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

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Abstract
Purpose: Chronic lymphocytic leukemia (CLL) is characterized by the development of drug resistance. The underlying biologic and genetic reasons for this resistance are complex, but the bcl-2 gene family seems to play a critical role. This retrospective study assessed the clinical impact of a common single nucleotide polymorphism of the pro-apoptotic bax gene in patients with chronic lymphocytic leukemia. Patients and Methods: The frequency of the novel polymorphism, G(−248)A, in the promoter region of the bax gene and bax protein expression was assessed in 203 CLL patients. The results were correlated with clinical outcome. Results: The polymorphism was found in 23% of the CLL cohort and 15% of normal controls with no significant difference in allele frequency between the two groups (P = .15). It was associated with lower Bax protein expression and a shorter overall survival, especially in the treated patient group (P = .03). Furthermore, the adverse impact of the polymorphism was accentuated when comparing survival from the date of first treatment rather than diagnosis (P = .012). No significant difference in age at diagnosis, stage of disease at presentation, lymphocyte doubling time, time to first treatment, or progression-free survival were observed. Conclusion: The presence of this single nucleotide polymorphism in CLL critically influences the response to treatment and overall survival. Given the relatively high prevalence of this polymorphism in the normal population, further prospective studies in CLL and other human malignancies are indicated.