Prognostic Assessment of BCL2 C938A Polymorphism in Chronic Lymphocytic Leukemia (CLL).
Authors: Rossi Davide , Rasi Silvia , Cerri Michaela , Deambrogi Clara , Cresta Stefania , Capello Daniela , Gaidano Gianluca 
Published: April 2020

Abstract
BCL2 expression is increased in CLL cells and associates with decreased survival of CLL patients. BCL2 C938A polymorphism is localized in the inhibitory P2 promoter of BCL2 and modulates BCL2 expression. Accordingly, BCL2 expression is significantly increased in CLL carrying BCL2 938 AA genotype, compared to CLL carrying BCL2 938 CC genotype. We aimed at testing the prognostic impact of BCL2 C938A in a series of 182 consecutive CLL. Genotyping of BCL2 C938A was performed by SNP minisequencing. Biological covariates were CD38 expression, IGHV mutation, FISH karyotype, and p53 mutations. Clinical covariates were age, sex, Rai and Binet stages, number of nodal areas, largest lymph node size, splenomegaly, lymphocyte count, Hb, platelet count, bone marrow lymphocytes, pattern of bone marrow involvement, lymphocyte doubling time (LDT), beta-2-microglobulin (B2M), LDH, alkaline phosphatase, albumin. Genotype distribution of BCL2 C938A in CLL was 47/182 (25.8%) AA, 96/182 (52.7%) AC, and 39/182 (21.5%) CC. Allele frequencies were in accordance with Hardy-Weinberg equilibrium (A: 0.522; C: 0.478; p=0.749, χ2). Biological and clinical variables at diagnosis distributed without significant differences among AA, AC and CC genotypes. Treatment free survival (TFS) did not differ in AA, AC and CC genotypes when analyzed separately (5-year TFS AA=58.1%; AC=46.4%; CC=50.0%; p=.228), after pooling C-allele carriers (5-year TFS AA=58.1%; AC/CC=47.6%; p=.414), or after pooling A-allele carriers (5-year TFS AA/AC= 50.1%; CC=50.0%; p=.247). Overall survival (OS) did not differ in AA, AC and CC genotypes when analyzed separately (5-year OS AA=80.1%; AC=76.8%; CC=76.1%; p=.900), after pooling C-allele carriers (5-year OS AA=80.1%; AC/CC=76.5%; p=.837), or after pooling A-allele carriers (5-year OS AA/AC= 77.9%; CC=76.1%; p=.649). The independent prognostic value of BCL2 C938A was assessed separately for biological and clinical variables by Cox multivariate analysis. When tested along with biological covariates, BCL2 C938A was not an independent predictor of TFS or OS. Biological covariates independently predicting TFS were del11q22–23 (HR 5.52; 95%CI 2.26–11.87; p&lt;.001), p53 inactivation by deletion and/or mutation (HR 4.02; 95%CI 2.14–7.52; p&lt;.001), +12 (HR 3.08; 95%CI 1.67–5.68; p&lt;.001), IGHV unmutated (HR 2.26; 95%CI 1.33–3.84; p=.002), CD38 expression (HR 1.87; 95%CI 1.12–3.13; p=.016), and normal FISH karyotype (HR 0.37; 95%CI 0.12–0.73; p=.004). Also, when tested along with clinical covariates, BCL2 A938C was not an independent predictor of TFS or OS. Clinical covariates independently predicting TFS were LDT &lt;12 months (HR 10.83; 95%CI 5.37–21.8; p&lt;.001), Rai III/IV (HR 4.32; 95%CI 2.09–8.91; p&lt;.001), lymphocyte count &gt;20 × 109/l (HR 2.85; 95%CI 1.75–4.64; p&lt;.001), involvement of ≥3 nodal areas (HR 2.42; 95%CI 1.42–4.14; p=.001), and B2M (HR 2.08; 95%CI 1.21–5.55; p=.007). Clinical covariates independently predicting OS were age &gt;65 years (HR 8.93; 95%CI 3.26–24.4; p&lt;.001), albumin &lt; 35 g/l (HR 4.23; 95%CI 1.84–9.71; p=.001), Binet B/C (HR 3.76; 95%CI 1.78–7.92; p&lt;.001), and male sex (HR 2.88; 95%CI 1.33–6.23; p=.007). At variance with previous studies (Nückel et al., Blood2006; 109: 290), BCL2 C938A does not display prognostic relevance in our CLL series. This discrepancy may be ascribed to the more balanced distribution of BCL2 C938A genotypes throughout CLL stages in our series. Alternatively, differences in the prognostic role of BCL2 C938A may be the consequence of the different genetic background of the populations investigated.