MDM2 SNP309 promoter polymorphism, an independent prognostic factor in chronic lymphocytic leukemia

Abstract

In this report, with a high proportion of B-CLL patients with an advanced Binet stage and with an unmutated IgVH gene, MDM2 SNP309 was found to be independently associated with OS. The survival difference was more pronounced in younger patients.

Molecular genetic studies on Chronic Lymphocytic Leukemia and Acute Myeloid Leukemia - with focus on prognostic markers

“…chlorambucil is based on the concept to upregulate an intact wildtype p53 protein stimulating apoptosis. CLL patients with 17pdel and/or TP53 mutation are associated with treatment resistance and short survival (Döhner et al, 1995, Wattel et al, 1994, Rossi et al, 2009, Willander et al, 2010. Relapsed and refractory CLL show high frequencies of 17pdel/TP53 mutation (Zenz et al, 2011).…”

“…Instead, the mutated p53 protein gets new properties, as transactivation of other genes beneficial for the tumor, as the oncogene MYC, which induce increased proliferation (gain-of function) (Dittmer et al, 1993, Bode & Dong, 2004. However, there may be other mechanisms to attenuate the p53 signaling, such as high levels of MDM2 through gene amplification/overexpression (Watanabe et al, 1994) or single nucleotide polymorphism (SNP) in the promoter region of the MDM2 gene (Bond et al, 2004, Gryshchenko et al, 2008, Willander et al, 2010. Further, mutations/deletions in the ATM gene is also able to decrease activation of p53.…”

Genetics of Chronic Lymphocytic Leukemia: Practical Aspects and Prognostic Significance

“…Overexpression of the MDM2 protein was also observed in CLL and this was significantly more frequent in the advanced rather than the earlier stages (Watanabe et al, 1996). The MDM2 SNP309 in B-CLL has been suggested to be an unfavorable prognostic marker; however the results of several recent publications are conflicting (Willander et al, 2010). The CLL upregulated gene 1 (CLLU1) located at 12q22 was overexpressed exclusively in CLL and its expression was shown to have a strong prognostic significance in patients younger than 70 years, namely higher expression was associated with shorter overall survival (Josefsson et al, 2007).…”

MDM2 promotor polymorphism and disease characteristics in chronic lymphocytic leukemia: results of an individual patient data-based meta-analysis

“…[1][2][3][4] While the potential effects of gene polymorphisms are widely acknowledged, most studies investigating the impact of individual SNPs on prognosis in chronic lymphocytic leukemia (CLL) have been controversial. [5][6][7][8][9][10][11] None of the allelic variants described so far contribute to relevant current clinical risk models in CLL. 12,13 Sample sizes of studies to detect associations between SNP markers and clinical end points should be reasonably large, taking into account the very large number of candidate SNPs.…”

“…16 The exceptionally well documented functional consequences of the MDM2 SNP309 and the important prognostic role of p53, 17,18 as well as the particularly striking effects of the SNP in CLL in one study, has led to the study of the MDM2 SNP309 in many centers, providing conflicting results. 5,6,[9][10][11]19 In the current study, we aimed to clarify the prognostic value of MDM2…”