MDM2 SNP309 G allele decreases risk but does not affect onset age or survival of Chinese leukaemia patients

Abstract

Although mutations in p53 are rare in leukaemia, MDM2, the negative regulator of p53, is often overexpressed. Recently, a single nucleotide polymorphism (SNP) in the MDM2 promoter - within the oestrogen-receptor-binding region - resulting in either a G or T allele was shown to affect its transcription, with elevated MDM2 being produced when it is a G allele. Expectedly, SNP309G females were found to be at a higher risk of accelerated onset of cancers. We have therefore analysed, in a pilot study, whether the status of MDM2 SNP309 and p53 codon-72 polymorphism, which was also shown to affect cancer predisposition, would affect cancer risk, onset age, overall survival and response to therapy in Chinese leukaemia patients. p53 SNP was not associated with any of the parameters. However, in contrast to expectations, the MDM2 SNP309G allele was associated with reduced risk of leukaemia. No other association was found between SNP309 and other parameters in both males and females. Thus, the data highlights ethnic differences in the effects of this SNP on cancer risk.

Introduction

p53 is a critical tumour suppressor gene that is mutated in almost 50% of all human cancers.1, 2 However, leukaemia represents a class of cancers that does not contain significant levels of p53 mutations.³ Nonetheless, in cases where there are no direct p53 mutations, the p53 pathway has been suggested to be defective due to alterations in either upstream or downstream regulators.4, 5 Leukaemia indeed provides an example for such a phenomenon, whereby MDM2, the critical negative regulator of p53, is often overexpressed.6, 7, 8, 9, 10, 11, 12 Hence, it is conceivable that MDM2 overexpression could weaken the p53 pathway, thereby contributing to leukaemiogenesis.

Single nucleotide polymorphisms (SNPs) in p53 and genes in the p53 pathway have been identified, and have been proposed to affect tumourigenecity.4, 5, 13 Of note is the codon 72 polymorphism of p53 that has been intensely studied. This SNP, resulting in either a C or G nucleotide, leads to either a Proline (Pro) or Arginine (Arg) residue at codon 72, respectively. Both these variants have been shown to preferentially affect the different functional properties of p53. For example, the Arg variant has been shown to be more potent in apoptosis induction whereas the Pro variant was shown to be better in inducing cell-cycle arrest and in its ability to repair damaged-DNA.14, 15, 16 Not unexpectedly, these variants have been associated with cancer predisposition, though there is no uniform agreement to which variant predisposes individuals to higher risk of cancer.16, 17, 18, 19 In leukaemias, whereas the Pro variant increased the risk of chronic myeloid leukaemia (CML), the Arg allele was associated with increased risk of chronic lymphocytic leukaemia (CLL).20, 21 By contrast, no association of p53 codon 72 polymorphism was noted with acute myeloid leukaemia (AML), the B-type CLL (B-CLL)22, 23, 24 and even CLL.²⁵

Similarly, a SNP in the promoter of MDM2 - the SNP309 - results in either a G or T allele.²⁶ This SNP is found in the Sp-1 binding site of the promoter, which lies in the oestrogen-receptor-binding region.²⁷ The G allele results in a higher affinity site for Sp-1 binding, and hence leads to enhanced MDM2 transcription.²⁷ It has therefore been postulated that females carrying the G allele in particular are more sensitised to cancer formation and initial reports have indicated that in familial cancers, SNP309G carriers succumbed to earlier onset of cancers.²⁷ Furthermore, various reports have suggested a correlation between the G allele and earlier onset of many cancers, though lack of correlation has also been reported.28, 29, 30, 31 In lymphoid malignancies, the role of this SNP has not been extensively studied, except for two reports that either showed lack of correlation with survival in mantle cell lymphoma and CLL, or an association of the G allele with early onset age in childhood acute lymphoblastic leukaemia (ALL), particularly in Caucasian and Black populations but not in Hispanic populations.12, 25, 32

There is an ethnicity-based bias for the prevalence of both the codon 72 p53 and the MDM2 SNP309 polymorphsims. The Arg variant of p53 has been shown to be prevalent in Caucasian populations living further away from the equator whereas the Asians and Africans tend to contain more of the Pro carriers.³³ Similarly, the MDM2 SNP309T allele was found to be enriched in the Caucasians who contain extremely low frequencies of the G allele, in contrast to the Asians and Azhkenazi Jews who have a significantly higher percentage of the SNP309 G allele.27, 34

We have therefore evaluated if both the polymorphisms in p53 and MDM2 would affect the risk of leukaemia formation, the age of onset, response to therapy and overall survival, in Chinese Asians living in Singapore, who are descendants from Southern China and who have similar MDM2 SNP frequencies as the Chinese from China.³⁴ The data presented indicate that contrary to expectations, it is the G allele of the MDM2 SNP309 that was associated with a decreased risk of leukaemia. p53 status did not affect any of the parameters. Importantly, there was no gender bias, suggesting that the effects of MDM2 SNP309 may be manifested in an ethnicity-based manner and does not support the hypothesis that the G allele always predisposes or accelerates the onset of cancers in females.