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Journal of Clinical Oncology, Vol 26, No 14 (May 10), 2008: pp. 2244-2245 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.7818
Comprehensive Single Nucleotide Polymorphism Study Supports the Role of MDM2 in p53-Competent Chronic Lymphocytic LeukemiaDivision of Hematology-Oncology, Department of Internal Medicine, Ohio State University, Columbus, OH In this issue, Gryshchenko et al1 report that a known single nucleotide polymorphism (SNP) in the promoter region of MDM2 is associated with treatment-free and overall survival in chronic lymphocytic leukemia (CLL) patients. This SNP was additionally found to influence MDM2 levels in CLL cells, adding important evidence to support the functional relevance of this SNP. This study exemplifies how the impact of SNPs on clinical outcome should be reported in specific diseases. The human genome has millions of SNPs, but relatively few have been shown to have functional significance. Although myriad reports exist in the literature of biologically interesting SNPs that are associated with cancer, it seems that an equal number of reports can be found that refute the initial results. CLL is no different; the clinical relevance of several interesting polymorphisms in key genes such as Mcl-1, Bax, and Bcl-2 has not always been validated by subsequent independent work. Reasons for this are many; differences in technique, study populations, statistical interpretation, and chance can all contribute to discordant results from outwardly similar investigations. The focus of this particular study, a G versus T polymorphism at nucleotide 309 of MDM2 intron 1, has been the subject of broad investigation since its discovery in 2004. The original report describing MDM2 SNP309 was an impressive work, with an intriguing hypothesis, successful SNP search, mechanistic validation, and finally confirmation of biologic relevance in patients with Li-Fraumeni syndrome.2 A follow-up study by members of the same group delved further into the function of SNP309, elegantly filling in mechanistic blanks and providing additional evidence of SNP309's importance.3 Not surprisingly, these persuasive data sparked multiple attempts to associate the occurrence of SNP309 with clinical parameters in a variety of solid tumors including lung, breast, liver, and colon. Some groups found links; others did not. In fact, the overall impression of these efforts is not so much of doubt but of uncertain value; if multiple follow-up studies fail to show significance, how could such a parameter be useful? The answer of course is complex, but, in this case, was at least partially unraveled by the original team. As reported by Bond and Levine,4 several aspects complicate MDM2 SNP309 prognostication. First, the SNP309 alteration affects the binding site of transcription factor Sp1, so a greater impact will be found in tumors that benefit from active Sp1-mediated transcription. A principal example of this is certain types of breast cancer in which elevated estrogen receptor (ER) signaling induces MDM2. Bond and Levine4 state: "Indeed, the G-allele of SNP309 only associated with an earlier age of onset in high ER-positive but not ER-negative [invasive ductal carcinoma] formation in two independent patient populations. If the levels of estrogen receptor in the breast tumors were ignored, no significant differences were observed between the different genotypes of the SNP309 locus." Therefore, previous studies could have missed an SNP309 association simply because the disease of their study populations was too biologically diverse. A second complicating factor is that, of the millions of SNPs, there are several in the p53 pathway that can alter function. Furthermore, mutations or defects in other p53 modulators such as ATM may affect the ability of p53 to induce apoptosis. Even outright deletion of p53 as in del(17p13.1) cases still can leave one allele and partial function intact. Thus, in different patients, alternative defects or modifications of p53 pathway components, either in protein amount or function, may conspire to produce different sensitivities to changes in MDM2 activity. Several groups noted that the SNP309 alteration has only modest effects on MDM2 levels. However, in the face of p53 function already impaired by a second defect, even a two-fold change (or less) in MDM2 expression may be the difference between responsive and progressive disease. Certainly, there are many other examples showing how the influence of a SNP may be modulated, each illustrating the hazard of simply screening for a particular SNP of interest and declaring it relevant or not. Gryshchenko et al1 are to be commended for addressing several of the challenges mentioned above. First, from what we know of MDM2 SNP309, it is insufficient to investigate this SNP without concurrent evaluation of p53 defects, and in fact, they report that such defects (as assessed both by interphase cytogenetics and single conformation polymorphism mutational studies) do have a different impact on treatment-free survival when considered together with SNP309 status. Additionally, the authors perform one of the most important tasks of such investigations; that is, they analyze a second independent cohort of patients. Although this by itself is no guarantee of finding biologic or clinical relevance, it goes a long way toward eliminating chance findings. Especially with smaller studies, confirmation in an independent population should be considered essential when reporting SNP correlations with clinical parameters. So the question remains: What do these results mean to CLL patients? The results of Gryshchenko et al1 echo the data from other tumor types in that the occurrence of the G/G form of SNP309 does not predispose to CLL, and given the complexity of the pathway and the variance within populations of patients who exhibit one genotype or another, examination of this SNP on an individual patient basis would not be useful. However, obviously this is just one factor, and even well-validated prognostic parameters are of limited use when considered in isolation. One can envision the development of a large assay panel that, in total, produces a meaningful prediction of how a patient will perform with a specific therapy. The SNP309 findings presented in this work add another layer of detail to the evaluation of p53 pathway function in a patient, with clear implications for which treatments are likely to be more or less effective. But this is only part of the story. There is immediate value of such SNP investigations, not just of MDM2 SNP309 as reported here, but of any others that can be shown to have a biologic function. This value is in pointing investigators to flaws in apoptotic pathways, exactly as SNP309 did in the initial studies. SNPs are like tracers in the genome, and with each one that is functionally characterized and associated with clinical parameters, we increase the likelihood of uncovering some aspect of how tumor cells survive, grow, and evade immune destruction. Perhaps the finding with elevated ER-mediated MDM2 regulation in breast tumors provides a lead to investigation in CLL. The role of ER in CLL is hardly intuitive, but ER expression in CLL cells has in fact been reported,5 and it is not unreasonable that MDM2 levels may be increased in such cases. More importantly, we have justification to ask what other factors might bind or affect binding at this site in tumor cells and what regulates these factors. SNPs are now beginning to receive the attention they deserve, not only as prognostic factors, but also as molecular clues to our understanding of cancer biology. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: David M. Lucas, John C. Byrd Financial support: David M. Lucas, John C. Byrd Administrative support: David M. Lucas, John C. Byrd Provision of study materials or patients: David M. Lucas, John C. Byrd Collection and assembly of data: David M. Lucas, John C. Byrd Data analysis and interpretation: David M. Lucas, John C. Byrd Manuscript writing: David M. Lucas, John C. Byrd Final approval of manuscript: David M. Lucas, John C. Byrd ACKNOWLEDGMENTS We receive funding from the National Cancer Institute, the Leukemia and Lymphoma Society of America, and the D. Warren Brown Foundation. REFERENCES
1. Gryshchenko I, Hofbauer S, Stoecher M, et al: MDM2 SNP309 is associated with poor outcome in B-cell chronic lymphocytic leukemia. J Clin Oncol 26:2252-2257, 2008 2. Bond GL, Hu W, Bond EE, et al: A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119:591-602, 2004[CrossRef][Medline] 3. Arva NC, Gopen TR, Talbott KE, et al: A chromatin-associated and transcriptionally inactive p53-Mdm2 complex occurs in mdm2 SNP309 homozygous cells. J Biol Chem 280:26776-26787, 2005 4. Bond GL, Levine AJ: A single nucleotide polymorphism in the p53 pathway interacts with gender, environmental stresses and tumor genetics to influence cancer in humans. Oncogene 26:1317-1323, 2007[CrossRef][Medline] 5. Rosen ST, Maciorowski Z, Wittlin F, et al: Estrogen receptor analysis in chronic lymphocytic leukemia. Blood 62:996-999, 1983 Related Article
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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