Early onset lung cancer, cigarette smoking and the SNP309 of the murine double minute-2 (MDM2) gene

Human cells have developed a complex system to protect themselves from genotoxic damage where the p53 tumor suppressor gene plays an important role in protecting against such insults by serving as an integrator of the signals produced by DNA damage. The MDM2 protein inhibits p53 transactivation activity and promotes its export from the nucleus by binding to the transcriptional activation domain of p53 [1] and acts as an ubiquitin ligase upon p53 pushing fast degradation of the suppressor [2, 3].

Recently, a SNP (SNP309, G2580T) at the intronic p53-response promoter of MDM2 was identified and associated with altered Sp1 binding affinity and expression levels of MDM2 RNA and protein [4]. Contradictory results were reported regarding the MDM2 SNP309 association with lung cancer [5‐8]. In addition the polymorphism was correlated with a decreased age at the time of lung cancer diagnosis in Li-Fraumeni syndrome and sporadic sarcoma patients [4]. Our study is the first report on a large German case-control study of young lung cancer patients (age of onset < 51 years) investigating the MDM2 SNP 309.

Reports have shown an increased risk of lung cancer for the G allele of the MDM2 SNP309 in Korean and Chinese populations [7, 16, 17]. In contrast, in our study of 635 Caucasian lung cancer patients with age of onset < 51 years and 1300 controls the MDM2 SNP309 was not associated with lung cancer. We did not observe a significant overall association either with the G allele or with the T allele as reported by Li et al. (2006) where they showed an increased lung cancer risk with the T/T genotype in a non-Hispanic white population [18]. We had a 90% power (alpha = 0.05, two sided test) to detect a minimum overall OR of 1.4 for the MDM2 SNP309 T allele. Thus our study had sufficient power to detect an OR of 1.6 (95% CI: 1.1–2.5) and 1.8 (95% CI: 1.5–2.3) reported in other studies [6, 7]. The estimated allele frequency (T: 0.66, G: 0.34) agrees well with further reported allele frequencies in Caucasian populations [6, 8]. Differences between the two case populations were statistically not palpable (Table 1, 2, 3, 4, 5) but the HLC-sample was enriched with NSCLC-cases. According to Steffens et al. 2006 [12] we can assume the German population to be nearly free of population stratification, which may lead to false positive or false negative association findings in genetic case control studies. Differences in ethnicity between our population and those reported by Zhang et al. 2006 [7], Park et al. 2006 [16] and Jun et al. 2007 [19] may provide a partial explanation for the lack of association in our study. On the other hand Hu et al. 2006 [5] also did not observe an association between the MDM2 SNP309 and lung cancer in a Chinese population. Our results were similar to the report of Pine et al. (2006) [8]. They also did not find any overall association between the MDM2 SNP309 and lung cancer in a Caucasian (USA) population. Similarly, we did not observe an interaction between the MDM2 SNP309 and smoking. A combined analysis of the available genotype data of the MDM2 SNP309 showed an increased risk of lung cancer for the GG versus the TT genotype (OR: 1.3, 95% CI: 1.1–1.4) [20]. A main difference between the two study populations is the age of cases. Therefore one possible explanation would be, that the MDM2 variant is only associated with risk of later onset lung cancer. On the other hand a large study of 1787 Caucasian lung cancer patients could also not confirm the results of this meta-analysis. They did not find any significant association of the MDM2 SNP309 and lung cancer [21]. The populations used in the meta-analysis are mostly of Asian origin so possibly pointing to population heterogeneity.

Lind et al. (2006) [6] recently reported a gender specific risk disposing effect of the T allele of MDM2 SNP309 for NSCLC cases. They investigated NSCLC-cases and found female carriers of the GG-genotype associated to LC by an OR of 4.1, while male homozygotes showed a non significant OR of 1.3. Our data slightly tends to confirm this finding, but the corresponding OR for NSCLC women is just 1.4 (1/0.71 of Table 4), which is much smaller and not significant (p = 0.323). In our study none of the gender specific ORs nor a test of gender differences yielded significance. But we noticed discrepancies of such a gender specific genetic association between the two case-samples of our investigation. A gender difference was almost significant (p = 0.08) for the much smaller single center case-sample of the HLC-study. There, the OR for female carriers of the GG-Genotype (corresponding to Lind et al. (2006)) was 1.9 (1/0.54 of Table 4) and for male carriers 0.6 (1/1.56 of Table 4). With n = 67 female and n = 96 male cases these subsamples are quite small and the tests for association are underpowered. Thus our investigation provides no significance for such gender specific associations by itself. Comparing our study samples to that of Lind et al. (2006) the major difference is the age of onset of LC. The presented investigation focused on early onset LC cases which are in the mean 20 years younger than those of Lind et al. (2006). As the population by Lind et al. (2006) is of Norwegian origin there might also be different gene-environmental interactions.

MDM2 SNP309 was reported by Bond et al. 2004 [4] to be associated with an earlier onset of disease for Li-Fraumeni syndrome and sporadic sarcoma patients. We did not observe a lower age of diagnosis in our study, similar findings are also described by Hu et al. 2006 [5] and Pine et al. 2006 [8]. Our sample size is large enough to detect a shift of two years for the time of diagnosis with 90% power (alpha = 0.05) for heterozygous as well as for homozygous allele carriers. Recently Bond et al. 2006 [22] reviewed the possible interaction between the SNP309 and the oestrogen receptor status in women. Within women of the LUCY case population we could observe an earlier onset of disease of 10 months (95% CI: 0.3 to 20 months, p = 0.044), but only 6 months (95% CI: -10 to 22 months, p = 0.496) in the by far smaller HLC-case population. Recent data suggest that the promoter polymorphism in the MDM2 gene may influence the age of cancer onset in a gender specific way [23‐25].