PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Cancer Causes Control. Author manuscript; available in PMC 2010 March 1.
Published in final edited form as:
PMCID: PMC2631619
NIHMSID: NIHMS70183

A functional SNP in the MDM2 promoter, pigmentary phenotypes, and risk of skin cancer

Abstract

The MDM2 oncoprotein is a key negative regulator of the tumor suppressor p53. A functional MDM2 single nucleotide polymorphism (SNP309) in the promoter region increases the affinity of transcription activator Sp1 for the MDM2 gene promoter, resulting in higher expression of MDM2 and thus inhibition of p53 transcriptional activity. UV-induced p53 activation promotes cutaneous transient pigmentation, and the common p53 Arg72Pro polymorphism alters the protein’s transcriptional activity. We evaluated the effect of the MDM2 SNP309 and its interaction with the p53 Arg72Pro polymorphism on pigmentary phenotypes and skin cancer risk in a nested case-control study within the Nurses’ Health Study (NHS) among 219 melanoma cases, 286 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 873 controls, and among controls from other studies. We found that the G allele of the MDM2 SNP309 was inversely associated with the presence/absence of moles on the arm among 3207 women pooled from controls of three nested case-control studies within the NHS. Compared with the MDM2 SNP309 T/T genotype, adjusted odds ratios (ORs) of having moles on the arms for T/G and G/G genotypes were 0.92 (95% confidence interval (CI), 0.78–1.08) and 0.68 (95%CI, 0.53–0.87), respectively (P, trend, 0.005). We observed suggestive evidence of the association between the carriage of the MDM2 SNP309 G allele and childhood tanning tendency (adjusted OR, 1.30; 95% CI, 1.01–1.68). No significant associations were found between the MDM2 SNP309 and any of the three types of skin cancer. For SCC, the trend of increased risk across the three genotypes of MDM2 was stronger among p53 Pro carriers (p, trend, 0.05) than p53 Arg/Arg wildtype group (p, trend, 0.99; p, interaction, 0.07). These results provide evidence for the potential involvement of MDM2 SNP309 in pigmentary traits.

Keywords: MDM2, p53, pigmentary phenotypes, skin cancer

Introduction

Skin cancer is the most common form of cancer in the United States, with approximately 1 million new cases per year [1]. Ultraviolet (UV) radiation is a well-established skin cancer risk factor and can cause DNA damage [2,3]. The tanning response to UV irradiation and development of dark pigmentation is an important host protective factor against sun exposure-induced skin cancer [4,5].

The human homologue of mouse double minute 2 (MDM2) acts as a major regulator of the tumor suppressor p53 by targeting its destruction. The MDM2 protein binds to p53 directly, resulting in ubiquitination and subsequent degradation of p53; i.e., their physical interaction inhibits the transcriptional activity of p53 by regulating its location, stability, and activity [6,7].

Recently, Cui et al. demonstrated that UV-induced p53 activation promotes cutaneous transient pigmentation such as the tanning response by increasing the transcriptional activation of pro-opiomelanocortin (POMC) in the skin [8]. POMC is the precursor of α-MSH, which activates the melanocortin 1 receptor (MC1R) and induces melanin products [9,10]. One functional polymorphism of the p53 gene is located at codon 72, which encodes the amino acids proline (Pro) and arginine (Arg) [11]. It has been shown that, compared with Arg allele, the Pro allele has higher transcriptional activity and lower capacity to induce apoptosis [12,13]. We also found that the Pro allele is associated with the tanning response [14].

A functional MDM2 single nucleotide polymorphism (called SNP309) is the T/G substitution at the 309 nucleotide position in the promoter region. It was shown that the G allele of the SNP309 increases the affinity of the transcriptional activator Sp1 for the MDM2 gene promoter, resulting in higher expression of MDM2 than that produced by the T allele, and subsequent inactivation of the p53 pathway [15].

We evaluated the effect of MDM2 SNP309 and its interaction with the p53 codon 72 polymorphism on pigmentary phenotypes (including childhood tanning tendency, childhood sunburn reaction, and the presence/absence of moles on the arm) and skin cancer risk in a nested case-control study within the Nurses’ Health Study (NHS).

Materials and Methods

Study population

The NHS was established in 1976, when 121,700 female registered nurses between the ages of 30 and 55, residing in 11 larger U.S. states, completed a self-administered questionnaire on their medical histories and baseline health-related exposures. Updated information has been obtained by questionnaires every 2 years. Between 1989 and 1990, blood samples were collected from 32,826 of the cohort members. The distribution of risk factors for skin cancer in the subcohort of those who donated blood samples was very similar to that in the overall cohort. Eligible cases in this study were women with incident skin cancer from the subcohort who had given a blood specimen, including SCC and BCC cases with a diagnosis any time after blood collection up to June 1, 1998 and melanoma cases up to June 1, 2000 who had no previously diagnosed skin cancer. A common control series was randomly selected from participants who gave a blood sample and were free of diagnosed skin cancer up to and including the questionnaire cycle in which the case was diagnosed. One or two controls were matched to each case by year of birth (±1 year). The nested case-control study consisted of 219 melanoma cases, 286 SCC cases, 300 BCC cases, and 873 matched controls. The study protocol was approved by the Committee on Use of Human Subjects of the Brigham and Women’s Hospital, Boston, MA.

Exposure data

Information regarding skin cancer risk factors was obtained from the prospective biennial questionnaires and a retrospective supplementary questionnaire mailed to cases and controls in 2002. Questions on natural hair color at age 20 (black, dark brown, light brown, blonde, and red), childhood and adolescent tanning tendency (practically none, light tan, average tan, and deep tan), and childhood sunburn reaction (practically none, some redness only, burn, painful burn, and painful burn with blisters) were asked in the 1982 prospective questionnaire; number of moles on the arms (larger than 3 mm diameter) in the 1986 prospective questionnaire; and ethnic group in the 1992 questionnaire. In the skin cancer nested case-control study, natural skin color and other sun exposure-related information was collected by the retrospective supplementary questionnaire. Estimation of past sunlight exposure for each subject was described previously [16].

Laboratory assays

The MDM2 SNP309 (rs2279744) was genotyped by restriction fragment length polymorphism (RFLP), while the p53 Arg72Pro polymorphism (rs1042522) was genotyped by the 5 nuclease assay (TaqMan®) in 384-well format, using the ABI PRISM 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA). TaqMan® primer and probe were designed using the Primer Express® Oligo Design software v2.0 (ABI PRISM). Laboratory personnel were blinded to case-control status, and 10% blinded quality control samples (duplicated samples) were inserted to validate genotyping procedures; concordance for the blinded quality control samples was 100%. Primers, probes, and conditions for genotyping assays are available upon request.

Statistical methods

In addition to the skin cancer nested case-control study, we had MDM2 SNP309 genotyping data for the participants in nested case-control studies of breast cancer and endometrial cancer as well as p53 codon 72 polymorphism genotyping data for women in the breast cancer nested case-control study in the NHS. To increase statistical power, we assessed the effect of the MDM2 SNP309 on pigmentary phenotypes (including childhood tanning tendency, childhood sunburn reaction, and the presence/absence of moles on the arm) among the 3207 women pooled from controls in three nested case-control studies of skin cancer, breast cancer, and endometrial cancer. Also, we used 2009 controls from two nested case-control studies (skin cancer and breast cancer) to evaluate the interaction between the MDM2 SNP309 and the p53 codon 72 polymorphism on pigmentary phenotypes.

We used a χ2 test to assess whether the MDM2 genotype and the p53 genotype were in Hardy-Weinberg equilibrium among the controls. The genotype distributions of two SNPs were in Hardy-Weinberg equilibrium. We evaluated the association of the MDM2 SNP309 with pigmentary phenotypes among the controls. In the evaluation of pigmentary phenotypes as outcomes, the responses to a question about childhood tanning tendency were grouped into tan (light tan or average tan or deep tan) and non-tan (practically none); the responses to the question of childhood sunburn reaction were grouped into burn (some redness only, burn, painful burn, and painful burn with blisters) and non-burn (practically none); the responses to the question of number of moles on the arms were grouped into presence (the number of moles ≥1) and absence (none). A test for trend was performed across the three MDM2 genotypes. Unconditional logistic regression was used to calculate the association between the MDM2 SNP309 and pigmentary phenotypes as well as interactions between the MDM2 SNP309 and the p53 codon 72 polymorphisms on pigmentary phenotypes. Unconditional logistic regression was also employed to assess the interaction between the MDM2 SNP309 and the childhood tanning tendency (or childhood sunburn reaction, or natural hair color) on the presence/absence of moles on the arm. To summarize multiple constitutional phenotypic variables, we constructed a multivariate confounder score for skin cancer [17]. Briefly, we applied the logistic regression coefficients from a multivariate model, including age, race, natural skin color, natural hair color, childhood or adolescent tendency to burn, and the number of moles on arms, to each individual’s values for the latter four variables and summed the values to compute a susceptibility risk score in the logit scale. We used this score to define women with low and high constitutional susceptibility based on median among controls. We evaluated the association of the MDM2 SNP309 and its interaction with the p53 codon 72 polymorphism on the constitutional susceptibility score among controls of the skin cancer nested case-control study using unconditional logistic regression.

We evaluated the effects of the MDM2 SNP309 and its interaction with the p53 polymorphisms on skin cancer risk using unconditional regression models. We compared each type of skin cancer to the common control series in the skin cancer nested case-control study to increase statistical power.

In the interaction analysis, we used cross-classified categories of the MDM2 SNP309 and p53 polymorphisms (or childhood tanning tendency, childhood sunburn reaction, or natural hair color) compared to a common reference category. We modeled these predictors as ordinal variables to test the statistical significance of a single multiplicative interaction term.

Results

Descriptive Characteristics of Cases and Controls

A detailed description of the characteristics of cases and controls in the skin cancer nested case-control study has been provided elsewhere [18]. In brief, at the beginning of the follow-up of this nested case-control study, the nurses were between 43 and 68 years old (mean age 58.7). The mean age at diagnosis of incident melanoma cases was 63.4 years, and that of SCC cases and BCC cases was 64.7 and 64.0 years, respectively. A family history of skin cancer was a risk factor. Compared with controls, skin cancer cases had lighter pigmentation (skin color and hair color), more number of moles on the arms, higher cumulative sun exposure while wearing a bathing suit, and more lifetime severe sunburns that blistered.

Association between the MDM2 SNP309 and pigmentary phenotypes

We tested whether the MDM2 SNP309 was correlated with pigmentary phenotypes including childhood tanning tendency, childhood sunburn reaction, and the presence/absence of moles on the arm among controls from three nested case-control studies (Table 1). The G/G genotype was significantly inversely associated with the presence/absence of moles on the arm. This association was similar after adjusting for natural hair color, childhood tanning tendency, and childhood sunburn reaction. Compared with the T/T genotype, adjusted odds ratio (ORs) of the presence/absence of moles on the arm for T/G and G/G genotypes were 0.92 (95% confidence interval (CI), 0.78–1.08) and 0.68 (95% CI, 0.53–0.87), respectively (P, trend, 0.005). We did not observe a significant association between the MDM2 SNP309 and the constitutional susceptibility score among controls (P, trend, 0.23) (data not shown).

Table 1
Relationship between the MDM2 SNP309 and childhood tanning tendency, childhood sunburn reaction, and the presence/absence of moles on the arm

No significant trends were observed between the three genotypes of MDM2 SNP309 and childhood tanning tendency (P, trend, 0.15), childhood sunburn reaction( P, trend, 0.31) (Table 1), or natural hair color (p, trend, 0.51) (data not shown). However, we observed a marginally significant association between the carriage of the G allele and childhood tanning tendency (adjusted OR, 1.30; 95% CI, 1.01–1.68). This association was not found for childhood sunburn reaction (Table 1).

Interaction between the MDM2 SNP309 and the p53 Arg72Pro polymorphism on pigmentary phenotypes

We evaluated the interaction between the MDM2 SNP309 and the p53 Arg72Pro polymorphism on pigmentary phenotypes (including childhood tanning tendency, childhood sunburn reaction, and the presence/absence of moles on the arm) among controls from two nested case-control studies. The tests for departure from multiplicative interaction between the MDM2 SNP309 and the p53 Arg72Pro polymorphism on childhood tanning tendency (p, interaction, 0.29), childhood sunburn reaction (p, interaction, 0.70), or the presence/absence of moles on the arm (p, interaction, 0.77) were not statistically significant (Table 2). There was no significant interaction between the MDM2 SNP309 and the p53 Arg72Pro polymorphisms on the constitutional susceptibility score among controls (p, interaction, 0.86) (data not shown).

Table 2
Interaction between the MDM2 SNP309 and the p53 Arg72Pro polymorphism on childhood tanning tendency, childhood sunburn reaction, and the presence/absence of moles on the arm

We also explored the interaction between the MDM2 SNP309 and childhood tanning tendency, childhood sunburn reaction, and natural hair color on the presence/absence of moles on the arm among controls from three nested case-control studies, none of the tests for departure from multiplicative interaction between the MDM2 SNP309 and childhood tanning tendency (p, interaction, 0.37), childhood sunburn reaction (p, interaction, 0.62), and natural hair color (p, interaction, 0.78) on the presence/absence of moles on the arm showed statistical significance (data not shown).

Association between the MDM2 SNP309 and skin cancer risk

No significant associations were detected between the MDM2 SNP309 and any of the three types of skin cancer (Table 3).

Table 3
The MDM2 SNP309 and skin cancer risk

No significant associations between the MDM2 SNP309 and age of diagnosis were found in the case of melanoma, SCC, and BCC. The p-value for ANOVA test was 0.90, 0.81, and 0.90, respectively. The mean age (years) at diagnosis of melanoma cases according to T/T, T/G, and G/G genotypes of MDM2 was 63.7, 63.2, and 63.4, respectively; that of SCC cases was 64.8, 64.8, and 64.0, respectively; and that of BCC cases was 64.0, 64.1, and 64.6, respectively.

Interaction between the MDM2 SNP309 and the p53 Arg72Pro polymorphism on skin cancer risk

For SCC, the trend of increased risk across the three genotypes of MDM2 was stronger among p53 Pro carriers (p, trend, 0.05) than p53 Arg/Arg wildtype group (p, trend, 0.99; p, interaction, 0.07) (Table 4). Similar interaction patterns were also observed for BCC and melanoma, however, the tests for departure from multiplicative interaction did not approach statistical significance (p-values for interaction for BCC and melanoma were 0.17 and 0.40, respectively).

Table 4
Interaction between the MDM2 SNP309 and the p53 Arg72Pro polymorphism on skin cancer risk

We also found no significant interactions between the MDM2 SNP309 and pigmentary phenotypes, sun exposure, and the number of lifetime severe sunburns on skin cancer risk (data not shown).

Discussion

In this study, we observed a significant inverse association of the MDM2 SNP309 G/G genotype with the presence/absence of moles on the arm. Few studies have attempted to assess the association of single nucleotide polymorphisms of candidate genes with development of nevi or freckles; and no statistically significant associations have been found [19,20]. Mole (nevus) known as the presumed precursor to melanoma occurs when melanocytes cluster together forming nests at the dermo-epidermal junction. Both benign and dysplastic nevi are characterized by disruption of the epidermal melanin transfer system where each melanocyte transfers melanin-containing melanosome to the suprabasal keratinocytes via dendrites, leading to an increased number of melanocytes [21]. Most moles appear in early childhood and during the first 20 years of a person’s life. van Schanke et al. reported that excessive exposure to sunlight may play a role in the formation of acquired moles [22]. This leads to the hypothesis that the MDM2 SNP309 interacts with acquired or congenital pigmentary phenotypes to affect the development of moles. Therefore, we further explored the interaction between the MDM2 SNP309 and pigmentary phenotypes including childhood tanning tendency, childhood sunburn reaction, and natural hair color. However, we did not find any significant interactions. This result suggests that the effect of MDM2 SNP309 on development of moles may not be substantially influenced by other pigmentary phenotypes.

We found a significant correlation between the carriage of SNP309 G allele and childhood tanning tendency. However, no such a correlation was observed for childhood sunburn reaction. Sunburn is UV-induced apoptosis of keratinocytes, whereas tanning is UV-induced melanin synthesis and production in melanocytes [23,24]. This suggests that burning and tanning responses may be two different types of skin responses to UV involving independent molecular pathways. On the other hand, we cannot rule out the possibility that the effect on childhood tanning tendency could be due to chance. The issue of population stratification is important in assessment of the association of the SNP309 with childhood tanning tendency because light pigmented populations have less capacity to tan. In this study, we performed our analyses in Caucasian women only. The frequency of the G allele (35%) was similar with average frequency of G in Caucasians (37%), which was reported by Wilkening et al. based on several studies [25]. Furthermore, in our study, the similar genotype distribution among Southern Europeans and Scandinavians indicated that “sub-population” stratification is likely to be minimal.

In some previous studies, the MDM2 SNP309 was associated with the development of cancers such as hepatocellular carcinoma, endometrial cancer, or lung cancer [2527], whereas other studies reported no significant associations between the SNP309 and cancer risk such as colorectal cancer, breast cancer, or ovarian cancer [25,28,29]. Wilkening et al. reported that the MDM2 SNP309 affected neither the risk nor the age at onset of BCC [30], which is consistent with our results. We observed no significant associations between the MDM2 SNP309 and either the age at skin cancer diagnosis or the risk of the three types of skin cancer.

Because the MDM2 oncoprotein is a key negative regulator of the tumor suppressor p53, MDM2 overexpression is considered one mechanism of p53 inactivation [6,31]. MDM2 downregulates p53 activity by binding it directly and forming the MDM2-p53 complex, which results in ubiquitination and proteosomal degradation of p53 through the E3 ubiquitin ligase activity of MDM2 [32,33]. The functional MDM2 SNP309 locus is located in the transcriptional activator Sp1-binding site in the MDM2 promoter region. It has been shown that the G allele of SNP309 increases the affinity of Sp1 to the MDM2 promoter, resulting in increased expression levels of MDM2 mRNA and protein and thus increased inhibition of p53 activity [15]. Cui et al. reported that p53 can partially control the transient tanning response [8]. There is a common functional p53 Arg/Pro polymorphism at codon 72 in exon 4 [34]. The Pro allele was positively associated with the transcriptional activity of p53 [13] and childhood tanning response [14]. In this regard, reduced p53 activity by the G allele of MDM2 SNP309 should attenuate the transient tanning response. However, we observed a positive association between the carriage of the MDM2 SNP309 G allele and childhood tanning tendency. We did not find any significant interactions between the MDM2 SNP309 and the p53 Arg72Pro polymorphisms on pigmentary phenotypes such as childhood tanning tendency, childhood sunburn reaction, or the presence/absence of moles on the arm. MDM2 is highly expressed in both the basal and suprabasal layers of the skin, where keratinocytes initiate differentiation [35,36]. Although the MDM2-p53 dependent pathway is well-characterized, some previous studies reported that MDM2 expression in keratinocytes and epithelia and its activity in cell cycle progression, differentiation, and transformation are independent of p53 [3638]. A study using transgenic mice showed that MDM2 overexpression induced increased proliferation of the basal layer and thickening of the epidermis, resulting in a specific skin phenotype that appears to be p53-independent [35]. Hence, it is plausible that MDM2 is involved in distinct molecular pathways to modify pigmentary phenotypes, such as mole counts and the development of skin cancer.

Exposure misclassification is always a concern in epidemiologic studies. The high education level and interest in health of cohort members allows high quality and valid information to be collected on self-administered forms. In our study, because most of constitutional host factor information was collected prior to diagnosis we will avoid the potential for differential misclassification, i.e. recall bias. Test-retest reliability of collecting phenotypic factors from questionnaires is moderate to substantial, including skin color, tanning/burning tendency, and sunburn history [3941]. The majority of studies on nevus counts have shown substantial agreement between nevus self-counts and dermatologist-counts [4244]. The Spearman correlation coefficient was 0.91 between nevus counts by patients and physicians, suggesting quite a good correlation between the two measurements [45]. These previous reports support the reliability and validity of self-reported skin characteristics. Nevertheless, we cannot exclude the potential misclassification because the information regarding mole counts was limited on the arms and only asked once in this study.

In conclusion, our study showed a significant association of the MDM2 SNP309 G/G genotype with the presence/absence of moles on the arm. We also observed suggestive evidence of the association between the MDM2 SNP309 and childhood tanning tendency. No associations were found between the MDM2 SNP309 and childhood sunburn reaction, or skin cancer risk. We found no significant interaction between the MDM2 SNP309 and the p53 Arg72Pro polymorphism on pigmentary phenotypes. These results provide evidence for the potential involvement of MDM2 SNP309 in pigmentary traits.

Acknowledgments

We thank Ms. Qun Guo for her programming support. We are indebted to the participants in the Nurses’ Health Study for their dedication and commitment.

Grant sponsor: NIH; Grant numbers: - CA128080 and CA122838.

Abbreviations

BCC
basal cell carcinoma
SCC
squamous cell carcinoma
CI
confidence interval
OR
odds ratio
UV
ultraviolet

References

1. Howe HL, Wingo PA, Thun MJ, et al. Annual report to the nation on the status of cancer (1973 through 1998), featuring cancers with recent increasing trends. J Natl Cancer Inst. 2001;93:824–842. [PubMed]
2. Brash DE. Sunlight and the onset of skin cancer. Trends Genet. 1997;13:410–414. [PubMed]
3. de Gruijl FR, van Kranen HJ, Mullenders LH. UV-induced DNA damage, repair, mutations and oncogenic pathways in skin cancer. J Photochem Photobiol B. 2001;63:19–27. [PubMed]
4. Lin JY, Fisher DE. Melanocyte biology and skin pigmentation. Nature. 2007;445:843–850. [PubMed]
5. Tucker MA, Goldstein AM. Melanoma etiology: where are we? Oncogene. 2003;22:3042–3052. [PubMed]
6. Bond GL, Hu W, Levine AJ. MDM2 is a central node in the p53 pathway: 12 years and counting. Curr Cancer Drug Targets. 2005;5:3–8. [PubMed]
7. Fuchs SY, Adler V, Buschmann T, Wu X, Ronai Z. Mdm2 association with p53 targets its ubiquitination. Oncogene. 1998;17:2543–2547. [PubMed]
8. Cui R, Widlund HR, Feige E, et al. Central role of p53 in the suntan response and pathologic hyperpigmentation. Cell. 2007;128:853–864. [PubMed]
9. Pathak MA, Fanselow DL. Photobiology of melanin pigmentation: dose/response of skin to sunlight and its contents. J Am Acad Dermatol. 1983;9:724–733. [PubMed]
10. Schauer E, Trautinger F, Kock A, et al. Proopiomelanocortin-derived peptides are synthesized and released by human keratinocytes. J Clin Invest. 1994;93:2258–2262. [PMC free article] [PubMed]
11. Thomas M, Kalita A, Labrecque S, et al. Two polymorphic variants of wild-type p53 differ biochemically and biologically. Mol Cell Biol. 1999;19:1092–1100. [PMC free article] [PubMed]
12. Dumont P, Leu JI, Della Pietra AC, George DL, Murphy M. The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet. 2003;33:357–365. [PubMed]
13. Pim D, Banks L. p53 polymorphic variants at codon 72 exert different effects on cell cycle progression. Int J Cancer. 2004;108:196–199. [PubMed]
14. Nan H, Qureshi AA, Hunter DJ, Han J. Interaction between p53 codon 72 polymorphism and melanocortin 1 receptor variants on suntan response and cutaneous melanoma risk. Br J Dermatol 2008 [PMC free article] [PubMed]
15. 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. 2004;119:591–602. [PubMed]
16. Han J, Colditz GA, Hunter DJ. Risk factors for skin cancers: a nested case-control study within the Nurses' Health Study. Int J Epidemiol. 2006;35:1514–1521. [PubMed]
17. Miettinen OS. Stratification by a multivariate confounder score. Am J Epidemiol. 1976;104:609–620. [PubMed]
18. Han J, Kraft P, Colditz GA, Wong J, Hunter DJ. Melanocortin 1 receptor variants and skin cancer risk. Int J Cancer. 2006;119:1976–1984. [PubMed]
19. James MR, Hayward NK, Dumenil T, et al. Epidermal growth factor gene (EGF) polymorphism and risk of melanocytic neoplasia. J Invest Dermatol. 2004;123:760–762. [PubMed]
20. James MR, Roth RB, Shi MM, et al. BRAF polymorphisms and risk of melanocytic neoplasia. J Invest Dermatol. 2005;125:1252–1258. [PubMed]
21. Chin L. The genetics of malignant melanoma: lessons from mouse and man. Nat Rev Cancer. 2003;3:559–570. [PubMed]
22. van Schanke A, van Venrooij GM, Jongsma MJ, et al. Induction of nevi and skin tumors in Ink4a/Arf Xpa knockout mice by neonatal, intermittent, or chronic UVB exposures. Cancer Res. 2006;66:2608–2615. [PubMed]
23. Kulms D, Schwarz T. Molecular mechanisms of UV-induced apoptosis. Photodermatol Photoimmunol Photomed. 2000;16:195–201. [PubMed]
24. Van Laethem A, Claerhout S, Garmyn M, Agostinis P. The sunburn cell: regulation of death and survival of the keratinocyte. Int J Biochem Cell Biol. 2005;37:1547–1553. [PubMed]
25. Wilkening S, Bermejo JL, Hemminki K. MDM2 SNP309 and Cancer Risk: A Combined Analysis. Carcinogenesis. 2007;28:2262–2267. [PubMed]
26. Dharel N, Kato N, Muroyama R, et al. MDM2 promoter SNP309 is associated with the risk of hepatocellular carcinoma in patients with chronic hepatitis C. Clin Cancer Res. 2006;12:4867–4871. [PubMed]
27. Walsh CS, Miller CW, Karlan BY, Koeffler HP. Association between a functional single nucleotide polymorphism in the MDM2 gene and sporadic endometrial cancer risk. Gynecol Oncol. 2007;104:660–664. [PubMed]
28. Campbell IG, Eccles DM, Choong DY. No association of the MDM2 SNP309 polymorphism with risk of breast or ovarian cancer. Cancer Lett. 2006;240:195–197. [PubMed]
29. Cox DG, Deer D, Guo Q, et al. The p53 Arg72Pro and MDM2 -309 polymorphisms and risk of breast cancer in the nurses' health studies. Cancer Causes Control. 2007;18:621–625. [PubMed]
30. Wilkening S, Hemminki K, Rudnai P, et al. No association between MDM2 SNP309 promoter polymorphism and basal cell carcinoma of the skin. Br J Dermatol. 2007;157:375–377. [PubMed]
31. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408:307–310. [PubMed]
32. Momand J, Zambetti GP, Olson DC, George D, Levine AJ. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell. 1992;69:1237–1245. [PubMed]
33. Oliner JD, Pietenpol JA, Thiagalingam S, et al. Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature. 1993;362:857–860. [PubMed]
34. Matlashewski GJ, Tuck S, Pim D, et al. Primary structure polymorphism at amino acid residue 72 of human p53. Mol Cell Biol. 1987;7:961–963. [PMC free article] [PubMed]
35. Alkhalaf M, Ganguli G, Messaddeq N, Le Meur M, Wasylyk B. MDM2 overexpression generates a skin phenotype in both wild type and p53 null mice. Oncogene. 1999;18:1419–1434. [PubMed]
36. Dazard JE, Augias D, Neel H, et al. MDM-2 protein is expressed in different layers of normal human skin. Oncogene. 1997;14:1123–1128. [PubMed]
37. Dubs-Poterszman MC, Tocque B, Wasylyk B. MDM2 transformation in the absence of p53 and abrogation of the p107 G1 cell-cycle arrest. Oncogene. 1995;11:2445–2449. [PubMed]
38. Sigalas I, Calvert AH, Anderson JJ, Neal DE, Lunec J. Alternatively spliced mdm2 transcripts with loss of p53 binding domain sequences: transforming ability and frequent detection in human cancer. Nat Med. 1996;2:912–917. [PubMed]
39. Branstrom R, Kristjansson S, Ullen H, Brandberg Y. Stability of questionnaire items measuring behaviours, attitudes and stages of change related to sun exposure. Melanoma Res. 2002;12:513–519. [PubMed]
40. Glanz K, Schoenfeld E, Weinstock MA, et al. Development and reliability of a brief skin cancer risk assessment tool. Cancer Detect Prev. 2003;27:311–315. [PubMed]
41. Westerdahl J, Anderson H, Olsson H, Ingvar C. Reproducibility of a self-administered questionnaire for assessment of melanoma risk. Int J Epidemiol. 1996;25:245–251. [PubMed]
42. Buettner PG, Garbe C. Agreement between self-assessment of melanocytic nevi by patients and dermatologic examination. Am J Epidemiol. 2000;151:72–77. [PubMed]
43. Little P, Keefe M, White J. Self screening for risk of melanoma: validity of self mole counting by patients in a single general practice. BMJ. 1995;310:912–916. [PMC free article] [PubMed]
44. Melia J, Harland C, Moss S, Eiser JR, Pendry L. Feasibility of targeted early detection for melanoma: a population-based screening study. Br J Cancer. 2000;82:1605–1609. [PMC free article] [PubMed]
45. Mikkilineni R, Weinstock MA. Is the self-counting of moles a valid method of assessing melanoma risk? Arch Dermatol. 2000;136:1550–1551. [PubMed]