A newly discovered important protective role of p53 was its ability to regulate the suntan response. Cui et al. found that p53 can directly modulate transcriptional activity of the POMC promoter following UV exposure 9
. It is notable that the prevalence of p53 Arg72Pro polymorphism exhibits substantial latitudinal differences, with dark pigmented populations closer to the equator having increased Pro allele frequency 26,27
. In this regard, it is speculated that p53 Pro allele is a more competent inducer of POMC transcription, an evolutionary selection in heavily sun-exposed areas 28
. This speculation is consistent with the fact that the Pro allele was associated with increased transcriptional activity 17
. In this study, we evaluated the association between p53 Arg72Pro polymorphism and childhood tanning tendency according to different hair color. At the outset, we surmised that the effect of functional p53 polymorphism on tanning responses could only be evaluated in individuals with an intact MC1R pathway, e.g. in individuals with MC1R polymorphisms resulting in red hair, we would not be able to evaluate the effect of p53 as tanning responses are poor. As expected, only among the women with black/dark brown hair, the test for trend showed a borderline positive correlation of Pro allele with childhood tanning tendency. This finding may provide a plausible molecular explanation for different tanning response to UV among people with similar pigmentation.
The melanocortin 1 receptor (MC1R) gene is located at 16q24.3. It encodes a seven-transmembrane, G-protein-coupled receptor of 317 amino acids, and can be activated by its ligand α-MSH or adrenocorticotrophic hormone (ACTH) 29,30
. Valverde et al. illustrated that variants in the coding region of the MC1R play an important role in tanning and pigmentation in humans 24
. MC1R variants encode receptor proteins with decreased function to increase cAMP, resulting in decreased constitutional and transient pigmentation 31,32
. We found that the women with RHC variants are less likely to tan; these associations were not modified by the p53 Arg72Pro polymorphism. The role of MC1R in skin pigmentation is predominant, and the variants of MC1R, especially RHC alleles, are consistently associated with constitutional and transient pigmentation 19
. This result suggests that the propensity of the p53 Arg72Pro to increase the tanning response is mitigated by the strong influence of MC1R variants in the POMC/α-MSH-induced tanning response.
Previous studies reported that MC1R variants are associated with an increased risk of developing melanoma and are also associated with phenotypic features such as fair skin and red hair, which are strong risk factors for skin cancer 33-36
. These observations are consistent with the findings of this study; i.e., the women who had MC1R RHC variants or red hair had statistically increased risk of melanoma. Similar result was also found for the women with high constitutional susceptibility score. The constitutional susceptibility score reflects the multiple constitutional phenotypic variables including hair color, skin color, childhood tendency to burn, and the number of palpably raised moles on arms, simultaneously. Interestingly, these associations were strongest among women who carried the p53 Pro/Pro genotype; namely, darker pigmentation substantially attenuated the melanoma risk associated with p53 Pro/Pro genotype. In an analysis on the same participants from this study, Han et al. observed that the Pro/Pro genotype carriers had higher melanoma risk than the Arg/Arg genotype carriers 37
. In the present study, we observed that the p53 Pro allele was more strongly associated with tanning response among dark haired women, presumably those retaining substantial function of MC1R. These data suggest that the p53 Pro allele maybe a more active transcription factor of POMC than the Arg allele in tanning response, resulting in darker pigmentation. However, the Pro allele is associated with lower capacity to induce apoptosis than the Arg allele 16
. Hence, even though the Pro allele is associated with tanning response, its reduced activity to induce apoptosis plays a predominant role in melanoma development among Caucasians.
The nested case-control design, high follow-up rate, and high response rate for the retrospective supplementary questionnaire are among strengths of this study. The limitations of the study include self-reported assessment of pigmentary phenotypes, which may lead to misclassification. Nevertheless, we observed that the Pro allele was associated with tanning response, probably due to enhanced induction of POMC transcription. The association of the p53 Pro/Pro genotype with cutaneous melanoma risk was strongest among the women with light pigmentation. The underlying mechanism of the p53 Arg72Pro polymorphism in the etiology of cutaneous melanoma remains to be demonstrated.