By examining the relationship between UVR and C43 incidence across 182 countries, our analysis suggests that:
- Countries with low UVR exposure had high C43 incidence rates.
- Countries with greater percentage of European descendants (Europeans %) had higher C43 incidence rates.
- There was negligible correlation between UVR exposure and country specific C43 incidence when percentage of European population was kept statistically constant (residue of C43 incidence standardized on country-specific Europeans %).
- In Europe, countries with high level of depigmentation had higher C43 incidence rate. Statistically, country-level depigmentation negatively correlated with country-specific UVR exposure in a stepwise model indicating its long-term evolutionary adaptation to low UVR.
Our results indicate that UVR may not be the primary cause of C43 worldwide. From the perspective of human evolution, it may be the magnitude of heritable depigmentation due to adaptation to low UVR exposure that may predispose to C43 worldwide irrespective of direct individual exposure to sunlight. We applied the modern evolutionary theory to interpreting how human adaptation has produced the underlying cause for C43 over a number of generations.
The findings of our study contradict the common belief that high UVR exposure of individual humans is the primary or major risk factor for C43 [5, 77-80]. Biologically, the human body readily responds to changing environmental stresses, such as UVR, until they are adapted to keep themselves fit and survive. The adaptation process involves a mutation, or genetic change to make adapting traits inheritable. Vitamin D is essential for maintaining strong bones and ensuring essential healthy functioning including the lungs, cardiovascular system, immune system, and brain . Although UVR only constitutes approximately 10% of the total light output of the sun, it is the best natural force for producing vitamin D. Melanin, produced in melanocytes, is able to dissipate more than 99.9% of UVR radiation absorbed by the skin . More melanin in skin not only protects the skin cells, including the pigment cells – melanocytes – against UV damage, but also against destruction of folate [45-47]. If too much melanin is produced in the epidermis for absorbing UV irradiation, skin cells may be protected, but synthesis of vitamin D may be inhibited because of lack of penetration of UV into skin [83-85]. However, if there is not enough melanin produced in the skin, cells in skin would not have enough protection from UVR damage because more UVR would be able to penetrate deeper into the epidermis.
People living in areas with low UVR, would be advantaged by carrying the genes/ mutations which could alter their cell physiology for producing less melanin to allow more UVR penetration for more vitamin D genesis and proper levels of folate . Populations lacking those genes/ mutations favoured by natural selection for sufficient vitamin D production would be unfit, and selection pressure would favour elimination of high-melanin genes because the essential health effect of vitamin D was not sufficient. These mutations may evolve into inheritable genetic signatures of populations with low UVR exposure [63, 86]. In people living in areas with low level of UVR exposure for generations, the amount of melanin in human skin must be balanced between allowing enough UV penetration to produce vitamin D and preventing over-exposure from creating potential solar damage to skin cells .
Almost all laymen and professionals believe that too much exposure to UV radiation is the main determining factor for carcinogenic damage to skin cells, including melanocytes. However, our study, statistically suggests that C43 occurrence is not attributable to UVR exposure. Worldwide, the negative correlation between UVR and C43 indicates that low UVR, instead of too much UVR exposure, may be the principal risk factor for C43 at the population level. Europeans who live in the lowest UVR situations have the highest C43 incidence rates (Table 2, Figure 3-1). Extensive epidemiological studies in C43 and demographic statistics have focused on the European populations. We took advantage of these data for our analyses of the relationships between UVR and C43 in different models.
Within the WHO Europe Region, C43 incidence correlates positively with depigmentation while it correlates negatively with UVR exposure. The first relationship is independent of UVR exposure, but the latter is dependent on depigmentation. Further regression analyses implied that, statistically, 1) low UVR and Europeans % explained each other for their contributing effects to C43. 2) if Europeans could live in any other WHO Region with higher UVR exposure, their C43 incidence may be at the similar level to Europe, and significantly different from people who have lived in that region for generations. Evolutionarily, low UVR has forced Europeans to depigment, and the genetically determined depigmentation may have made Europeans more susceptible to C43 independent of the environmental factor, UVR. The results of our study are in agreement with the finding that C43 can develop in skin areas with little or no UVR exposure [40, 41]. A recent study even revealed the whole-genome landscapes of major C43 subtypes which could occur without UVR . Also, a study conducted by Rampen and Fleuren postulated that C43 may not be caused by UVR, but by xenobiotic influence .
Large-scale primary C43 prevention programmes aiming at little UVR exposure have not yet been proven effective [32, 34, 89], or unexpectedly, exacerbated C43 initiation [33, 35-37]. This may be explained by our hypothesis that C43 may primarily be a genetic disease due to long-term adaptation to low UVR, but this process aids vitamin D production to maintain essential healthy functioning including the bones, lungs, cardiovascular system, immune system, and brain .
The other key finding in this study is that, worldwide, countries with low UVR had the trend to have high C43 incidence. This is completely opposite to the current commonly accepted belief, “high UVR, high risk for C43” which was primarily concluded from previous C43 epidemiology studies in Australia and New Zealand. As shown in Figure 1, Australia and New Zealand have the highest C43 incidence rates internationally (34.90 and 35.80 per 100,000 respectively) , but their UVRs (3206 and 2487 J/m2 respectively) are much lower than in many countries with low C43 incidence rates . This finding is not explained by the common conclusion of “high UVR, high C43”.
Australians and New Zealanders are predominately European descendants, coming mostly from Northern Europe that includes Britain and Ireland. Australia and New Zealand do have somewhat higher UVR levels (3206 and 2487 J/m2 respectively) than Europe (2198 J/m2), while their C43 incidence rates (34.90/100,000 and 35.80/100,000 respectively) are very much greater than in Europe (7.53/100,000). While the UVRs in both Australia and New Zealand are lower than the worldwide mean UVR (3802 J/m2), their C43 rates are much higher than the worldwide rate (3.0/ 100,000). Although, there has been no clinical trial showing that high UVR causes C43 , most people, including laymen and professionals may still have been misled to believe that high UVR is the primary risk factor for C43 in Australia and New Zealand, or even globally. We have considered several factors which may make the correlation of high UVR with high C43 apparently spurious in Australia and New Zealand:
1) Australia and New Zealand have the highest rates of skin cancer incidence in the world, almost four times the rates registered in Canada, the United Kingdom and the United States of America  despite their UVR exposure being below the world average. Australians and New Zealanders have learned how to minimize sun exposure, how to seek cancer screening and self-diagnose skin cancers from a young age. For instance, skin cancer has been considered as a “National Cancer” . This strong awareness of skin cancer, compounded by a high level of medical service delivery, has enabled Australians and New Zealanders to be diagnosed with more C43 through self-diagnosis and cancer screening. These effects have increased incidence statistics.
2) Non-melanoma skin cancers (NMSC), most of which are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), account for over 98% of total skin cancers. Patients with BCC and/or SCC may have an increased risk for developing C43 [91-95] and certainly have the highest possibility of early melanoma diagnosis their skin being clinically assessed multiple times during BCC and SCC treatments.
3) The 5-year survival rate in C43 is very high (>90%) in Australia and New Zealand, while the history of C43 has a defined chance for reoccurrence . Even “cured” patients with past melanoma are subject to a higher risk of developing a further new C43, making C43 incidence even higher in these countries.
4) High levels of medical services and nutrition have substantially reduced natural selection. Almost all Australians and New Zealanders survive their full reproductive period, and they have the opportunity to pass on their C43 mutations/genes to the next generation. When this process repeats for 4-5 generations, the C43 mutations/ genes accumulate and the phenotype of C43 then becomes noticeable at the population level [64, 68].
5) Low fertility rates have been associated with cancer risks in both females and males [67, 96, 97]. Fertility rates in Australia and New Zealand are much lower than in many other countries. This may also partially explain the higher C43 rates in these two countries.
It has been reported that vitamin D may protect against the development of cancers, including C43 [98-100]. Although people who lived for generations in areas with low UVR exposure produce less melanin allowing more UVR to penetrate skin for more vitamin D genesis, they still have higher risk of developing C43. There may be two reasons: 1) Mutations have occurred in the genome of the people living in low UVR area, which made them prone to develop C43. Although those people could have favourable factors, such as sufficient vitamin D production, they still have high risk of developing C43 because their C43 is a genetically determined disease. 2) Vitamin D alone may not be capable of attenuating or preventing C43 occurrence.
In our study, skin reflectance correlated with C43 (r= 0.325, p=0.057, n=35) at a similar level, but positively, to the negative correlation of UVR with C43 (r=-0.515, r<0.001, n=171) in non-parametric analysis. However, the former correlation between armpit skin reflectance and C43 incidence lost significance and became weak (r = 0.153, r = 0.505 df =19) in the subsequent partial correlation. The explanations could be: 1) The smaller sample size of armpit skin reflectance. 2) Armpit skin reflectance may not be a precise measure of melanin production in the skin because great variability of skin colour in different seasons and body sites [101-103]. Pigmentation may vary 70-100% in skin . Therefore, pigmentation of UVR unexposed skin, including the armpit or inside of the upper arm cannot fully represent the constitutive skin pigmentation [50-52, 104].