Download Sunlight and Reduced Risk of Cancer: Is The Real Story Vitamin D?

Sunlight and Reduced Risk of Cancer: Is The Real
Story Vitamin D?
Kathleen M. Egan, Jeffrey A. Sosman, William J. Blot
Solar radiation is a well-established skin carcinogen, responsible for more cancers worldwide than any other single agent
(1). Yet, evidence is beginning to emerge that sunlight exposure,
particularly as it relates to the vitamin D synthesized in the skin
under the influence of solar radiation, might have a beneficial
influence for certain cancers.
In this issue of the Journal, two independent epidemiologic
studies (2,3) suggest that sunlight may reduce the risk of nonHodgkin lymphoma (NHL) and may be associated with increased
survival rates in patients with early-stage melanoma. In a large
population-based case–control study of more than 3700 patients
with incident lymphoma and nearly 3200 control subjects in
Sweden and Denmark, Smedby et al. (2) reported a 20% to 40%
reduction in the risk of this cancer. The reduction in risk was doserelated with increasing indices of prior sun exposure. In a followup study of more than 500 melanoma patients who participated in
a U.S. case–control study in the 1990s, Berwick et al. (3) noted
that subsequent mortality from melanoma was approximately
one-half as high among those with signs of solar elastosis assessed
by means of a standardized physical examination as among those
without solar elastosis. The association of this biomarker of sun
exposure and melanoma mortality persisted after adjustment for
potential confounding factors, including thickness of the lesion
and other established melanoma prognostic factors. The association was not confounded by early detection or various screening
behaviors, including skin awareness, and skin self- or physician
examination, or by social class.
The notion that sun exposure might have a salutary influence for some types of cancers has been around for several
decades. Among Caucasians in the United States, cancer mortality for several prominent cancers, including cancer of the
breast, prostate, and colon, shows a striking latitudinal gradient,
with increased mortality rates among individuals residing in the
northern states compared with individuals residing the southern
states (4). These patterns persist even after confounding variables
like socioeconomic status, urban and rural residence, Hispanic
heritage, and other risk factors are taken into account (5,6). In
1990, it was proposed that vitamin D, which is synthesized in the
skin upon exposure to ultraviolet B light (UVB), might be the
agent that accounts for these geographical patterns (7). 1,25-Dihydroxyvitamin D3 has multiple cellular effects, including inhibiting the G1/S cell cycle checkpoint, increasing expression of the
cyclin-dependent kinase inhibitors p21 and p27, and potentially
inducing apoptosis via a number of pathways (8–10). The ability
to convert the provitamin to the active 1,25-dihydroxyvitamin
D3 is much reduced at northern latitudes, and populations living
far from the equator are at increased risk of vitamin D deficiency
during the winter months (11).
The findings from Berwick et al. (3) are consistent with laboratory
evidence and are in line with some previous epidemiologic observations. Melanoma cell lines express the vitamin D receptor
and are responsive to the antiproliferative and prodifferentiation
effect of 1,25-dihydroxyvitamin D3 (12). Even more provocative
is the observation of low 1,25-dihydroxyvitamin D3 serum levels in patients with malignant melanoma (13) and an association
in some studies of specific vitamin D receptor polymorphisms
with the development and outcome of melanoma (14). The incidence of melanoma of the skin on intermittently exposed sites is
reduced among outdoor workers compared with indoor workers
(15). This pattern of incidence among workers has usually been
attributed to the fact that skin tanning from habitual exposure
may reduce the incidence of sunburning, a known melanoma risk
factor. However, an alternative hypothesis is that outdoor workers
are less likely to be deficient in vitamin D because of their more
regular exposure to sunlight. This latter hypothesis might also
help to explain the difficulties in demonstrating any clear protective influence from the use of sunblocking agents (16). High SPF
sunscreens can completely block vitamin D synthesis in the skin
(17) and thus persons that habitually use sunscreens may not reap
Affiliations of authors: Vanderbilt University Medical Center, VanderbiltIngram Cancer Center, Nashville, TN (KME, JAS, WJB); International Epidemiology Institute, Rockville, MD (WJB).
Correspondence to: William J. Blot, PhD, International Epidemiology Institute,
1455 Research Blvd., Ste. 550, Rockville, MD 20850 (e-mail: [email protected]).
DOI: 10.1093/jnci/dji047
Journal of the National Cancer Institute, Vol. 97, No. 3, © Oxford University
Press 2005, all rights reserved.
Journal of the National Cancer Institute, Vol. 97, No. 3, February 2, 2005
EDITORIALS
161
the benefits of sunlight exposure with respect to the endogenous
synthesis of vitamin D.
The study by Berwick et al. (3) involved mostly patients
with early stage melanoma, and it is plausible that the known
antiproliferative and antiangiogenic properties of vitamin D
may be inversely associated with melanoma progression. However, it should be noted that solar elastosis and other sun exposure markers in the study reflected prediagnostic exposures to
sunlight. Sun avoidance is the most predictable response to a
melanoma diagnosis (18), so it is not clear whether the results
of Berwick et al. (3) reflect benefits related to continued sunlight
exposure, or (as seems more likely) a different pathogenesis in
melanomas that arise in persons at risk to develop actinic skin
damage. Melanomas are genetically heterogenous tumors and
evidence is fast accumulating that these tumors can develop
along different genetic pathways, in which different patterns of
sun exposure may be involved (19). For example, recent studies
show that B-raf mutations are common in melanomas that
develop from intermittently sun-exposed sites, but not in tumors
that develop from chronically sun-exposed (20) or consistently
sun-protected (mucosal, uveal tract) sites (20–23). Whether B-raf
involvement affects the biologic behavior of melanomas is yet to
be determined. The results of Berwick et al. (3) should also be
interpreted with caution because we know that persons with one
primary melanoma are at a statistically significantly increased
risk to develop another melanoma, and continued intense and/or
intermittent sun exposure will almost certainly increase the risk.
The results for the Scandinavian study (2) for lymphoma are
of particular interest because these malignancies were suspected
to have a common etiology with cancer of the skin. Incidence
rates of non-Hodgkin lymphoma have increased worldwide in
recent decades in parallel with increased melanoma incidence
(24). Certain other descriptive features of the disease (higher
rates in Caucasians and in males; increased rates before and after
the diagnosis of a UV-related skin cancer) also seem to mirror the
epidemiology of both melanoma and nonmelanoma skin cancer,
which are both strongly linked to sunlight exposure. The only
established risk factor for lymphoma, immune suppression, also
fits with the idea that sunlight is a causal agent, because UVB is
known to suppress the immune response (25). The findings from
the Scandinavian study (2), however, which are consistent with a
study published recently from Australia (26), cast serious doubt
on the likelihood that heavy sun exposure might be a cause of
lymphoma. The Scandanavian study (2) encompassed the entire
population of Denmark and Sweden, and included a systematic
evaluation of multiple measures of solar exposure in a population where sun bathing is still a common practice (approximately
half the general population control subjects reported sun bathing
at least twice per week at age 20 years, with 40% still reporting
this frequency of exposure in recent years). Various proxies for
sun exposure, including sunbathing habits and history of sunburn
(though not constitutional factors like pigmentation and skin reaction to the sun) were consistently associated with a reduced
incidence of lymphoma in this study. Likewise, in the population-wide Australian study (23), risk of non-Hodgkin lymphoma
decreased with different measures of increasing self-reported sun
exposure. The fact that a history of skin cancer was a statistically
significant risk factor in the Scandinavian study (2), controlling
for sunlight exposures, implies that some other risk factor (impairment of a specific DNA repair pathway, for example) may be
common to both cancers.
162
EDITORIALS
Assuming the findings of Smedby et al. (2) and of Berwick
et al. (3) are confirmed, what is the most rational public health
message regarding safe levels of sun exposure? Ultraviolet
radiation in the solar spectrum is an established human carcinogen, one of only approximately 60 agents so designated
by the World Health Organization. More than 1 million cases
of skin cancer diagnosed annually in the United States are attributable to this exposure (1). However, of these skin cancers, melanoma represents a small (an estimated 54 000 new
cases are diagnosed per year in the United States) but important fraction because skin melanoma may be a fatal disease
and because skin melanoma contributes disproportionately to
cancer-related death rates among young adults (27). Thus, the
risks and benefits of sun exposure have to be weighed against
many factors, including medical history, personal attributes
such as pigmentation and the proneness to sunburn, and family
and personal history of cancer. Although it is clearly premature to make dietary recommendations based on the findings
of these two studies (2,3), it is known that a substantial proportion of people residing in northern latitudes are deficient
in vitamin D during the winter months (28). The few dietary
sources of vitamin D include milk purchased in the United
States, some brands of orange juice (which are now supplemented with vitamin D), cod liver oil and oily fish, such as
salmon, mackerel, and sardines, and vitamin D supplements
are available.
In summary, the two studies (2,3) in this issue of the Journal
provide intriguing new evidence that solar radiation may have a
beneficial influence in both the incidence and outcome of cancer.
In view of the major potential public health consequence of these
results, further studies of sunlight and the vitamin D connection
to cancer are certainly warranted.
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