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Blood, 1 January 2008, Vol. 111, No. 1, pp. 466-468.
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CORRESPONDENCE
Prognostic assessment of BCL2-938C>A polymorphism in chronic lymphocytic leukemia
To the editor:
The recent report by Nückel et al pointed to the prognostic role of the BCL2-938C > A polymorphism in chronic lymphocytic leukemia (CLL).1 In this report, the BCL2-938 AA genotype emerged as an independent predictor of shorter treatment-free-survival (TFS) both by univariate and multivariate analysis.1 We aimed at testing the prognostic impact of BCL2-938C > A in an independent series of 182 consecutive chronic lymphocytic leukemia (CLL) from our institution.
Genotyping of BCL2-938C > A was performed by single nucleotide polymorphism (SNP) minisequencing (ABI Prism SNaPshot Multiplex kit; Applied Biosystem, Foster City, CA), after validation of this approach by DNA direct sequencing in a pilot panel of cases (n = 30; data not shown).2 The genotype distribution of BCL2-938C > A in CLL was 47 of 182 (25.8%) AA, 96 of 182 (52.7%) AC, and 39 of 182 (21.5%) CC. Allele frequencies were in accordance with Hardy-Weinberg equilibrium (A: 0.522; C: 0.478; P = .749,  )2. Biologic and clinical variables at diagnosis distributed without significant differences among AA, AC, and CC genotypes (Table 1). In our series, TFS and overall survival (OS) did not differ in AA, AC, and CC genotypes when analyzed separately or after pooling C-allele carriers (Tables 1, 2).
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Table 1. Biologic and clinical characteristics at diagnosis and clinical outcome according to BCL2-938C>A genotypes
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The independent prognostic value of BCL2-938C > A was assessed separately for biologic and clinical variables by Cox multivariate analysis. Biologic covariates were CD38 expression, immunoglobulin heavy chain variable gene (IGHV) mutation status, IGHV3-21 usage, and FISH karyotype. Clinical covariates were age, sex, Rai and Binet stage, number of nodal lesions, largest lymph node size, splenomegaly, lymphocyte count, hemoglobin, platelet count, lymphocyte doubling time (LDT), bone marrow lymphocytes, bone marrow infiltration pattern, beta-2-microglobulin, LDH, alkaline phosphatase, and albumin. When tested along with biologic covariates, BCL2-938C > A in our CLL series was not an independent predictor of TFS (Table 2). In addition, when tested along with clinical covariates, BCL2-938C > A in our CLL series was not an independent predictor of TFS (Table 2). As observed for TFS, multivariate analysis did not identify BCL2-938C > A as a predictor of OS in our series.
The discrepancy between our results and the study by Nückel et al cannot be ascribed to differences in BCL2-938C > A genotype distribution (this study: AA = 25.8%, AC = 52.7%, CC = 21.5% vs Nückel et al: AA = 34.1%, AC = 44.7%, CC = 21.1%; P = .263, 2) or allele frequency (this study: A = 0.522 vs Nückel et al: A = 0.57; P = .301, 2) between the 2 CLL series.1 Other potential explanations may account, at least in part, for the observed discrepancy. In the study by Nückel et al, 17 of 37 (45.9%) AA patients were in Binet stages B or C versus 17 of 77 (22.1%) AC/CC patients (P = .005, 2, causing a potential bias in the distribution of unfavorable Binet stages among BCL2-938C > A genotypes.1 Conversely, in our study, 12 of 47 (25.5%) AA patients were in Binet stages B or C versus 38 of 135 (28.1%) AC/CC patients (P = .729, 2) (Table 1). Excess of unfavorable Binet stages among AA patients may have powered the prognostic relevance of BCL2-938C > A observed by Nückel et al.1 This potential bias is notable because Nückel et al reported that unfavorable Binet stage was an independent predictor of TFS stronger than BCL2-938C > A.1 Alternatively, the discrepancy between this study and that of Nückel et al may be the consequence of the different genetic background of the 2 populations investigated. In fact, genetic variability due to ethnicity may influence the prognostic value of specific polymorphisms in CLL and other cancer settings.3–7 In this respect, it is remarkable that the prognostic assessment of polymorphisms of other genes, namely P2X7 and BAX, has yielded conflicting results in CLL.5,7–10
Authorship
Contribution: D.R. designed the study, analyzed data, and wrote the manuscript; S.R. and D.C. performed and interpreted molecular and immunophenotypic analysis; and G.G. contributed to data analysis and wrote the manuscript.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Davide Rossi, MD, Division of Hematology, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Eastern Piedmont, Via Solaroli 17, 28100 Novara, Italy; e-mail: rossidav{at}med.unipmn.it.
Davide Rossi,
Silvia Rasi,
Daniela Capello, and
Gianluca Gaidano
This study has been approved by the local Institutional review board and was supported by Ricerca Sanitaria Finalizzata and Ricerca Scientifica Applicata, Regione Piemonte, Torino, Italy; PRIN 2006, Rome, Italy; and Novara-AIL Onlus, Novara, Italy.
References
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- Wang Y and Armstrong SA. Genome-wide SNP analysis in cancer: leukemia shows the way. Cancer Cell 2007; 11:308–309.[CrossRef][Medline]
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- Spinola M, Falvella FS, Galvan A, et al. Ethnic differences in frequencies of gene polymorphisms in the MYCL1 region and modulation of lung cancer patients' survival. Lung Cancer 2007; 55:271–277.[CrossRef][Medline]
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- Thunberg U, Tobin G, Johnson A, et al. Polymorphism in the P2X7 receptor gene and survival in chronic lymphocytic leukaemia. Lancet 2002; 360:1935–1939.[CrossRef][Medline]
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- Starczynski J, Pepper C, Pratt G, et al. The P2X7 receptor gene polymorphism 1513 A–>C has no effect on clinical prognostic markers, in vitro sensitivity to fludarabine, Bcl-2 family protein expression or survival in B-cell chronic lymphocytic leukaemia. Br J Haematol 2003; 123:66–71.[CrossRef][Medline]
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- Starczynski J, Pepper C, Pratt G, et al. Common polymorphism G(-248)A in the promoter region of the bax gene results in significantly shorter survival in patients with chronic lymphocytic Leukemia once treatment is initiated. J Clin Oncol 2005; 23:1514–1521.[Abstract/Free Full Text]
- Skogsberg S, Tobin G, Krober A, et al. The G(-248)A polymorphism in the promoter region of the Bax gene does not correlate with prognostic markers or overall survival in chronic lymphocytic leukemia. Leukemia 2006; 20:77–81.[CrossRef][Medline]
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- Nückel H, Frey UH, Sellmann L, et al. Bax gene G(-248)A promoter polymorphism and chronic lymphocytic leukemia: lack of association with incidence, disease stage and progression-free survival. Leukemia 2006; 20:724.[CrossRef][Medline]
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- Zhang LY, Ibbotson RE, Orchard JA, et al. P2X7 polymorphism and chronic lymphocytic leukaemia: lack of correlation with incidence, survival and abnormalities of chromosome 12. Leukemia 2003; 17:2097–2100.[CrossRef][Medline]
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- Nückel H, Frey UH, Durig J, Duhrsen U, Siffert W. 1513A/C polymorphism in the P2X7 receptor gene in chronic lymphocytic leukemia: absence of correlation with clinical outcome. Eur J Haematol 2004; 72:259–263.[CrossRef][Medline]
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Association of a novel regulatory polymorphism (–938C>A) in the BCL2 gene promoter with disease progression and survival in chronic lymphocytic leukemia
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