosomal imbalances were gains on chromosome 7 (six cases) and X (six cases), followed by gains on chromosome arm 18q (five cases). In contrast, the following aberrations were associated with a more complex karyotype (two or more aberrations): gains on 12q (P = .0004; average number of aberrations per case, 3.7), losses on 6q (P = .007; average number of aberrations, 3.6), and losses on 13q (P = .003; average number of aberrations, 4.9).

Association Among Cytogenetic, Histopathologic, and Clinical Baseline Parameters
The average number of aberrations per case increased with grade: 1.6 in FL grade 1, 1.9 in FL grade 2, and 3.8 in FL grade 3. Moreover, the number of patients with a complex karyotype (two or more imbalanced aberrations) was higher among grade 2 or 3 cases: 25 (34.4%) of 68 cases with FL grade 1, 10 (62.5%) of 16 with FL grade 2, and all seven cases (100%) with FL grade 3 (FL1 v FL2 and FL3, P < .0001) had complex genomic aberrations.

The 18q gains were found more frequently in male patients (nine of 11 patients with 18q gains were male v 29 of 71 patients without 18q gains; P = .02), in patients with younger age (nine of 11 with gains on 18q were 50 years or younger v 34 of 71 without gains on 18q; P = .05), and in patients with an elevated serum LDH level (five of 11 patients v 12 of 71 patients; P = .045).

Univariate Analysis of the Prognostic Impact of Clinical and Cytogenetic Characteristics
The following clinical characteristics were associated with a decreased probability of survival: more than one extranodal manifestation (P = .002), elevated serum LDH level (P = .022), age older than 60 years (P = .03), and ECOG score of 1 or higher (P = .042). Genomic aberrations associated with an inferior survival time were deletions involving chromosome bands 6q25 to 6q27 (P = .0001) and complex karyotypes (two or more imbalanced chromosomal aberrations; P = .018). Gains on Xq (P = .052) showed a borderline significance for inferior outcome. In contrast, the presence of a t(14;18) translocation had no significant impact on survival. We also tested the prognostic impact of all clinical and cytogenetic risk factors in the subgroup of 55 patients with a t(14;18) translocation or IgH-BCL2 fusion. In this group, the same clinical and cytogenetic characteristics were shown to be associated with an inferior outcome: more than one extranodal manifestation (P = .002), elevated serum LDH level (P = .03), age older than 60 years (P = .03), ECOG score of 1 (P = .04), complex karyotypes (P = .04), deletions involving chromosome bands 6q25 to 6q27 (P = .0001), and gains on chromosome arms 1q (P = .01) and Xq (P = .04) as well as complex karyotypes (P = .018).

The results of the univariate analyses for all clinical parameters and for genomic aberrations present in more than 5% of the cases are listed in Table 4 and Table 5.

View larger version (20K): [in this window] [in a new window]   Fig 2. Prognostic impact of different consensus regions of deletions on chromosome arm 6q: (a) genomic gains and losses on chromosome 6; (b) deletion of bands 6q14 to 6q16; (c) deletion of bands 6q25 to 6q27.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Gains on chromosome arms 7p, Xp, and 18q were the most frequent single genomic imbalances suggesting a role as an early event in the clonal evolution of FL. The role of 18q gains as frequent single chromosomal imbalances in FL has recently been described.³⁰ Moreover, we found a distinct pattern of clinical presentation in patients with gains on 18q: these patients were predominantly younger and male, and they had higher LDH levels than patients without this aberration. However, the presence of 18q gains did not translate into an inferior outcome. In contrast to diffuse large-cell lymphomas, in which the presence of the t(14;18) and 18q gains were mutually exclusive,³⁴ such 18q gains occurred with similar frequency in cases with and without the t(14;18) translocation (nine of 86 and three of 31, respectively).

In contrast, losses on 13q and 6q and gains on 12q were associated with a more complex karyotype. Recently, an association of 12q gains with histopathologic transformation of FL into diffuse large B-cell lymphoma was described.³⁵ In another study, 12q gains as well as losses on 13q were also more frequent in cases with aggressive histopathologic features.³⁶ This suggests a role of these aberrations in later stages of clonal evolution. Alternatively, they might lead to genetic instability resulting in the rapid development of further genomic defects. The complexity of genomic aberrations is a hallmark of genetic evolution in many tumors.³⁷ We also identified an association of complex genomic aberrations and grades 2 and 3 according to the WHO classification. This is in line with a previously published study using chromosomal banding analysis.³⁰ In contrast to other studies,^30,35,36 we did not find any significant association of specific chromosomal aberrations with aggressive histopathologic features.

The main focus of our study was the analysis of the prognostic impact of genomic aberrations in FL. In addition to an analysis of the entire group, we also examined the prognostic impact of genomic aberrations in the t(14;18)/IgH-BCL2–positive subgroup by univariate analysis. All aberrations, which had a significant impact on survival in the entire group, also proved to be statistically significant in the t(14;18)/IgH-BCL2–positive subgroup. In univariate analysis, the number of chromosomal imbalances and losses on a subregion of chromosome 6 (bands 6q25 to 6q27) were associated with a significantly decreased survival time. A negative prognostic impact has been described for 6q deletions in FL and in other types of lymphomas.^15,38 In B-cell lymphomas, at least four regions of minimal deletion have been identified on 6q, ie, 6q13 to 6q14, 6q21, 6q23, and 6q25 to 6q27.^38-41 In the present series, the strong prognostic impact was restricted to deletions of bands 6q25 to 6q27 (Fig 2). In the series of Tilly et al,¹⁴ deletions on chromosomal bands 6q23 to 6q26 had shown an adverse prognostic impact, supporting the presence of a pathogenetically relevant tumor suppressor gene localized within chromosome bands 6q25 to 6q26. Comprehensive studies have focused on a detailed characterization of the region of minimal deletions on bands 6q25 to 6q26.^42,43 Although several candidate genes have been identified for B-cell lymphomas and other tumors (eg, PLAGL1 [ZAC, LOT1],^44,45 ESR1,^46-48 and, more recently, RNASE6PL⁴⁹), there is no evidence for a functional relevance in B-cell lymphomas for any of these genes.

In only one previous study,¹⁴ clinical as well as cytogenetic risk factors were included in a multivariate model, but out from established clinical risk factors, only serum LDH levels were included in this analysis. To evaluate the prognostic relevance of cytogenetic aberrations, we included all clinical risk factors of the International Prognostic Index⁸ and of the prognostic model of the Intergruppo Italiano Linfomi¹⁰ (except for erythrocyte sedimentation rate) in the multivariate model. On the basis of the relative risk ratio, the loss of chromosomal material on bands 6q25 to 6q27 was the most powerful prognostic factor. Although the number of cases is low, this study indicates that genomic aberrations may contribute significantly to risk assessment in patients with FL. These additional risk factors may become a novel, distinct clinical adjunct since, at present, the majority of patients with this lymphoma are included in low-risk groups using established clinical prognostic scores (eg, 75%¹⁰). CGH can detect such genomic aberrations in paraffin-embedded tumor tissues and can therefore be used in the context of clinical trials.⁵⁰ Such an approach will provide prospective data of homogeneous cohorts of patients that can be used for the design of risk-adapted treatment strategies.

	ACKNOWLEDGMENTS

 
Supported by Deutsche Krebshilfe grant nos. 70-2840-Be3, 70-2312 Be2, and 10-1643-Si1 and the Interdisziplinäres Zentrum für klinische Forschung der Universität Ulm, Project C12.

We gratefully acknowledge Martina Enz and Carmen Hoppstock for excellent technical support. We also thank Birgit Hay for assistance in the statistical analyses and Sebastian Plötz for help with data acquisition. We thank Dr H. Merz and Prof A.C. Feller (University of Lübeck, Germany) as well as Dr M. Tiemann and Prof R. Parwaresch (University of Kiel) for providing histopathologic information for a subgroup of patients.

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Submitted December 3, 2001; accepted August 2, 2002.

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