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MDM2 SNP May Be Important in Predicting Outcome of CLL Patients

By John C. Byrd, MD

2008-09-01

Dr. Byrd indicated no relevant conflicts of interest.

Gryshchenko I, Hofbauer S, Stoecher M, et al. MDM2 SNP309 is associated with poor outcome in B-cell chronic lymphocytic leukemia. J Clin Oncol. 2008;26:2252-7.

The study of single-nucleotide polymorphism (SNP) function for important genes related to drug metabolism, genetic predisposition, and cancer has become a major research focus across multiple disciplines. With respect to CLL, several interesting polymorphisms in key genes such as Mcl-1, Bax, and Bcl-2 have been reported but not always validated by subsequent independent work. Reasons for this are many, including technique, study population, statistical interpretation, and blind chance of multiple exploratory analyses that identify an interesting SNP without subsequent verification. Many of these genes have demonstrable function, and the lack of clinical correlation does not imply lack of impact, but rather emphasizes the importance of multiple genes in producing a discernable phenotype.

One pathway that has been shown to be very important in CLL is the p53 pathway. Disruption of the p53 pathway has been implicated in resistance to alkylator-based therapy, nucleoside analog therapy, and rituximab therapy. p53 function can be inactivated through a variety of direct (mutation and/or deletion of p53) or indirect pathways such as overexpression of the MDM2 protein or mutation of genes such as ATM. Gryshchenko and colleagues reported that a G-versus-T polymorphism at nucleotide 309 of MDM2 intron 1 impacts CLL outcome. The original paper describing this MDM2 SNP309¹ validated the mechanistic relevance and a follow-up study provided further relevance of its function.² Gryshchenko's results support data from other tumor types in that the occurrence of the G/G form of SNP309 does not predispose to CLL. However, as in other tumor types, the G/G SNP309 does correlate with shortened treatment-free and overall survival in CLL patients.

The investigation of what we know about MDM2 SNP309 and the function of the p53 pathway provides clear rationale for concurrent evaluation of p53 defects with SNP assessment. This report is exemplary in that the investigators report that such defects (as assessed by both interphase cytogenetics and SSCP mutational studies of p53 mutations) do have a different impact on treatment-free survival when considered together with SNP309 status. The authors also perform one of the most important tasks in analyzing SNPs by using a second, independent cohort of patients to confirm their results. Even when a SNP has demonstrated function, confirming the relevance of such a biomarker on two independent patient data sets provides additional assurance that the finding is correct. This is especially true with smaller studies where confirmation in an independent population should be considered to avoid bias. What remains to be asked is the impact of the SNP309 with respect to IgV_H mutational status and potentially other prognostic features in CLL. Additionally, the impact of the SNP309 on treatment outcome should also be explored.

So, the question remains relative to what these results mean to patients with CLL and the physicians who care for them. Grysh-chenko's results echo the data from other tumor types in that the occurrence of the G/G form of SNP309 does not predispose to CLL, but does impact time to first treatment and overall survival of CLL patients with this. Given the complexity of the pathway and the variance within populations of patients who exhibit one genotype or another, examination of this SNP to predict an individual patient's outcome will likely be ineffective outside of consideration of a wide range of other prognostic features relevant to this pathway and many others that are disordered in CLL. The SNP309 findings presented in this work add another layer of detail to the evaluation of p53 pathway function that will require physicians to consider implications as therapeutic efforts move forward toward individualized treatment decisions based upon SNP and acquired genetic findings present in the tumor cell.