A single nucleotide polymorphism in the p53 pathway ... - CiteSeerX

Oncogene (2007) 26, 1317–1323

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REVIEW

A single nucleotide polymorphism in the p53 pathway interacts with gender, environmental stresses and tumor genetics to influence cancer in humans GL Bond1 and AJ Levine1,2 1 The Simons Center for Systems Biology, The Institute for Advanced Study, Princeton, NJ, USA and 2The Cancer Institute of New Jersey, New Brunswick, NJ, USA

Cancer biology finds itself in a post-genomic era and the hopes of using inherited genetic variants to improve prevention and treatment strategies are widespread. One of the largest types of inherited genetic variation is the single nucleotide polymorphism (SNP), of which there are at least 4.5 million. The challenge now becomes how to discover which polymorphisms alter cancer in humans and how to begin to understand their mechanism of action. In this report, a series of recent publications will be reviewed that have studied a polymorphism in the p53 tumor suppressor pathway, MDM2 SNP309. These reports have lent insights into how germline genetic variants of the p53 pathway could interact with gender, environmental stresses and tumor genetics to affect cancer in humans. Importantly, these observations have also exposed potential nodes of intervention, which could prove valuable in both the prevention and treatment of this disease in humans. Oncogene (2007) 26, 1317–1323. doi:10.1038/sj.onc.1210199 Keywords: MDM2; polymorphism; cancer; gender; stress; mutation

Even modest changes in mdm2 levels affect cancer The p53 pathway is activated upon cellular stresses, such as DNA damage and oncogene activation. Upon activation, p53 elicits cellular responses, such as cell cycle arrest, senescence and apoptosis. The p53 stress response has been shown to be crucial for the prevention of tumor formation in both mice and humans (Lane, 2005; Johnson and Attardi, 2006). One of the most well-described central nodes of the p53 pathway is the oncogene MDM2 (Bond et al., 2005b). The MDM2 protein binds directly to and inhibits p53 by regulating its location, stability and activity as a transcriptional activator. Consistent with its role as a negative regulator of an important tumor suppressor, altering MDM2 levels has been shown in many mouse models to affect p53-dependent tumor suppression (Poyurovsky and Correspondence: Dr A Levine, The Institute for Advanced Study, Einstein Drive, Princeton, NJ 08540-0631, USA. E-mail: [email protected]

Prives, 2006). For example, the overexpression of MDM2 in either the whole mouse (Jones et al., 1998), the mammary epithelium (Lundgren et al., 1997) or the adult dorsal skin (Ganguli et al., 2000) leads to significantly increased tumor formation. In contrast, even a modest reduction of MDM2 levels in mice enhances tumor resistance (Alt et al., 2003; Mendrysa et al., 2006). For example, Mendrysa et al. (2006) recently demonstrated that just a 20% reduction of MDM2 levels in mice leads to a significant reduction in intestinal adenoma formation. In humans, MDM2 has been shown to be overexpressed in a subset of tumors; this overexpression is associated with accelerated cancer progression and lack of response to therapy in some tumor types (Freedman et al., 1999; Onel and CordonCardo, 2004). Consistent with these observations in human tumors, a human tumor cell line engineered to express just twofold more MDM2 displayed significantly weakened p53 activity, when compared to the parental cell line (Ohkubo et al., 2006). As the proper regulation of MDM2 levels have been shown to be vital for p53 tumor suppression, and that even a modest change in levels could affect cancer in mice, it was reasoned, and evidence was provided, that a naturally occurring sequence variation in the MDM2 promoter/enhancer region results in altered expression of the MDM2 protein, and affects p53 tumor suppression and cancer in humans (Bond et al., 2004). Specifically, a model was proposed that the G-allele of the single nucleotide polymorphism (SNP309, T/G) in the promoter of MDM2 increases the DNA-binding affinity of the transcriptional activator, Sp1, which results in high levels of MDM2 mRNA and protein in human cells. Subsequently, in esophageal tissues, individuals G/G in genotype were observed to have up to 2.5-fold higher MDM2 mRNA levels than T/T individuals (Hong et al., 2005). The heightened MDM2 levels were also shown to associate with the attenuation of the p53 pathway and the acceleration of tumor formation in both hereditary and sporadic cancers (Bond et al., 2004; Arva et al., 2005). Specifically, in a hereditary cancer syndrome (LiFraumeni), germ-line p53 mutation carriers who possessed the G-allele of SNP309 were diagnosed with cancer, on average, 7 years earlier than those who were homozygous for the T-allele. This observation has been reproduced in two independent studies, in which p53

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mutation carriers with the G-allele of SNP309 were diagnosed with cancer on average ten or sixteen years earlier than those who were homozygous for the T-allele (Bougeard et al., 2006; Ruijs et al., 2007). It was proposed that the presence of high levels of MDM2, resulting from the G-allele of SNP309, in individuals who have only one wild-type p53 allele, produces a severely weakened p53 tumor suppressor pathway resulting in a higher mutation rate, poorer DNA repair processes and reduced apoptosis leading to faster and more frequent tumor formation (Bond et al., 2004, 2005a). Gender and the estrogen signaling pathway The MDM2 SNP309 locus is found in a well-characterized region of the MDM2 promoter, which is regulated by hormonal signaling pathways. Over 10 years ago, it was first noted that MDM2 mRNA and protein levels are heightened in breast tumors that express the estrogen receptor (ER), a critical component of the estrogen signaling pathway (Sheikh et al., 1993; Gudas et al., 1995; Marchetti et al., 1995; Okumura et al., 2002). Subsequently, the expression of ER-a was shown to induce transcription of MDM2. The ERdependent increase of MDM2 transcription was shown to be mediated, at least in part, through the region of the MDM2 promoter where the SNP309 locus resides (Okumura et al., 2002; Kinyamu and Archer, 2003; Phelps et al., 2003). In fact, the ER was shown to bind to this region of the promoter in vivo (Kinyamu and Archer, 2003). Given that ER binds to the same region of the MDM2 promoter that harbors the SNP309 locus, and that the G-allele of SNP309 was shown to alter the affinity of a well-characterized co-transcriptional activator for multiple hormone receptors, including ER, namely Sp1 (Khan et al., 2003; Petz et al., 2004; Stoner et al., 2004), a recent report reasoned that the estrogensignaling pathway could affect how the SNP309 locus influences MDM2 transcription, and, therefore, tumor formation in humans (Bond et al., 2006a). In this report, the data suggest that an active estrogen-signaling pathway is needed for the G-allele to accelerate tumor formation in humans (Bond et al., 2006a). This model was proposed based on the following observations made in patient populations diagnosed with either diffuse large B-cell lymphoma (DLBCL) or soft tissue sarcoma (STS) and in two patient populations diagnosed with invasive ductal carcinoma of the breast (IDC). Specifically, in 162 DLBCL patients of Ashkenazi Jewish ethnicity, the G-allele of SNP309 only associated with an earlier age of diagnosis in female patients (13 years earlier) and not in male patients. That this gender-specific difference could be owing to genderspecific hormones was supported by the observations that both in female DLBCL patients and in female STS patients, the differences in age-specific cancer incidence between G/G and T/T women were the largest below the average age of menopause (51 years of age), when gender-specific hormones, like estrogen, are at their highest levels (P ¼ 0.0049 and 0.05). Oncogene

In order to test if the G-allele of SNP309 could indeed accelerate tumorigenesis only in the presence of an active estrogen-signaling pathway in vivo, women with the same tumor type were studied. The tumor type studied was sporadic IDC, which accounts for the vast majority of all breast cancers. Some women develop IDC with an intact estrogen pathway, whereas others do not. It was reasoned that if the G-allele of SNP309 can accelerate tumorigenesis only in the presence of an active estrogen-signaling pathway, then an earlier age of tumor onset for G/G women versus T/T women should be greatest in the formation of tumors that express high levels of ER (X50%). This is because the percent of tumor cells that stain positive for ER has been shown to correlate with the tumor’s dependence on estrogen for growth (Beckmann et al., 1997; Osborne, 1998). Indeed, the G-allele of SNP309 only associated with an earlier age of onset in high ER-positive but not ER-negative IDC 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, similar to other published reports (Boersma et al., 2006; Campbell et al., 2006; Copson et al., 2006; Ma et al., 2006; Millikan et al., 2006; Wilkening et al., 2006). In the first population, 658 IDC patients of Ashkenazi Jewish ethnicity were studied. In those 127 women whose tumors expressed high levels of ER (X50%), G/G women showed a 7-year average earlier age of onset of IDC compared with T/T women (P ¼ 0.0094). In contrast, in those 136 women whose tumors expressed low levels of ER, no significant differences were seen. In the second population, made up of 258 Caucasian IDC patients, who were not selected for Ashkenazi Jewish ethnicity, very similar significant trends were observed. Furthermore, in both populations, the differences in age-specific cancer incidence between G/G and T/T women with high ER positive IDC were the largest below the average age of menopause (51 years of age), when estrogen levels are at their highest (P ¼ 0.0133 and 0.0061), thereby lending further support to the model that the G-allele of SNP309 could indeed accelerate tumorigenesis only in the presence of an active estrogen-signaling pathway in vivo. Interestingly, similar observations were made in another sporadic cancer, namely colorectal cancer (CRC) (Bond et al., 2006b). In 165 CRC patients with wild-type p53 in their tumors, women, but not men, who carried the G-allele of SNP309 in either the heterozygous or homozygous state, showed a significant 9-year average earlier age of tumor diagnosis (P ¼ 0.0013), reminiscent of the gender-specific difference seen in DLBCL patients. If the gender of the CRC patients was ignored, this difference was significantly smaller, similar to other published reports (Alhopuro et al., 2005; Sotamaa et al., 2005; Allazzouzi et al., 2006). That this gender-specific difference could be owing to genderspecific hormones was supported again by the enrichment of individuals carrying the G-allele in women diagnozed before the average age of menopause, compared to either women diagnosed after the average

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age of menopause or men, much like in DLBCL, STS and high ER þ IDC. This was observed in two independent CRC patient populations. For example, in one population, individuals with the G-allele of SNP309 make up 84% of the female CRC cases diagnosed by the age of 55, but only 67% of the female cases diagnosed above 55 years of age (P ¼ 0.002) and 62% of the male CRC cases (Po0.0001). In summary, it had been reasoned that the estrogen signaling pathway could affect how the SNP309 locus influences MDM2 transcription, and, therefore, tumor formation in humans, given that the estrogen receptor binds to the same region of the MDM2 promoter that harbors the SNP309 locus and that the G-allele of SNP309 was shown to alter the affinity of a wellcharacterized co-transcriptional activator for multiple hormone receptors, including ER, namely Sp1. Statistically robust observations made in six independent patient populations and four different tumor types (DLBCL, CRC, STS and IDC) support the hypothesis (Figure 1) that MDM2 SNP309 does indeed accelerate tumor formation in a gender-specific and hormonaldependent manner (Bond et al., 2006a, b). Therefore, it will be important when studying the MDM2 SNP309 locus to incorporate factors such as gender, age, menopausal status at diagnosis, hormonal receptor status of the tumor, and exogenous estrogen intake. These observations also offer a potential node of intervention for the prevention and treatment of these common tumor types. The data suggest that women with a G/G genotype for SNP309 could be affected

differently by estrogen signaling manipulation than women with a T/T genotype. For example, increasing estrogen levels in post-menopausal women with a G/G genotype, in order to alleviate menopausal symptoms, could significantly increase their risk to develop these cancers (DLBCL, STS, high ER-positive IDC and CRC). Furthermore, these observations imply that women with a G/G genotype and these cancers (DLBCL, STS, high ER þ IDC and CRC) would benefit from decreasing estrogen levels and that such a decrease could significantly retard the progression of their disease. Indeed, many studies have shown that reducing estrogen signaling in patients with high ER þ IDC significantly retards tumor growth and results in longer overall survival rates (Osborne, 1998; Elledge et al., 2000). It will be interesting to determine if reduction of estrogen signaling will also prove to be an effective treatment for G/G women with DLBCL, STS and CRC, as this model predicts. Environmental stresses: smoking and viral infection The p53 pathway responds to a wide variety of stress signals, such as DNA damage, inflammation signaling and even the mutational activation of selected oncogenes. It is thought that the purpose of the p53 stress response is to ensure the fidelity of the duplication process of DNA in the cell. Stresses, such as DNA damage, increase the error rate for the duplication of DNA; thus, p53 mediates a cell cycle arrest to provide Stresses such as smoking and chronic HCV infection

WT T T

Mdm2

p53

Active Estrogen Signaling Pathway SNP309

Tumor Formation Sp1 G G

Mdm2

p53

Stresses such as smoking and chronic HCV infection Figure 1 A model is proposed for the interaction of MDM2 SNP309, gender, hormones and environmental stresses. In the presence of an active estrogen-signaling pathway, the G allele of SNP309 raises the basal levels of MDM2 in cells, due to the creation of an enhanced Sp1 transcription factor-binding site in the MDM2 promoter. The higher basal levels of MDM2 in cells attenuate the p53 apoptotic responses that occur in people in response to extrinsic and intrinsic stresses such as smoking and chronic HCV infection. Therefore, in individuals with the G-allele of SNP309, the percentage of cells undergoing apoptosis or cell cycle arrest in response to stress is low, and the propagation of cells with mutations, over a lifetime, permits cancers to arise earlier and at greater frequencies. Oncogene

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the time to repair the DNA before duplication. p53 can also mediate senescence and apoptosis to eliminate clones of cells that would otherwise propagate with a high error rate (Bond et al., 2005a). Many environmental exposures, such as smoking, dietary carcinogen exposure and chronic viral infection, have been shown to elicit cellular stresses, such as DNA damage, and associate with increased risk of certain cancers. As previously proposed, it is likely that individuals with inherently different levels of p53 function will respond differently to such environmental stresses and have different levels of risk for developing the associated cancers (Bond et al., 2005a). Three recent studies have provided evidence that this could be the case (Hong et al., 2005; Zhang et al., 2006; Dharel et al., 2006). DNA damage is just one form of genotoxic stress that cells undergo when exposed to smoke (DeMarini, 2004). Two recent papers from the Chinese Academy of Medical Sciences suggest that smoking and a inherently weaker p53 stress response, interact to increase the risk for developing both lung and esophageal cancers (Hong et al., 2005; Zhang et al., 2006). For example, 1106 primary lung cancer patients of Han Chinese ethnicity and 1420 cancer-free control subjects were studied (Zhang et al., 2006). A significant enrichment of individuals carrying the G-allele of MDM2 SNP309 was observed in the lung cancer patient population compared to the cancer-free control population, which is a trend that has been subsequently observed in two other studies (Lind et al., 2006; Park et al., 2006), but not in three others (Hu et al., 2006; Li et al., 2006; Pine et al., 2006). Interestingly, the odds ratio associated with smoking and the increased risk for lung cancer development was significantly greater in individuals G/G in genotype compared to those T/T in genotype (G/G, OR 3.81, 95% CI 2.55–5.69 versus T/T, OR 2.23, 95% CI 1.51–3.29; Po0.0001). The authors suggested an additive interaction between smoking and MDM2 SNP309, because the odds ratio for the presence of both smoking and the G/G genotype was greater than the sum of the odds ratios for smoking and the genotype minus one. Very similar results were seen with smoking, the G-allele of SNP309, and another p53 pathway SNP (codon 72) in the risk of esophageal squamous cell carcinoma (Hong et al., 2005). Much like smoking, chronic hepatitis C (HCV) infection has also been shown to lead to significant increases in cellular stress signals, such as DNA damage and inflammation signaling, and is strongly associated with the development of hepatocellular carcinoma (Levrero, 2006). In a recent study, evidence was provided that the MDM2 SNP309 locus alters the risk of developing liver cancer associated with chronic HCV infection (Dharel et al., 2006). Specifically, in 435 Japanese patients with chronic HCV infection, a significant enrichment of individuals G/G in genotype at the SNP309 locus was found in those patients with hepatocellular carcinoma compared to cancer-free chronically infected patients. This resulted in an odds ratio of 2.28 (95% CI 1.30–3.98). In summary, these observations support the hypothesis that individuals with inherently Oncogene

lower levels of p53 function (e.g. individuals with the G-allele of SNP309) will respond poorly to environmental exposures that elicit stress responses (e.g. smoking and chronic HCV infection) and therefore have an increased risk for developing the associated cancers (e.g. esophageal, lung and liver; Figure 1). Such knowledge could prove beneficial in improving prevention strategies by using both germline genetics and known environmental risk factors to better define populations with a higher risk of developing cancer.

Tumor genetics: the p53 mutational status Almost every tumor has been found to collect somatic mutations, some of which have been shown to affect either the growth of the tumor and/or the response of the tumor to therapeutic intervention. As mentioned above, the p53 gene is one of the most highly mutated genes in human tumors and tumors with p53 mutations have been found to associate with a more aggressive phenotype and a worse prognosis in multiple tumor types (Royds and Iacopetta, 2006). Because somatic p53 gene mutation is such a frequent event in tumors and associates with altered cancer progression, a complete understanding of the effects of functional germline variations in the p53 pathway can only be gained by incorporating the mutational status of the p53 gene into studies. Interestingly, two recent articles have begun to describe interactions between MDM2 SNP309 and the somatic p53 mutational status in both cancer incidence (Menin et al., 2006) and survival (Boersma et al., 2006). One of the highest somatic rates of p53 mutation (44% of tumors) is found in CRCs (Olivier et al., 2002). The results presented in a recent report suggest that the G-allele of SNP309 might only influence the formation of those colorectal tumors which retain wild type p53 (Menin et al., 2006). In this report, 153 patients were stratified based on the p53 mutation status of their tumors. The authors observed that the G-allele of SNP309 associated with a significant 10-year earlier age of diagnosis (P ¼ 0.03) in those patients whose tumors retained wild type p53. By contrast, in those patients whose tumor mutated p53, no significant earlier age of diagnosis was seen. If this intriguing result can be repeated in other patient populations, it suggests that after the somatic mutation and subsequent inactivation of p53, the germline G-allele of SNP309 and the heightened MDM2 levels no longer attenuate p53 tumor suppression to accelerate tumorigenesis. The mutation of the p53 gene has been clearly shown in mouse models not only to accelerate tumorigenesis, but also to affect radiation therapy negatively and many chemotherapeutic therapies, as would be expected given the role of p53 in inducing apoptosis upon DNA damage (Lane, 2005). Based on these clear results in mice, much hope has been placed in using the tumor p53 mutational status of a tumor to optimize therapy and improve patient outcome. A recent study examined breast cancer survival, p53 mutation status and SNP309

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in breast tumors (Boersma et al., 2006). Two hundred and forty-eight women with breast cancer and available tumor samples were studied and the mean follow-up time was 55 months with a range of 12–140 months. Similar to previously published results (Pharoah et al., 1999), the 48 women with a mutated p53 gene (exons 5–8) in their tumors showed a significant increase in the risk ratio of death of 1.88–fold [95% CI 1.03–3.41, P ¼ 0.039] compared to the 200 women who retained a wild-type p53 gene. Interestingly, when the patients were analysed separately based on their SNP309 status, it became clear that the increased risk ratio of death associated with mutant p53 was only found in those women T/T in genotype and not in individuals who carry the G-allele of SNP309. Specifically, women T/T in genotype with mutant p53 in their tumors had a 2.33 fold increased risk ratio of death (95% CI 1.08–5.03, P ¼ 0.031) compared to women T/T in genotype with wild-type p53 in their tumors. By contrast, for women T/G and G/G in genotype, no significant p53 mutational status-based increased risk ratio of death was seen. The authors suggested that these observations support the model that the G-allele of SNP309, which produces higher MDM2 levels, is dominant over p53 function, because the differential effects of mutant versus wildtype p53 in breast cancer survival are masked in women with the G-allele but not in women T/T in genotype. Naturally, these intriguing observations will have to be confirmed in other populations of breast cancer patients, but they do offer hope that by combing both germline genetics and somatic genetics of the p53 pathway, we could better define populations of breast cancer patients who differ in their survival rates, in the hopes of optimizing therapy. It will be interesting to see if these observations, if robust, extend to other tumor types where the p53 mutation status also associates with altered survival (Royds and Iacopetta, 2006).

Conclusion Mouse models have clearly shown that even modest changes in MDM2 levels can affect the p53 pathway and subsequently cancer. These observations allow for the possibility that altering just a few (or even just one) base pair(s) in the gene could alter the levels of MDM2 enough to affect the p53 pathway and, therefore, cancer in humans. This hypothesis has been supported by the work on MDM2 SNP309. As the initial publication (Bond et al., 2004), multiple studies have shown that the G-allele of MDM2 SNP309 is associated with the attenuation of the p53 pathway and an enhanced early onset of and increased risk for, tumorigenesis (Bougeard et al., 2006; Hong et al., 2005; Swinney et al., 2005; Allazzouzi et al., 2006; Bond et al., 2006a, b; Dharel et al., 2006; Lind et al., 2006; Menin et al., 2006; Ohmiya et al., 2006; Park et al., 2006; Ruijs et al., 2007; Zhang et al., 2006). Because modest changes in levels of other central nodes of the p53 pathway (e.g. p53 and p19ARF) have also been shown to affect cancer in mice (Lane, 2005), it seems likely that SNPs in these genes could also affect cancer in humans, especially in combination with other functional germline variants, gender, hormones, environmental stresses and tumor genetics. Increased understanding of these relationships should lead to the development of better prevention and treatment strategies.

Acknowledgements We thank Elisabeth E Bond, Suzanne Christen and Wenwei Hu for their help in preparation of the manuscript. Support of this work comes from the Breast Cancer Research Foundation, The Simons Foundation and the Leon Levy Foundation.

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