Is it the sunlight or the vitamin by liaoqinmei

VIEWS: 8 PAGES: 44

									Sunlight, vitamin D and the prevention of cancer: a systematic
review of epidemiological studies




Han van der Rhee¹’*, Jan Willem Coebergh²’³, Esther de Vries²,




¹Department of Dermatology, Hagaziekenhuis, P.O. Box 40551, Leyweg 275, 2504 LN Den

Haag, Zuid-Holland, The Netherlands

²Department of Public Health, Erasmus MC, P.O. Box 1738, 3000 DR Rotterdam, The

Netherlands

³Eindhoven Cancer Registry, Comprehensive Cancer Centre South, P.O. Box 231, 5600 AE

Eindhoven, The Netherlands




* Corresponding author: Tel.: +31 703592039; fax: +31 703594068.

E-mail addresses: dermatologie@hagaziekenhuis.nl, hvdrhee@casema.nl (H.J. van der Rhee).




                                                                                       1
abstract


The number of studies reporting beneficial effects of sunlight and vitamin D on several types

of cancer with a high mortality rate is growing rapidly. Present health recommendations on

sun exposure are mainly based on the increased risks for skin cancer. We reviewed all

published studies concerning cancer and sun exposure and vitamin D respectively, excluding

those about skin cancer.

Most identified ecological, case-control and prospective studies on the incidence and

mortality of colorectal-, prostate-, breast carcinoma and non-Hodgkin lymphoma reported

a significantly inverse association with sun exposure.

The results of the included studies on the association between cancer risk and vitamin D were

much less consistent. Only those studies that prospectively examined the 25-hydroxyvitamin

D serum levels in relation to risk of colorectal cancer are homogeneous: they all reported

inverse associations, although not all reaching statistical significance. The results of the

intervention studies are suggestive of a protective role of high doses of vitamin D in cancer,

but they have been criticized in the literature.

We therefore conclude that there is accumulating evidence for sunlight as a protective factor

for several types of cancer. The same conclusion can be made concerning high vitamin D

levels and the risk of colorectal cancer. This evidence, however, is not conclusive, because the

number of (good quality) studies is still limited and publication biases cannot be excluded.

The discrepancies between the epidemiological evidence for a possible preventive effect of


                                                                                                 2
sunlight and vitamin D and the question of how to apply the findings on the beneficial effects

of sunlight to (public) health recommendations are discussed.




Keywords: review, cancer, prevention, sunlight, vitamin D




Introduction

                                                                                             3
The potential inverse association between sunlight, vitamin D and various types of cancer has

become an area of great scientific interest. The relation between solar radiation and reduced

cancer mortality in North America was identified more than 60 years ago (1). In 1980 Garland

and Garland proposed the hypothesis that vitamin D is a protective factor against colon cancer

(2) . Subsequently, the inverse association between ambient solar radiation and cancer

incidence and mortality rates has been described for many types of cancer in many countries.

In 2006 we reviewed all then published studies concerning sun exposure and cancer,

excluding those about skin cancer.(3) For many types of cancer only ecologic studies were

available. For colorectal-, prostate-, breast cancer, and non-Hodgkin lymphoma, in addition to

ecologic studies, several case-control and prospective studies were available. Since then the

number of studies on this subject has more than doubled.

The epidemiological evidence for a risk-reducing effect of vitamin D on cancer is considered

less convincing.(4) Additional mechanisms have been proposed, such as the influence of

(sun)light on the circadian rhythm(5) and the degradation of folic acid.(6)

We performed a new systematic review on the association between the incidence and

mortality of (non-skin) cancer and both sunlight and vitamin D in order to:

-update our previous review on sunlight and

-verify the discrepancies between the epidemiological evidence for a possible preventive

effect of sunlight and vitamin D respectively.




                                                                                                4
methods



Search strategy



A search was performed in 2 electronic databases: EMBASE (1980 to May 2009) and

MEDLINE (1966 to May 2009). Text words (or mesh terms) that were used included

cancer (NOT skin cancer) and, separately, the 20 most frequently occurring types of cancer in

Western Europe (prostate, bladder, breast, colon, rectal, pancreas, gall bladder,

stomach, oesophageal, liver, lung non-small cell, ovary, uterine cervix, uterus, pharynx,

larynx, brain, and oral cavity cancer; non-Hodgkin lymphoma, Hodgkin lymphoma and

leukaemia), using combinations with text words (or mesh terms) for sunlight or ultraviolet

rays and vitamin D. Citation lists of the found studies were used to identify other relevant

studies.



Inclusion criteria and review of the studies



Studies concerning the influence of sunlight and vitamin D on the incidence and mortality of

cancer, excluding skin cancer, were evaluated. All identified titles and abstracts (written in

English) were reviewed by one of the authors (Van der Rhee).




                                                                                                 5
Inclusion criteria were ecologic studies, case-control studies, cohort studies, and intervention

studies with original data that met the following demands:

studying the effect of sunlight and/or vitamin D on cancer, with a clear description of

methodology and containing effect estimates with p-value or confidence intervals.

Further details are described elsewhere.(3)




results


Colorectal carcinoma



Associations with sunlight


Fourteen studies meeting our inclusion criteria were identified: 9 ecological, 3 case-control

and 2 prospective studies. The ecological studies correlate geographical variation in colon

cancer incidence(7,8) or mortality(2,7,9-14) in the USA, Spain, Japan, China and 33

countries with latitude(2,10,12,14) or measured UV radiation.(7-9,11,13) In most cases the

correlations were significantly negative. In the study of Waltz et al. a positive correlation was

calculated.(8) In the study with the Chinese data only for women a negative association was

found.(14) In the study with Spanish data for colon cancer mortality no association was found

with latitude; for rectal cancer a significantly inverse association was found.(12) Some

authors corrected in their analyses for some potentially important confounders.(7,8,11,13,14)

Three case-control studies were identified.(15-17) The studies of Kampman et al.(16) and

Slattery et al.(17) were performed with the same cases. Kampman et al.(16) observed no



                                                                                                   6
statistically significant associations between sunshine exposure and colon cancer risk. Slattery

et al.(17) stratified in the same subjects for genetic variations in the androgen (AR) and

vitamine D receptor (VDR). Men with low levels of sunlight exposure and more than 23

polyglutamine (CAG) repeats of the AR had the greatest risk of colon cancer

(OR=1.51;95%CI: 1.09-2.09). In women a comparable phenomenon was observed. Freedman

et al. found an inverse association between colon cancer mortality and sunlight.(15)

Two cohort studies(18,19) found significant variations in prognosis by season of diagnosis.

Diagnoses during summer and early autumn revealed the lowest risk of colon cancer death. In

addition Lim et al.(19) found that cumulative sun exposure in the months preceding diagnosis

was a predictor of subsequent survival. Further details of the case-control and cohort studies

are given in table 1 and 2.



Associations with vitamin D




Twenty-eight studies were included: 11 case-control studies, 14 prospective studies, and 3

intervention studies.




Vitamin D intake studies


Eleven case-control and 6 prospective studies were included.

Four case-control studies(16,20-22) observed no associations between vitamin D intake and

the risk of colon carcinoma; 7 found an inverse association(17,23-28), two not reaching

statistical significance(25,26). In the study of Mizoue et al.(26) higher levels of dietary

vitamin D (men >532 IU/d, women >488 IU/d) were significantly associated with decreased

risk of colorectal cancer only among those who had fewer chances of sunlight exposure at



                                                                                                 7
work or in leisure (OR=0.63, 95%CI=0.36-1.08; P for trend=0.02). The inverse association

seemed stronger for the distal colon ( P for trend=0.08) than for other subsites in the

colorectum (P for trend, 0.23 and 0.21 for proximal colon and rectum). Kampman et al.(16)

observed no statistically significant associations between vitamin D intake and colon cancer

risk. Slattery et al.(17) used the same subjects as Kampman et al., but stratified for genetic

variations in the AR and VDR. In subgroups of the population they found a significant

protective effect of vitamin D intake. Lipworth et al.(28) found that adjusted ORs for colon

cancer decreased after the 5th decile of vitamin D intake (>121 IU/d) and reached 0.69 (95%

CI = 0.50-0.96) for the 9th and 10th deciles (>172 IU/d and >204 IU/d), reflecting a

statistically significant inverse trend. The inverse association appeared to be somewhat more

pronounced for the proximal than for the distal colon and was similar among strata of

geographic region and calcium intake. Vitamin D intake was not associated with incidence of

rectal cancer in this population. Five prospective studies(29-33) observed no significant

relation between vitamin D intake and colon cancer risk. Garland et al.(34) reported a

significantly inverse association, based on a very small number of cases (N=29).

In a meta-analysis of observational studies on colorectal cancer and dietary vitamin D intake

Huncharek et al.(35) found that vitamin D was associated with a nonsignificant reduction of

6% in the risk of colorectal cancer and concluded that low vitamin D intake in the study

populations might have limited the ability to detect a protective effect.




Vitamin D levels in serum


Eight prospective studies(36-43) were included: all reporting inverse associations between the

25-Vitamin D (=25-VD)serum levels and the risk of or mortality from colon and/or rectal


                                                                                                 8
cancer, in 4 studies not statistically significant.(37,38,42,43) Details of these studies are

shown in table 3.

In a meta analysis(44) the data of 5 studies (36-39,45) were combined. The pooled results

suggested that a 50% lower risk of colorectal cancer was associated with a serum 25-VD level

>80 nmol/L, compared to <30 nmol/L.




Intervention studies


Three intervention studies (double-blind, randomized placebo-controlled trials) were

included.(45-47). Their primary endpoint was studying the effect of vitamin D suppletion on

fractures and in one case mortality in general(46), not cancer mortality in particular. In two

studies examining the effect of vitamin D supplementation on cancer incidence(47) and colon

cancer incidence(45) was the secondary endpoint. Wactawski et al.(45) observed no

significant difference in incidence of invasive colorectal cancer between women assigned to 7

years of calcium plus vitamin D supplementation (400 IU of vitamin D3 daily) and those

assigned to placebo (168 vs 154 cases).

Trivedi et al.(46) supplemented 100.000 IU oral vitamin D3 every four months (800 IU daily)

over five years. They found no significant effects of vitamin D on total mortality or incidence

of cancer. However, female participants in the vitamin D treatment group had a significant

lower incidence of colon cancer (0 vs 4 cases). In the study of Lappe et al.(47) subjects were

randomly assigned to 4 years of calcium alone, calcium plus 1100 IU vitamin D3 daily

(sufficient to raise serum 25-VD >80 nmol/L), or placebo. Among the 446 participants

assigned to the vitamin D the total cancer incidence was significantly lower compared with

288 participants assigned to placebo (13 vs 20). Numbers were very small: for colon cancer


                                                                                                 9
the difference in incidence was 1 vs 2 cases.




Prostate carcinoma



Associations with sunlight


Seventeen studies were included: 11 ecological, 3 case-control studies and 3 prospective

studies. The ecological studies have been performed with data from the USA

(7,9,11,48,50,51), 32 predominantly Caucasian countries(52), 33 developed and developing

countries(8), 71 countries(49), Spain(12) and Japan(13). Eight studies reported significantly

inverse associations between sunlight and incidence(7,50) or mortality(7,9,11,48-52) of

prostate carcinoma. In 3 studies no correlations were found between sunlight and prostate

cancer mortality (Spain and Japan(12,13)) or incidence.(33 countries(8))

All case-control(15,53,54) and prospective studies(18,19,55) showed significantly negative

relations between sunlight and the risk of prostate cancer. In the prospective study from

Norway(18) and the UK(19) the influence of season of diagnosis on case fatality was studied.

Details of the case-control and prospective studies are shown in table 1 and 2.



Associations with vitamin D




                                                                                             10
Twenty-five studies were included: eight (3 case-control and 5 prospective) studies

concerning the influence of vitamin D intake and 16 (all prospective) studies on the

relationship between 25-VD and 1,25-VD serum levels and risk of prostate cancer.

No intervention studies specifically investigating the effect of vitamin D supplementation on

prostate cancer risk were identified.




Vitamin D intake studies


Three case-control(56-58) and 4 prospective studies.(59-62) found no relationship between

the intake of vitamin D and prostate cancer risk. The study of Ahn et al.(63) showed

comparable results, however with one exception: men who used more than 600 IU of

supplemental vitamin D had a 40% risk reduction compared with men not using vitamin D

supplements (RR=0.61; 95% CI=0.41-0.89). In a meta-analysis of observational studies on

prostate cancer and dietary vitamin D intake Huncharek et al.(64) found that dietary vitamin

D intake was not associated with prostate cancer risk. They stated, however, that almost all

studies showed relatively low vitamin D intakes among patients in the highest category as

defined by individual authors, and therefore the true effects of vitamin D might not be

determined from the available data.




Vitamin D levels in serum


Seventeen prospective studies were included. Eight studies(40,65-71) found no association.

One additional study of Ahn et al. observed no statistically significant trend in overall prostate

cancer risk with increasing season-standardized serum 25-VD level. However, serum 25-VD



                                                                                               11
concentrations greater than the lowest quintile (12.8-42.0 nmol/L) were associated with

increased risk of aggressive disease.(72) Eight studies (41,73-79) found a negative

association, two of them did not reach significance.(41,75)

In a study with 17,000 Finnish men Ahonen et al.(77) found that prostate cancer risk,

analyzed by quartiles of the 25-VD levels, was inversely related to 25-VD. Men with 25-VD

concentration below the median had an adjusted relative risk (OR) of 1.7(95%CI=1.2-2.6)

compared to men with 25-VD level above the median. The prostate cancer risk was highest

among younger men (<52 years at entry) and low serum 25-VD (OR=3.5,95%CI=1.7-7.0). In

an additional study they were able to extend their study with cohorts of other Scandinavian

countries to a total of more than 200,000 men.(76) They examined serum 25-VD levels of 622

prostate cancer cases and 1,451 matched controls and found that both low (<19 nmol/l) and

high (>80nmol/l) 25-VD serum concentrations were associated with higher prostate cancer

risk. The normal average serum concentration of 25-VD (40–60 nmol/l) comprised the lowest

risk of prostate cancer. Tretli et al. (79) observed that 123 prostate cancer patients with

medium (50-80nmol/L) or high (>80 nmol/L) pretreatment levels of serum 25-VD had a

significantly better prognosis (RR: 0.33, 95%CI:0.14-0.77; RR: 0.16, 95%CI:0.05-0.43)

compared with patients with lower levels (<50 nmol/L).



In 3 studies of the group of Giovannucci(73,74,78) the role of vitamin D receptor (VDR)

polymorphisms and their interaction with 25-VD levels was investigated in relation to

prostate cancer risk.

No significant associations between VDR polymorphism or 25-VD levels and prostate cancer

risk were observed. However, men who had low 25-VD levels and the less functional FokI ff

genotype had increased risks of total (OR=1.9, 95% CI: 1.1–3.3) and aggressive prostate

cancer (OR=2.5, 95% CI: 1.1–5.8). Among men with plasma 25-VD levels above the median,



                                                                                              12
the ff genotype was no longer associated with risk. Conversely, among men with the ff

genotype, a high plasma 25-VD level (above versus below the median) was related to

significant 60%-70% lower risks of total and aggressive prostate cancer. In an analysis

restricted to men with plasma 25-hydroxyvitamin D below the median, they also observed a

57% reduction (RR 0.43, 95% CI: 0.19-0.98) in risk for those with the BB versus the bb

genotype.




Breast cancer


Associations with sunlight


Twenty studies were included (10 ecological, 4 case-control and 6 prospective studies).

Six ecological studies found a significant inverse association between sunlight and mortality

in the USA(7,9,80,81) or incidence in the USSR(82), and in 107 countries(83). In 4 studies no

significant associations were observed with breast cancer incidence in the USA(8) or

mortality in Spain(12), Japan(13), and China(14).

Four case-control studies observed significantly negative correlations between risk of breast

cancer(84-86) or breast cancer mortality(15) and sun exposure. Blackmore et al.(86), using

the same subjects as Knight et al.(84), found that the risk reduction was particularly

associated with ER+/PR+ tumours (ER=oestrogen receptor; PR=progesterone receptor).

Five prospective studies on breast cancer also showed a negative correlation with

sunlight.(18,19,87-89) The study of Millen et al.(88) from the USA showed mixed results:

region of residence was not consistently related to risk of breast cancer. However, women

who reported spending on average less than 30 minutes versus more than 2 hours outside in



                                                                                             13
daylight the year round had an increased risk for breast cancer (RR:1.20,95%CI:1.02-1.41; P

for trend=0.001). A sixth prospective study using data from the Nurses Health Study found no

significant differences in incidence of breast cancer between 4 regions in the VS ( California,

the Northeast, the Midwest and the South).(90)

Details of the case-control and prospective studies are given in tables 1 and 2.



Associations with vitamin D


Twenty-four studies were included: eleven (4 case-control and 7 prospective) studies

concerning the influence of vitamin D intake and 9 (1 ecological, 6 case-control and 2

prospective) studies on the relationship between 25-VD and 1,25-VD serum levels and risk of

breast cancer.

Four intervention studies specifically investigating the effect of vitamin D supplementation on

breast cancer risk were identified.



Vitamin D intake studies




One of the 4 case-control studies(91) observed no association. The study of Abbas et al.(92)

showed a significantly inverse association between breast cancer risk and vitamin D intake.

The OR for the highest intake (>=200 IU/day) category was 0.50 (95%CI=0.26-0.96)

compared with the lowest (<80 IU/day/d). Blackmore et al.(86) found a significantly reduced

risk of ER+/PR+ tumours by increased intake of vitamin D (from the sun and diet), e.g. the

OR was 0.76 (95% CI: 0.59-0.97) for cod-liver oil at adolescence. Rossi et al. found no

association with vitamin D up to the seventh decile (129-143 IU/d).(93) In higher deciles the

OR declined, so that the overall trend was statistically significantly inverse. Intake of vitamin

D >143 IU per day was associated with a decreased risk of breast cancer.


                                                                                               14
Three prospective studies showed no relation with vitamin D intake.(94-96). John et al.(87)

observed a non-significant trend to an inverse association. Robien et al. (97) found that the

association of high vitamin D intake with breast cancer was strongest in the first 5 years after

baseline dietary assessment (RR = 0.66; 95% CI:0.46–0.94 compared with lowest-intake

group). In a study of Lin et al.(98) higher intakes of vitamin D were moderately associated

with a lower risk of premenopausal breast cancer; the hazard ratio in the group with the

highest relative to the lowest quintile of intake was 0.65 (95% confidence interval, 0.42-

1.00;P =0.07 for trend). Shin et al.(99) also found that in premenopausal women, vitamin D

intake was inversely associated with risk of breast cancer. The multivariable RR comparing

highest (>500 IU/day) and lowest (=<150 IU/day) intake categories was 0.72 (95% CI = 0.55-

0.94). Meta-analyses of the intake of vitamin D and risk of breast cancer found no association

between the amount of vitamin D intake and the risk of breast cancer. However, most studies

reported on very low intakes of vitamin D. Restricting the analyses to intakes >= 400 IU/day

yielded a trend towards less breast cancer.(100)



Vitamin D levels in serum


Nine studies were included: 1 ecological study, 6 case-control, and 2 prospective studies. In

an ecological study in 107 countries Mohr et al.(83) found that the dose–response gradient

between modeled serum 25-VD levels and incidence rates of breast cancer followed a

standard inverse dose–response curve.

Two case-control studies(101,102) observed no relationship between serum vitamin D levels

and breast cancer risk. Four studies(103-106) found a significant lower risk of breast cancer in

women with high 25-VD levels. Lowe et al.(105) found that this risk was influenced by VDR

polymorphism. After adjustment for age and menopausal status, the OR for breast cancer risk

for women with insufficient levels of 25-VD and the bb genotype was 6.82 (95% CI=2.31–



                                                                                                15
14.7) while women with insufficient 25-VD levels alone had an OR of 3.54 (95% CI 1.89–

6.61) for breast cancer risk.

In their prospective study Bertone-Johnson et al.(107) found that high levels of both 25-VD

and 1,25-VD were associated with a non-significant lower risk of breast cancer. Hiatt et al.

(108) found no relationship between breast cancer and 1,25-VD serum levels at an average of

15 years before diagnosis.



Intervention studies



Three intervention studies (400 IU/day(45,109)) and 800 IU/day(46)) showed no significant

differences in the incidence of breast cancer between women assigned to vitamin D

supplementation and those assigned to placebo. Lappe et al. (1100 IU/day (47)) found

differences between these groups (4 cases in the intervention vs 7 cases in the placebo group),

but did not mention the significance of this finding.




Hematological malignancies


Associations with sunlight


A considerable number of studies were performed on non-Hodgkin lymphoma (NHL).

Twenty-two studies met the inclusion criteria: 11 ecological studies, 10 case-control studies

and 1 prospective study. Four ecologic studies reported positive (3 significant and 1 non-

significant) correlations between sunlight and NHL incidence(8,110,111) or mortality.(112)



                                                                                                16
Seven reported inverse associations with incidence(7,113) or mortality.(7,9,11,12,114,115)

Most studies reporting positive associations used relatively old lymphoma classifications.

The case-control studies(116-125) observed significantly negative correlations between the

risk of NHL and sunlight, with 2 exceptions(119,125) . Purdue et al.(126), who studied the

same subjects as Hartge et al.(120) observed that VDR polymorphisms influence the

correlation between NHL risk and sun exposure.

Kricker et al.(124) analysed in a meta-analysis the pooled results of 5 of the studies

mentioned above(117-121) and 5 additional studies, covering 8,243 cases and 9,697 controls

in the USA, Europe and Australia. They concluded that the protective effect of recreational

sun exposure was statistically significant at 18–40 years of age and in the 10 years before

diagnosis, for B cell, but not T cell, lymphomas.

A prospective study of Adami et al.(127) found a significantly positive relation between NHL

incidence and latitude.



Nine studies were included regarding Hodgkin’s lymphoma: 4 ecological and 5 case-control

studies. Of the 4 ecological studies 3 report inverse associations(7,11,115), in 1 study not

statistically significant.(115) The 4th study found no correlation between latitude and mortality

of Hodgkin.(12)

Four case-control studies(118,121,122,125) observed inverse associations between sun

exposure and the risk of Hodgkin; in only 1 study(121) this association reached statistical

significance. An additional large European case-control study observed no relation.(128) A

prospective study reported that patients with a diagnosis of Hodgkin in summer or early

autumn had a 20% better prognosis.(129)

Details of the case-control and prospective studies are shown in tables 1 and 2.




                                                                                               17
Associations with vitamin D


Four case-control and 3 prospective studies were included. Three case-control

studies(120,130,131) observed no correlation between the risk of NHL and vitamin D intake.

Polesel et al.(132) found an inverse association between vitamin D intake and NHL

risk(OR=0.6; 95% CI: 0.4–0.9).

In the prospective study of Freedman et al.(40) no relations were found between 25-VD levels

and mortality of NHL. In the Finnish Alpha-Tocopherol Beta-Carotene Cancer Prevention

Study cohort an inverse association was found for NHL cases diagnosed less than 7 years

from baseline (not for later diagnoses): the OR for highest versus the lowest tertile was 0.43

(95% CI=0.23-0.83).(133)

Using data of the Health Professionnels Follow-up Study, Giovannucci et al.(41) calculated

that an increment 25 nmol/L of the predicted 25-VD levels was associated with a, non-

significant, risk reduction of NHL.



Lung carcinoma


Associations with sunlight


Seven studies were included: 4 ecological and 3 prospective studies. Three ecological studies

found significantly inverse associations between lung cancer mortality and sunlight.(9,14,134)

One study had heterogeneous results: a positive correlation for men, no correlation for

women.(12)

Three prospective studies reported that season of diagnosis or treatment is a strong prognostic

factor for lung cancer survival.(19,135,136)

Details of the prospective studies are given in table 2.



                                                                                                 18
Associations with vitamin D


Zhou et al.(135) found a significant association between vitamin D intake and recurrence-free

survival (RFS) in lung cancer patients. Patients who had surgery during summer with the

highest vitamin D intake had better RFS (AHR=0.33; 95%CI=0.15-0.74) than patients who

had surgery during winter with the lowest vitamin D intake, with 5-year RFS rates of 56%

(34-78%) and 23% (4-42%), respectively. Similar associations of surgery season and vitamin

D intake with overall survival were also observed. They found that VDR polymorphism may

be associated with survival. Circulating 25-VD levels showed an inverse association with

survival in early-stage but not in advanced non-small-cell lung cancer.(137-139)

Freedman et al.(40) observed no correlation between 25-VD levels and lung cancer mortality.

Giovannucci et al.(41) calculated that an increment of 25 nmol/L of the predicted 25-VD

levels was associated with a non-significant risk reduction of lung cancer. Kikkinen et al.

found that serum 25-VD levels were inversely associated with lung cancer incidence for

women (highest versus lowest tertile OR=0.16;95%CI=0.04-0.59) and younger participants

(OR=0.34;95%CI=0.13-0.90) but not for men or older participants.(140)




Ovary carcinoma


Included were 8 ecological studies, 1 case-control study, and 1 prospective study on the

relations between ovary carcinoma and sunlight. Five ecological studies(9,11,12,141,142)

and the case-control study(15) found inverse negative associations; in one study not

significant.(12) Three ecological studies(7,8,13) found no associations. In the prospective




                                                                                              19
study from Norway no influence of season of diagnosis on mortality of ovary cancer was

found.(143)

Details of the case-control and prospective studies are given in tables 1 and 2.

Two prospective studies(144,145) found no significant associations between 25-VD levels

and risk of ovarian carcinoma.




Endometrial-, stomach-, pancreatic-, oesophageal-, and renal
carcinoma

Associations with sunlight


Five ecological studies were identified concerning endometrial carcinoma. In 4 of them

significantly inverse associations were found between sunlight and incidence(7) or

mortality(7,9,11,146). In a study with Spanish data a positive association was found with

endometrial carcinoma mortality.(12)

All ecological studies observed significantly inverse associations between sunlight and

incidence or mortality of stomach-(7,9,11,12,14), pancreatic-(7,9,11-13,147), oesophageal-

(7,9,11,13,14), and renal carcinoma.(7,9,11,148)

No case-control or prospective studies on an association between sunlight and any of these

tumours were identified.




Associations with vitamin D




                                                                                             20
Three case control studies(149-151) reported on the association of dietary vitamin D and

endometrial cancer risk and offered conflicting results. Meta-analyses of vitamin D and the

risk of endometrial cancer showed no correlations.(152)

In a case-control study La Vecchia et al.(153) found no trend in risk of gastric carcinoma for

vitamin D intake. In a prospective study Chen et al.(154) observed no associations with

vitamin D serum levels.

Giovannucci et al.(41) calculated that an increment of 25 nmol/L of the predicted 25-VD

levels was associated with a non-significant risk reduction of gastric cancer.

Skinner et al.(155) conducted prospective studies in cohorts of 46,771 men ages 40 to 75

years as of 1986 (the Health Professionals Follow-up Study), and 75,427 women ages 38 to 65

years as of 1984 (the Nurses' Health Study), documenting incident pancreatic cancer through

the year 2000. Compared with participants in the lowest category of total vitamin D intake

(<150 IU/d), pooled multivariate relative risks for pancreatic cancer were 0.78 (95% CI=0.59-

1.01) for 150 to 299 IU/d, 0.57 (95% CI=0.40-0.83) for 300 to 449 IU/d, 0.56 (95% CI=0.36-

0.87) for 450 to 599 IU/d, and 0.59 (95% CI=0.40-0.88) for 600 IU/d (Ptrend = 0.01).

Giovannucci et al.(41) calculated that an increment of 25 nmol/L of the predicted 25-VD

levels was associated with a significant risk reduction of pancreatric cancer (RR = 0.49, 95%

CI = 0.28-0.86).

Stolzenberg-Solomon et al.(156) found the opposite in the ‘Alpha-Tocopherol, Beta-Carotene

Cancer Prevention Cohort’ of male Finnish smokers: higher vitamin D concentrations were

associated with a 3-fold increased risk for pancreatic cancer (highest versus lowest quintile,

>65.5 versus <32.0 nmol/L: OR=2.92; 95%CI=1.56-5.48, Ptrend = 0.001).

A nested case-control study with data of the Prostate, Lung, Colorectal, and Ovarian

Screening Trial cohort observed that serum vitamin D concentrations were not associated with




                                                                                                 21
pancreatic cancer: the OR of the highest (>82.3 nmol/L) versus the lowest (<45.9 nmol/L)

quintile being 1.45 (0.66-3.15, P for trend=0.49)(157)

In a case-control study of Launoy et al.(158) vitamin D intake appeared as an independent

protective factor for oesophageal carcinoma. In a prospective study Freedman et al.(40) found

no association between oesophageal cancer mortality and 25-VD levels. Chen et al.(154)

found that among Chinese subjects with low vitamin D status higher 25-VD levels were

associated with significantly increased risk of oesophageal carcinoma in men, but not in

women.

Giovannucci et al.(41) calculated that an increment of 25 nmol/L of the predicted 25-VD

levels was associated with a significant risk reduction of oesophageal cancer (RR = 0.37, 95%

CI = 0.17-0.80).

In a case-control study Bosetti et al. found that the OR of renal cancer risk for the upper

quintile of intake of vitamin D (>163 IU/d) when compared with the lowest one (<87 IU/d)

was 0.76 (95%CI=0.57-1.01).(159)

Giovannucci et al.(41) calculated that an increment of 25 nmol/L of the predicted 25-VD

levels was associated with a non-significant risk reduction of renal cancer.



Other malignancies

A few, mainly ecological, studies(7,9,11,12,14,1143) also report on the relation between

sunlight or vitamin D and the risk of cancer of the cervix, vulva, bladder, small intestine, gall

bladder, liver, larynx, oropharynx, nasopharynx, pleura, thyroid, brain and leukemia. The data

of these studies are limited and/or heterogeneous.




                                                                                               22
Age and effect of sunlight


Eleven of the included studies(53,55,83,87,114,117,118,122,124-126) dealt with the

relationship between age and the potential risk-reducing effect of sunlight. All these studies

reported that sun exposure was important in both childhood and adulthood. In two studies sun

exposure in childhood seemed more important(117,118), in three others (79,108,119) the

sunlight in the ten years preceding diagnosis was more important. Petridiou et al.(116) studied

the risk of NHL in childhood only and observed that sunlight was associated with a reduced

risk.




discussion



Solar radiation has been accepted as the most important risk factor for skin cancer in

humans.(160) There is a linear relationship between the degree of sun exposure and squamous

cell carcinoma of the skin.(161,162) The relationship between melanoma, the most aggressive

type of skin cancer, and sunlight, however, is complicated. Excessive intermittent sun

exposure causing (severe) sunburn is the most important exogenous risk factor, whereas a

certain degree of chronic (continuous) exposure and occupational exposure might have a

preventive effect. Moreover, chronic sun exposure might be associated with increased

survival from melanoma.(163-168) Diagnosis in summer or early autumn has been reported to

improve the prognosis of melanoma patients.(169,170) For basal carcinoma both chronic and

intermittent sun exposure seem to play a role in the etiology.(161,162)




                                                                                                 23
The steady rise in the incidence of skin cancer during the last decades, largely caused by

increased sun exposure, has in most western countries led to public health recommendations

that sun exposure should be avoided.



Recent studies have suggested a possible beneficial effect of sunlight in reducing the risk of

various types of cancer. Much of the research that supports a protective effect of sunlight on

cancer risk is of ecological type. Ecological studies have well-known limitations: the most

important are the so-called ecological fallacy (occurring when associations of groups of

individuals are not the same as those for individuals), confounding, and misclassification of

exposure.(172) Although ecological studies suffer from many potential methodological

problems, they often provide useful clues for further research. It was through the combination

of clinical observations and ecological studies that the link between sun exposure and skin

cancers was identified, with more skin cancer cases occurring in populations residing in areas

of high sun exposure. In a similar way, many studies have by now observed a gradient

opposite to that of the skin cancer gradient for many solid, and haematological malignancies.

The great majority of the ecological studies performed in countries with a Caucasian

population indicate a possible protective effect of sun exposure for these tumours. The

number of these type of studies is growing quickly: from 14 in our previous study(3) in 2006

to 29 in May 2009. A total of 24 ecological studies on colon-, prostate-, breast-, lung-, ovary

carcinoma and NHL, performed in countries with a majority of Caucasian inhabitants, could

be included now. In 18 of them significantly inverse associations between the incidence/ or

mortality of the studied tumours and sun exposure were found. Four studies, mainly on NHL,

using old lymphoma classifications, reported positive associations.

Some of the ecological studies, mostly the early ones, simply plotted latitude of residence

against cancer incidence and/or mortality rates and presented the strength of the correlation



                                                                                                 24
between these two. Other, more sophisticated, studies tried to infer (mean) UV-B levels at the

residential locations from several sources: satellites, ground-based UV-B monitoring stations,

heat zones, average hours of solar radiation, etc. Some of these studies corrected for the

prevalence of other cancer risk factors, such as food intake, income, race and physical

activity.

From our review, it becomes clear that the number of case-control and cohort studies

increased as well. We could identify 20 case-control and 11 cohort studies. Seventeen of the

case studies and 5 of the prospective studies have individual-level information on sun

exposure, prevalence of other cancer risk factors and the presence or absence of cancer.

Almost all case-control and prospective studies on colon-(15,17-19), prostate-(15,18,53-55),

breast cancer(15,18,84-90) and NHL(116-118,120-124) show significantly inverse

associations between exposure to sunlight and the incidence and mortality of these

malignancies. There were 4 exceptions: a prospective study on breast cancer(90) and a case-

control study on NHL(125), finding no correlation, and a case-control study(119) and a

prospective study on NHL(127), finding a positive association.

Particularly the number of case-control studies on NHL has increased, comprising a total of

about 11,000 cases with individual level information on sun exposure and an additional

16,000 cases with exposure measures based on residential sun exposure. The epidemiological

evidence for a protective role of sunlight in NHL is gradually approximating that of sunlight

as a risk factor in basal cell carcinoma.

Several independent case-control and prospective studies identified sunlight as a predictor for

prognosis for lung cancer(19,135,136) and melanoma(165-170) as well.

We therefore conclude that there is accumulating evidence for sunlight as a protective factor

for several types of cancer. This evidence, however, is not conclusive, because the number of

(good quality) studies is still limited and publication biases cannot be excluded.



                                                                                              25
The results of the included studies on the association between cancer risk and vitamin D are

much less consistent in comparison with those for sunlight. Only those studies that

prospectively examined the 25-VD levels in relation to risk of colorectal cancer are

homogeneous. They provide evidence of a decreased risk of colorectal cancer associated with

higher serum 25-VD levels, particularly levels higher than 80 nmol/L. Such levels may

require a vitamin D supplementation of at least 1500 IU/day, a safe but not generally

encouraged level. Healthy young and middle-aged adults who are exposed to sunlight and get

enough sun to cause a slight pinkness to the skin ( 1 minimal erythemal dose) produce in the

skin an amount of vitamin D comparable with an oral dosage of 20.000 IU. (171)

Most studies on the effect of sunlight or vitamin D restrict their observations to colon or

colorectal cancer. Several studies report the results of colon and rectal cancer separately. In

some the results are practically equal (15,16,17,23) and in others the results are more

pronounced for rectal cancer (24,28,37). Lipworth et al.(28) in contrast found no association

between vitamin D intake and the risk of rectal cancer. In two studies subsites were studied in

even more detail, distinguishing proximal and distal colon: in the study of Mizoue et al. the

associations appeared stronger with the distal, in that of Lipworth et al.(28) with the proximal

colon.

The studies on 25-VD levels in breast carcinoma and particularly in prostate-, lung- and

ovarian carcinoma and NHL have inconsistent results and thus are much less supportive for a

protective role of vitamin D in these malignancies.

The studies on vitamin D intake are inconsistent as well. Moreover, they probably are of little

value when examining the relationship between vitamin D and cancer risk, particularly

because the most important source of vitamin D, the sun, is disregarded in most of these

studies. In addition several meta-analyses (35,64) revealed that the low vitamin D intake in




                                                                                                  26
the studied populations might limit the possibility to detect a protective effect, which may

require higher dosages.



The results of the intervention studies are suggestive of a protective role of vitamin D in

cancer. They have, however, been criticized in the literature.(172) Generally they are

considered to be of insufficient duration for cancer prevention trials. With exception of the

trial of Lappe et al.(47) the dosage would be too low to reach adequate serum 25-VD levels.

The study of Lappe et al.(47)is criticized for its design and the low number of cases.



Several considerations might explain these inconsistent results for vitamin D. Firstly, it is

possible that vitamin D has a protective effect on colorectal cancer only and not on other

types of cancer.

Secondly for some of the types of cancer discussed in this paper the risk associated with low

vitamin D status may be conferred early in life (during tumor initiation), and thus studies of

circulating levels of 25-VD and dietary or supplement intake in adulthood may not capture the

relevant time period of exposure. However, the studies concerning the relationship between

age and the potential risk-reducing effect of sunlight do not show that childhood exposure is

of particular importance. Thirdly, for other cancers the effect of vitamin D could be more

relevant for cancer progression than for cancer initiation.(173) To investigate this, studies of

25-VD levels and vitamin D intake should be restricted to the period at or shortly before

diagnosis. Fourthly, the effects of vitamin D could be part of a more complex mechanism

involving gene polymorphisms like vitamin D receptors variants.(17,73,74,78,138,139)

Therefore polymorphisms    in the vitamin D receptor should, when possible, be included in all

epidemiological studies on the effect of 25-VD levels on cancer risk.




                                                                                                 27
Finally, the protective effect of sunlight may not be mediated by vitamin D alone. More

effects of sunlight on the human body could be involved. In this regard the effect of sunlight

on circadian rhythm(5) and on the degradation of folic acid(6) has been mentioned in the

literature. Interesting in this respect is the finding of Bizarri et al.(174) that 1,25-VD at low

doses strongly inhibited the proliferation of a rat breast cancer cell line. Melatonin

considerably increased the sensitivity of these cells to 1,25-VD. It might therefore be more

appropriate to speak of the ‘sunlight hypothesis’ in stead of the ‘vitamine D hypothesis’.



It is biologically plausible that vitamin D and consequently sunlight have an effect on cancer.

Many cell types, such as normal and malignant cells of colon, breast and prostate contain

vitamin D receptors. When these receptors are activated by the hormone 1,25-VD, the

biologically active form of vitamin D, they induce differentiation and apoptosis, and inhibit

proliferation, invasiveness, angiogenesis, and metastatic potential. Moreover, circulating 25-

VD was also shown to be potentially beneficial because many cell types including cancer

cells express 1-a-hydroxylase, and are thus able to convert 25VD into 1,25-VD. In addition,

the vitamin D cancer hypothesis has been supported by studies that administer 1,25-VD to

animals in various tumour models and in small phase II clinical studies in humans that show

that administration of 1,25-VD can slow the progression of cancer.(4,175-178) Regrettably,

reliable experiments on the direct effect of sunlight on carcinogenesis in animals other than

skin cancer have not been performed.



In summary, results of epidemiological studies suggest that (chronic)sun exposure, whether or

not (partially) mediated by vitamin D, decreases the risk of some cancers, particularly of the

colon, breast and prostate and NHL. There is also evidence that relatively high personal sun

exposure may improve the outcome of colon-, breast-, prostate-, lung carcinoma, melanoma

and Hodgkin lymphoma.


                                                                                                    28
Chronic sun exposure causes squamous cell- and to a lesser degree basal cell carcinoma of the

skin. Incidence rates of these cancers are increasing rapidly. However, the morbidity of these

skin tumours is generally minimal for individual patients and the mortality is very low. In the

Netherlands in 2006 about 35,000 new non-melanoma skin cancer patients were diagnosed. In

the same year, about 100 people died of a non-melanoma skin cancer. The number of new

patients with colon-, breast-,prostate cancer and NHL was comparable. However, the

morbidity of these malignancies is much more serious and the mortality was 11,500 in

2006.(179)

If the evidence for the ‘sunlight hypothesis’ is getting more convincing a stimulation of

chronic sun exposure should be considered, because the advantages considerably outweigh

the disadvantages. Even then warnings against excessive intermittent sun exposure still

remain appropriate.




                                                                                             29
legends to tables

Table 1. Characteristics and outcomes of case-control studies investigating the association

between sunlight and cancer risk.

Table 2a Characteristics and outcomes of cohort studies investigating the relation between sun

exposure and cancer risk.

Table 2b Characteristics and outcomes of cohort studies investigating the relation between

sun exposure and cancer survival.

Table 3 Characteristics and outcomes of studies on the association between prediagnostic 25-

hydroxyvitamin D serum levels and colorectal cancer risk and survival.




                                                                                              30
reference list

1. Apperly FL. The relation of solar radiation to cancer mortality in North America. Cancer
Res 1941;1:191–195.
2. Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer?
Int J Epidemiol 1980; 9:227-31.
3. van der Rhee HJ, de Vries E, Coebergh JW. Does sunlight prevent cancer? A systematic
review. Eur J Cancer 2006;42:2222-32.
4. Giovannucci E. The epidemiology of vitamin D and cancer incidence and mortality: A
review. Cancer Causes and Control 2005;16:83–95.
5. Kolstad HA. Nightshift work and risk of breast cancer and other cancers-a critical review of
the epidemiologic evidence. Scand J Work Environ Health 2008;34:5-22.
6. Steindal AH, Porojnicu AC, Moan J. Is the seasonal variation in cancer prognosis caused
by sun-induced folate degradation? Med Hypotheses 2007;69:182-185.
7. Boscoe FP, Schymura MJ. Solar ultraviolet-B exposure and cancer incidence and mortality
in the United States, 1993-2002. BMC Cancer 2006;6:264-273.
8. Waltz P, Chodick G. Assessment of ecological regression in the study of colon, breast,
ovary, non-Hodgkin's lymphoma, or prostate cancer and residential UV. Eur J Cancer Prev
2008;17:279-86.
9. Grant WB. An estimate of premature cancer mortality in the U.S. due to inadequate doses
of solar ultraviolet-B radiation. Cancer 2002;94:1867-75.
10. Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon
cancer? Int J Epidemiol 2006:35:217-220.
11. Grant W, Garland CF. The association of solar ultraviolet B (UVB) with reducing risk of
cancer: multifactorial ecologic analysis of geographic variation in age-adjusted cancer
mortality rates. Anticancer Research 2006;26:2687-2700.
12. Grant WB. An ecologic study of cancer mortality rates in Spain with respect to indices of
solar UVB irradiance and smoking. Int J Cancer 2006:120:1123-1128.
13. Mizoue T. Ecological study of solar radiation and cancer mortality in Japan. Health Phys
2004;87:532-8.
14. Grant WB. Does solar ultraviolet irradiation affect cancer mortality rates in China. Asian
Pacific J Cancer Prev 2007;8:236-242.
15. Freedman DM, Dosemeci M, McGlynn K. Sunlight and mortality from breast, ovarian,



                                                                                              31
colon, prostate, and non-melanoma skin cancer: a composite death certificate based case-
control study. Occup Environ Med 2002;59:257-62.
16. Kampman E, Slattery ML, Caan B, Potter JD. Calcium, vitamin D, sunshine exposure,
dairy products and colon cancer risk (United States). Cancer Causes Control 2000;11:459-66.
17. Slattery ML, Sweeney C, Murtaugh M et al. Associations between vitamin D, vitamin D
receptor gene and the androgen receptor gene with colon and rectal cancer. Int J Cancer
2006;118:3140-46.
18. Robsahm TE, Tretli S, Dahlback A, Moan J. Vitamin D3 from sunlight may improve the
prognosis of breast-, colon- and prostate cancer (Norway). Cancer Causes Control 2004;15:
149-58.
19. Lim HS, Roychoudhuri R, Peto J, Schwartz G, Baade P, Moller H. Cancer survival is
dependent on season of diagnosis and sunlight exposure. Int J Cancer 2006;119:1530-1536.
20. Benito E, Stiggelbout A, Bosch FX et al. Nutritional factors in colorectal cancer risk: a
case-control study in Mallorca. Int J Cancer 1991;49:161-7.
21. Ferraroni M, La Vecchia C, D’Avanzo B, Negri E, Franceschi S, Decarli A. Selected
micronutrient intake and the risk of colorectal cancer. Br J Cancer 1994;70:1150-5.
22. Boutron MC, Faivre J, Marteau P, Couillault C, Senesse P, Quipourt V. Calcium,
phosphorus, vitamin D, dairy products and colorectal carcinogenesis: a French case-control
study. Br J Cancer 1996;74:145-51.
23. Marcus PM, Newcomb PA. The association of calcium an Vitamin D, and colon and
rectal cancer in Wisconsin women. Int J Epidemiol 1998;27:788-93.
24. Pritchard RS, Baron JA, Gerhardsson de Verdier M.
Dietary calcium, vitamin D, and the risk of colorectal cancer in Stockholm, Sweden.
Cancer Epidemiol Biomarkers Prev 1996;5:897-900.
25. Peters RK, Pike MC, Garabrant D, Mack TM. Diet and colon cancer in Los Angeles
County, California. Cancer Causes Control 1992;3:457-73.
26. Mizoue T, Kimura Y, Toyomura K, et al. Calcium, dairy foods, vitamin D, and colorectal
cancer risk: the Fukuoka colorectal cancer study. Cancer Epidemiol Biomarkers Prev
2008;17:2800-7.
27. Theodoratou E, Farrington SM, Tenesa A, et al. Modification of the inverse association
between dietary vitamin D intake and colorectal cancer risk by a Fok1 variant supports a
chemoprotective action of vitamin D intake mediated through VDR binding. Int J Cancer
2008;123:2170-79.



                                                                                                32
28. Lipworth L, Bender TJ, Rossi M, et al. Dietary vitamin D intake and cancers of the colon
and the rectum: a case-control study in Italy. Nutr Cancer 2009;61:70-5.
29. Jarvinen R, Knekt P, Halkulinen T, Aromaa A. Prospective study on milk products,
calcium and cancers of the colon and rectum. Eur J Clin Nutrition 2001;11:100-7.
30. Kearney J, Giovannucci E, Rimm EB, et al. Calcium, Vitamin D, and dairy foods and the
occurrence of colon cancer in men. Am J Epidemiol 1996;143:907-17.
31. Martinez ME, Giovannucci EL, Colditz GA, et al. Calcium, vitamin D, and the occurrence
of colorectal cancer among women. J Natl Cancer Inst 1996;88:1375-82.
32. Bostick RM, Potter JD, Sellers TA, McKenzie DR, Kushi LH, Folsom AR. Relation of
calcium, vitamin D, and dairy food intake to incidence of colon cancer among older women.
The Iowa Women's Health Study. Am J Epidemiol 1993;137:1302-17.
33. Ishihara J, Inoue M, Iwasaki M, Sasazuki S, Tsugane S. Dietary calcium, vitamin D, and
the risk of colorectal cancer. Am J Clin Nutr 2008;88:1576-83.
34. Garland C, Shekele RB, Barrett-Connor E, Cirque MH, Rossof AH, Paul O. Dietary
vitamin D and calcium and risk of colorectal cancer: a prospective study in men. Lancet
1985;8424:307-310.
35. Huncharek M, Muscat J, Kupelnick B. Colorectal cancer risk and dietary intake of
calcium, vitamin D, and diary products: a meta-analysis of 26,335 cases from 60
observational studies. Nutr Cancer 2009; 61:47-69.
36. Wu K, Feskanich D, Fuchs CS, Willett WC, Hollis BW, Giovanucci EL. A nested case
control study of plasma 25-hydroxyvitamin D concentrations and risk of colorectal cancer. J
Natl Cancer Inst 2007;99:1120-9.
37. Tangrea J, Helzlsouer K, Pietinen P, et al. Serum levels of Vitamin D metabolites and the
subsequent risk of colon cancer in Finnish men. Cancer Causes Control 1997;8:615-25.
38. Braun MM, Helzlsouer KJ, Hollis BW, Comstock GW. Colon cancer and serum vitamin
D metabolite levels 10-17 years prior to diagnosis. Am J Epidemiol 1995;142:608-11.
39. Garland CF, Comstock GW, Garland FC, Helsing KJ, Shaw EK, Gorham ED. Serum 25-
hydroxyvitamin D and colon cancer: eight-year prospective study. Lancet 1989;8673:1176-8.
40 Freedman DM, Looker AC, Chang SC, Graubard BI. Prospective Study of Serum Vitamin
D and Cancer. Mortality in the United States. J Natl Cancer Inst 2007;99:1594 – 602.
41. Giovannucci E, Liu Y, Rimm EB, et al. Prospective study of predictors of vitamin D
status and cancer incidence and mortality in men. J Cancer Inst 2006;98:451-459.




                                                                                           33
42. Otani T, Iwasaki M, Sasazuki S, Inoue M, Tsugane S. Plasma vitamin D and risk of
colorectal cancer: the Japan Public Health Center-Based Prospective Study. Br J Cancer.
2007;97:446-451.
43. Ng K, Meyerhardt JA, Wu K, Feskanich D, Hollis BW, et al. Circulating 25-
hydroxyvitamin D levels and survival in patients with colorectal cancer. J Clin Oncol
2008;26:2984-2991.
44. Gorham ED, Garland CF, Garland FC, et al. Optimal Vitamin D Status for Colorectal
Cancer Prevention A Quantitative Meta Analysis. Am J Prev Med 2007;32:210–216.
45. Wactawski-Wende J, Kotchen JM, Anderson GL, et al. Calcium plus vitamin D
supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684 –96.
46. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 and
(cholecalciferol) on fractures and mortality in men and women living in the community:
randomised double blind controlled trial. Br Med J 2003;326:469-75.
47. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and
calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr
2007;85:1586–91.
48. Hanchette CL, Schwartz GG. Geographic patterns of prostate cancer mortality. Evidence
for a protective effect of ultraviolet radiation. Cancer 1992;70:2861-9.
49. Colli JL, Colli A. International comparison of prostate cancer mortality rates with dietary
practices and sunlight levels. Urol Onc 2006;24:184-194.
50. Schwartz GG, Hanchette CL. UV, latitude, and spatial trends in prostate cancer mortality:
All sunlight is not the same (United States). Cancer Causes Control 2006;17:1091-1101.
51. Colli JL, Grant WB. Solar ultraviolet B radiation compared with prostate cancer incidence
and mortality rates in United States. Urology 2008;71:531-5.
52. Grant WB. A multicountry ecologic study of risk and risk reduction factors for prostate
cancer mortality. Eur Urol 2004;45:271-9.
53. Bodiwala D, Luscombe CJ, French ME, et al. Associations between prostate cancer
susceptibility and parameters of exposure to ultraviolet radiation. Cancer Lett 2003;200:141-
8.
54. John EM, Schwartz GG, Koo J, Van Den Berg D, Ingles SA. Sun exposure, vitamin D
receptor gene polymorphisms, and risk of advanced prostate cancer. Cancer Res
2005;65:5470-9.
55. John EM, Koo J, Schwartz GG. Sun exposure and prostate cancer risk: evidence for a
protective effect of early-life exposure. Cancer Epidemiol Biomarkers Prev 2007;16:1283-86.


                                                                                              34
56. Tavani A, Bertuccio P, Bosetti C, et al. Dietary intake of calcium,vitamin D, phosphorus
and the risk of prostate cancer. European Urology 2005;48:27–33.
57. Kristal AR, Cohen JH, Qu P, Stanford JL. Associations of energy, fat, calcium, and
vitamin D with prostate cancer risk. Cancer Epidemiol Biomarkers Prev 2002;11:719–725.
58. Chan JM, Giovannucci E, Andersson SO, Yuen J, Adfami HO, Wolk A. Dairy products,
calcium, phosphorous, vitamin D, and risk of prostate cancer (Sweden)
Cancer Causes Control 1998;9:559-66.
59. Park SY, Murphy SP, Wilkens LR, Stram DO, Henderson BE, Kolonel LN. Calcium,
vitamin D, and dairy product intake and prostate cancer risk. The Multiethnic Cohort Study.
Am J Epidemiol 2007;166:1259–1269.
60. Tseng M, Breslow RA, Graubard BI, Ziegler RG. Dairy, calcium, and vitamin D intakes
and prostate cancer risk in the National Health and Nutrition Examination Epidemiologic
Follow-up Study cohort. Am J Clin Nutr 2005;81:1147–54.
61. Berndt SI, Carter HB, Landis PK, Tucker KL, Hsieh LJ, Metter EJ, Platz EA. Calcium
intake and prostate cancer risk in a long-term aging study: the Baltimore Longitudinal Study
of Aging. Urology 2002;60:1118-23.
62. Rodriguez C, McCullough ML, Mondul AM, et al. Calcium, dairy products, and risk of
prostate cancer in a prospective cohort of United States men. Cancer Epidemiol Biomarkers
Prev 2003;12:597-603.
63. Ahn J, Albanes D, Peters U, et al. Dairy products, Calcium intake, and risk of prostate
cancer in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol
Biomarkers Prev 2007;16:2623–30.
64. Huncharek M, Muscat J, Kupelnick B. Diairy products, dietary calcium, vitamin D intake
as risk factors for prostate cancer: a meta-analysis of 26,769 cases from 45 observational
studies. Nutr Cancer 2009; 61:421-441.
65. Faupel-Badger JM, Diaw L, Albanes D, Virtamo J, Woodson K, Tangrea JA. Lack of
association between serum levels of 25-hydroxyvitamin D and the subsequent risk of prostate
cancer in Finnish men. Cancer Epidemiol Biomarkers Prev 2007;16:2784-86.
66. Jacobs ET, Giuliano AR, Martınez ME, Hollis BW, Reid ME, Marshall JR. Plasma levels
of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and the risk of prostate cancer. Journal of
Steroid Biochemistry & Molecular Biology 2004; 89–90:533–537.
67. Nomura AMY, Stemmermann GN, Lee J, et al. Serum vitamin D metabolite levels and
the subsequent development of prostate cancer (Hawaii, United States). Cancer Causes
Control 1998;9:425-432.


                                                                                              35
68. Gann PH, Ma J, Hennekens CH, Hollis BW, Haddad JG, Stampfer MJ. Circulating
vitamin D metabolites in relation to subsequent development of prostate cancer. Cancer
Epidemiol Biomarkers Prev 1996;5:121-126.
69. Braun MM, Helzlsouer KJ, Hollis BW, Comstock GW. Prostate cancer and prediagnostic
levels of serum vitamin D metabolites (Maryland, United States). Cancer Causes Control
1995;6:235-239.
70. Corder EH, Guess HA, Hulka BS, et al. Vitamin D and prostate cancer: a prediagnostic
study with stored sera. Cancer Epidemiol Biomarkers Prev 1993;2: 467-472.
71. Baron JA, Beach M, Wallace K, et al. Risk of prostate cancer in a randomized
clinical trial of calcium supplementation. Cancer Epidemiol Biomarkers Prev 2005;14:586-
589.
72. Ahn J, Peters U, Albanes D, et al. Serum vitamin D concentration and prostate cancer risk:
a nested case-control study. J.Natl.Cancer Inst 2008;100:796-804.
73. Mikhak B, Hunter DJ, Spiegelman D, Platz EA, Hollis BW, Giovannucci E. Vitamin
Dreceptor (VDR)gene polymorphisms and haplotypes, interactions with plasma 25-
hydroxyvitamin D and 1,25-dihydroxyvitamin D, and prostate cancer risk. Prostate 2007;67:
911–923.
74. Li H, Stampfer MJ, Hollis JBW, et al. A prospective study of plasma vitamin D
metabolites, vitamin D receptor polymorphisms, and prostate cancer. PLoS Med 2007;4:562-
70.
75. Platz EA, Leitzmann MF, Hollis BW, Willett WC, Giovannucci E. Plasma 1,25-
dihydroxy- and 25-hydroxyvitamin D and subsequent risk of prostate cancer. Cancer Causes
Control 2004;15:255–265.
76. Tuohimaa P, Tenkanen L, Ahonen M, et al. Both high and low levels of blood vitamin D
are associated with a higher prostate cancer risk: a longitudinal, nested case/control study in
the Nordic countries. Int. J. Cancer 2004;108:104–108.
77. Ahonen MH, Tenkanen L, Teppo L, Hakama M, Tuohimaa P. Prostate cancer risk and
prediagnostic serum 25-hydroxyvitamin D levels (Finland). Cancer Causes Control
2000;11:847-852.
78. Ma J, Stampfer MJ, Gann PH, et al. Vitamin D receptor polymorphisms, circulating
vitamin D metabolites, and risk of prostate cancer in United States Physicians. Cancer
Epidemiol Biomarkers Prev 1998;7:385-90.
79. Tretli S, Hernes E, Berg JP, Hestvik UE, Robsahm TE. Association between serum
25(OH)D and death from prostate cancer. Br J Cancer 2009;100:450-54.


                                                                                                  36
80. Garland FC, Garland CF, Gorham ED, Young JF. Geographic variation in breast cancer
mortality in the United States: a hypothesis involving exposure to solar radiation. Prev Med
1990;19:614-22.
81. Grant WB. An ecologic study of dietary and solar ultraviolet-B links to breast carcinoma
mortality rates. Cancer 2002;94:272-81.
82. Gorham ED, Garland FC, Garland CF. Sunlight and breast cancer incidence in the USSR.
Int J Epidemiol 1990;19:820-4.
83. Mohr SB, Garland CF, Gorham ED, Grant WB, Garland FC. Relationship between Low
Ultraviolet B Irradiance and Higher Breast Cancer Risk in 107 Countries. Breast J.
2008;14:255-60.
84. Knight JA, Lesosky M, Barnett H, Raboud JM, Vieth R. Vitamin D and reduced risk of
breast cancer: a population-based case-control study. Cancer Epidemiol Biomarkers Prev
2007;16:422-9.
85. John EM, Schwartz GC, Koo J, Wang W, Ingles SA. Sun exposure, vitamin D receptor
gene polymorphisms, and breast cancer risk in a multiethnic population. Am J Epidemiol
2007;166:1409-19.
86. Blackmore KM, Lesosky M, Barnett H, et al. Vitamin D from dietary intake and sunlight
exposure and the risk of hormone-receptor-defined breast cancer. Am J Epidemiol
2008;168:915-24.
87. John EM, Schwartz GG, Dreon DM, Koo J. Vitamin D and breast cancer risk: the
NHANES I Epidemiologic follow-up study, 1971-1975 to 1992. National Health and
Nutrition Examination Survey. Cancer Epidemiol Biomarkers Prev 1999;8:399-406.
88. Millen AE, Pettinger M, Freudenheim JL, et al. Incident invasive breast cancer ,
geographic location of residence, and reported average time spent outside. Cancer Epidemiol
Biomarkers Prev 2009;18:495-507.
89. Sturgeon SR, Schairer C, Gail M, McAdams M, Brinton LA, Hoover RN. Geographic
variation in mortality from breast cancer among white women in the United States. J Natl
Cancer Inst 1995;87:1846-53.
90. Laden F, Spiegelman D, Neas LM, et al. Geographic variation in breast cancer incidence
rates in a cohort of U.S. women. J Natl Cancer Inst 1997;89:1373-8.
91. Simard A, Vobecky J, Vobecky JS. Vitamin D deficiency and cancer of the breast: an
unprovocative ecological hypothesis. Can. J. Public Health 1991;82:300-3.
92. Abbas S, Linseisen J, Chang-Claude J. Dietary vitamin D and calcium intake and
premenopausal breast cancer in a German case-control study. Nutr Cancer 2007;59:54-61.


                                                                                               37
93. Rossi M, McLaughlin JK, Lagiou P, et al. Vitamin D and breast cancer risk: a case-control
study in Italy. Ann Oncol 2009;20:374-8.
94. McCullough ML, Stevens VL, Diver WR, et al. Vitamin D pathway gene polymorphisms,
diet, and risk of postmenopausal breast cancer: a nested case-control study. Breast Cancer Res
2007;9:R9.
95. McCullough ML, Rodriguez C, Diver WR, et al. Dairy, calcium, and vitamin D intake and
postmenopausal breast cancer risk in the Cancer Prevention Study II Nutrition Cohort. Cancer
Epidemiol Biomarkers Prev 2005;14:2898-904.
96. Frazier AL, Ryan CT, Rocket H, Willett WC, Colditz GA. Adolescent diet and risk of
breast cancer. Breast Cancer Res 2003;5:R59-R64.
97. Robien K, Cutler GJ, Lazovich D. Vitamin D intake and breast cancer risk in
postmenopausal women: the Iowa Women's Health Study. Cancer Causes Control
2007;18:775-82.
98. Lin J, Manson JE, Lee IM, Cook NR, Buring JE, Zhang SM. Intakes of calcium and
vitamin D and breast cancer risk in women. Arch Intern Med 2007;167:1050-9.
99. Shin MH, Holmes MD, Hankinson SE, Wu K, Colditz GA, Willett WC. Intake of dairy
products, calcium, and vitamin d and risk of breast cancer. J Natl Cancer Inst 2002;94:1301-
11.
100. Gissel T, Rejnmark L, Mosekilde L, Vestergaard P. Intake of vitamin D and risk of
breast cancer-A meta-analysis. J Steroid Biochem Mol Biol 2008;111:195-199.
101. de Lyra EC, da Silva IA, Katayama ML, et al. 25(OH)D3 and 1,25(OH)2D3 serum
concentration and breast tissue expression of 1alpha-hydroxylase, 24-hydroxylase and
Vitamin D receptor in women with and without breast cancer. J Steroid Biochem Mol Biol
2006;100:184-92.
102. Janowsky EC, Lester GE, Weinberg CR, et al. Association between low levels of 1,25-
dihydroxyvitamin D and breast cancer risk. Public Health Nutr 1999;2:283-91.
103. Abbas S, Linseisen J, Slanger T, et al. Serum 25-hydroxyvitamin D and risk of post-
menopausal breast cancer--results of a large case-control study. Carcinogenesis 2008;29:93-9.
104. Colston KW, Lowe LC, Mansi JL, Campbell MJ. Vitamin D status and breast cancer
risk.
Anticancer Res 2006;26:2573-80.
105. Lowe LC, Guy M, Mansi JL, et al. Plasma 25-hydroxy vitamin D concentrations,
vitamin D receptor genotype and breast cancer risk in a UK Caucasian population. Eur J
Cancer 2005;41:1164-9.


                                                                                           38
106. Abbas S, Chang-Claude J, Linseisen J. Plasma 25-hydroxyvitamin D and premenopausal
breast cancer risk in a German case-control study. Int J cancer 2009;124:250-255.
107. Bertone-Johnson ER, Chen WY, Holick MF, et al. Plasma 25-hydroxyvitamin D and
1,25-dihydroxyvitamin D and risk of breast cancer. Cancer Epidemiol Biomarkers Prev
2005;14:1991-7.
108. Hiatt RA, Krieger N, Lobaugh B, Drezner MK, Vogelman JH, Orentreich N.
Prediagnostic serum vitamin D and breast cancer. J Natl Cancer Inst 1998;90:461-3
109. Chlebowski RT, Johnson KC, Kooperberg C, et al. Calcium plus vitamin D
supplementation and the risk of breast cancer. J Natl Cancer Inst 2007;100:1581-1591.
110. Bentham G. Association between incidence of non-Hodgkin's lymphoma and solar
ultraviolet radiation in England and Wales. Br Med J 1996;312:1128-31.
111. McMichael AJ, Giles GG. Have increases in solar ultraviolet exposure contributed to the
rise in incidence of non-Hodgkin's lymphoma? Br J Cancer 1996;73:945-50.
112. Langford IH, Bentham G, McDonald AL. Mortality from non-Hodgkin lymphoma and
UV exposure in the European Community. Health Place 1998;4:355-64.
113. Hu S, Ma F, Collado-Mesa F, Kirsner RS. Ultraviolet radiation and incidence of non-
Hodgkin's lymphoma among Hispanics in the United States. Cancer Epidemiol Biomarkers
Prev 2004;13:59-64.
114. Hartge P, Devesa SS, Grauman D, Fears TR, Fraumeni JF, Jr. Non-Hodgkin's lymphoma
and sunlight. J Natl Cancer Inst 1996;88:298-300.
115. Uehara M, Takahashi K, Hoshuyama T, Pan G, Feng Y. Geographical correlation
between ambient UVB level and mortality risk of leukemia in Japan. Environ Res
2003;92:78-84.
116. Freedman DM, Zahm SH, Dosemeci M. Residential and occupational exposure to
sunlight and mortality from non-Hodgkin's lymphoma: composite (threefold) case-control
study. Br Med J 1997;314:1451-5.
117. Hughes AM, Armstrong BK, Vajdic CM, et al. Sun exposure may protect against non-
Hodgkin lymphoma: a case-control study. Int J Cancer 2004;112:865-71.
118. Smedby KE, Hjalgrim H, Melbye M, et al. Ultraviolet radiation exposure and risk of
malignant lymphomas. J Natl Cancer Inst 2005;97:199-209.
119. Zhang Y, Holford TR, Leaderer B, et al. Ultraviolet radiation exposure and risk of non-
Hodgkin’s lymphoma. Am J Epidemiol 2007;165:1255–64.
120. Hartge P, Lim U, Freedman DM, et al. Ultraviolet radiation, dietary vitamin D, and risk
of non-Hodgkin Lymphoma (United States). Cancer Causes Control 2006;17:1045-1052.


                                                                                           39
121 Weihkopf T, Becker N, Nieters A, et al. Sun exposure and malignant lymphoma: A
population-based case-control study in Germany. Int J Cancer 2007;120:2445-51.
122. Petridou ET, Dikalioti SK, Skalkidou A, Andrie E, Dessypris N, Trichopoulos D. Sun
exposure birth weight and childhood lymphomas : a case-control study in Greece. Cancer
Causes Control 2007;18:1031-37.
123. Soni LK, Hou L, Gapstur SM, Evens AM, Weisenburger DD, Chiu BCH. Sun exposure
and non-Hodgkin lymphoma: A population-based, case-control study. Eur J Cancer
2007;43:2388-95.
124. Kricker A, Armstrong BK, Hughes AM, et al. Personal sun exposure and risk of non
Hodgkin Lymphoma: A pooled analysis from the Interlymph Consortium. Int J Cancer
2008;122:144-155.
125. Grandin L, Orsi L, Troussard X, et al. UV radiation exposition, skin type and lymphoid
malignancies: results of a French case-control study. Cancer Causes Control 2008;19:305–
315.
126. Purdue MP, Hartge P, Davis S, et al. Sun exposure, vitamin D receptor gene
polymorphisms and risk of non-Hodgkin lymphoma. Cancer Causes Control 2007;18:989-99.
127. Adami J, Gridley G, Nyren O, et al. Sunlight and non-Hodgkin's lymphoma: a
population-based cohort study in Sweden. Int J Cancer 1999;80:641-5.
128. Boffetta P, van der Hel O,Kricker A, et al. Exposure to ultraviolet radiation and risk of
malignant lymphoma and multiple myeloma—a multicentre European case–control study. Int
J Epidemiol 2008;37:1080-94.
129. Porojnicu AC, Robsahm TE, Ree AH, Moan J. Season of diagnosis is a prognostic factor
in Hodgkin's lymphoma: a possible role of sun-induced vitamin D. Br J Cancer 2005;93:571-
4.
130. Talamini R, Polesel J, Montella M, et al. Food groups and risk of non-Hodgkin
lymphoma: a multicenter, case-control study in Italy. Int J Cancer 2006;118:2871-6.
131. Franceschi S, Serraino D, Carbone A, Talamini R, La Vecchia C. Dietary factors and
non-Hodgkin's lymphoma: a case-control study in the northeastern part of Italy. Nutr Cancer
1989;12:333–41.
132. Polesel J, Talamini R, Montella M, et al. Linoleic acid, vitamin D and other nutrient
intakes in the risk of non-Hodgkin lymphoma : an Italian case-control study. Ann Oncol
2006;17:713-8.
133. Lim U, Freedman DM, Hollis BW, et al. A prospective investigation of serum 25-
hydroxyvitamin D and risk of lymphoid cancers. Int J Cancer 2009;124:979-86.


                                                                                                 40
134. Mohr SB, Garland CF, Gorham ED, Grant WB, Garland FC. Could ultraviolet B
irradiance and Vitamin D be associated with lower incidence rates of lung cancer? J
Epidemiol Community Health 2008;62:69-74.
135. Zhou W, Suk R, Liu G, et al. Vitamin D is associated with improved survival in early-
stage non-small cell lung cancer patients. Cancer Epidemiol Biomarkers Prev 2005;14:2303-
9.
136. Porojnicu AC, Robsahm TE, Dahlback A, et al. Seasonal and geographical variations in
lung cancer prognosis in Norway. Does Vitamin D from the sun play a role? Lung Cancer
2007;55:263-70.
137. Zhou W, Heist RS, Liu G, et al. Circulating 25-hydroxyvitamin D levels predict survival
in early-stage non-small-cell lung cancer patients. J Clin Oncol 2007;25:479-85.
138. Heist RS, Zhou W, Wang Z, et al. Circulating 25-hydroxyvitamin D, VDR
polymorphisms, and survival in advanced non-small-cell lung cancer. J Clin Oncol
2008;26:5596-5602.
139. Zhou W, Heist RS, Liu G, et al. Polymorphisms of vitamin D receptor and survival in
early-stage non-small cell lung cancer patients. Cancer Epidemiol Biomarkers Prev
2006;15:2239-45.
140. Kikkinen A, Knekt P, Heliovaara M, et al. Vitamin D status and the risk of lung cancer: a
cohort study in Finland. Cancer Epidemiol Biomarkers Prev 2008;17:3274-8.
141. Lefkowitz ES, Garland CF. Sunlight, vitamin D, and ovarian cancer mortality rates in US
women. Int J Epidemiol 1994;23:1133-6.
142. Garland CF, Mohr SB, Gorham et al. Role of ultraviolet B irradiance and vitamin D in
prevention of ovarian cancer. Am J Prev Med 2006;6:512-4.
143. Porojnicu AC, Dahlback A, Moan J. Sun exposure and cancer survival in Norway:
changes in the risk of death with season of diagnosis and latitude. Adv Exp Med Biol.
2008;624:43-54.
144. Tworoger SS, Lee IM, Buring JE, Rosner B, Hollis BW, Hankinson SE. Plasma 25-
hydroxyvitamin D and 1,25- dihydroxyvitamin D and risk of incident ovarian cancer. Cancer
Epidemiol Biomarkers Prev 2007;16:783-8.
145. Koralek DO, Bertone-Johnson ER, Leitzmann MF, et al. Relationship between calcium,
lactose, vitamin D, and dairy products and ovarian cancer. Nutrition and Cancer 2006;56:22-
30.
146. Mohr SB, Garland CF, Gorham ED, Grant WB, Garland FC. Is ultraviolet B irradiance
inversely associated with incidence rates of endometrial cancer: an ecological study of 107


                                                                                              41
countries. J Prev Med 2007;45:327-31.
147. Neale RE; Youlden DR, Krnjacki L, Kimlin MG, van der Pols JC. Pancreas
2009;38:387-90.
148. Mohr SB, Gorham ED, Garland CF, Grant WB, Garland FC. Are low ultraviolet B and
high animal protein intake associated with risk of renal cancer. Int J Cancer 2006;119:2705-
2709.
149. Barbone F, Harland A, Partridge EE. Diet and endometrial cancer: a case-control study.
Am J Epidemiol 1993;137:393–403.
150. Negri E, La Vecchia C, Franceschi S, Levi F, Parazzini F. Intake of selected
micronutrients and the risk of endometrial carcinoma. Cancer 1996;77:917–923.
151. Salazar-Martinez E, Lazcano-Ponce E, Sanchez-Zamorano LM, Gonzalez-Lira G,
Escudero-De Los Rios P, Hernandez-Avila M. Dietary factors and endometrial cancer risk.
Results of a case-control study in Mexico. Int J Gynecol Cancer 2005;15:938–945.
152. McCullough ML, Bandera EV, Moore DF, Kushi LH. Vitamin D and calcium intake in
relation to risk of endometrial cancer: A systematic review of the literature. Prev Med
2008;46:298-302.
153. La Vecchia C, Ferraroni M, D’ Avanzo B, Decarli A, Franceschi S. Selected
micronutrient intake and the risk of gastric cancer. Cancer Epidemiol Biomarkers Prev
1994;3:393-8.
154. Chen W, Dawsey SM, Qiao YL, et al. Prospective study of serum 25(OH)-vitamin D
concentration and risk of oesophageal and gastric cancers. Br J Cancer 2007;97:123-8.
155. Skinner HG, Michaud DS, Giovannucci E, Willett WC, Colditz GA, Fuchs CS. Vitamin
D intake and the risk for pancreatic cancer in two cohort studies. Cancer Epidemiol
Biomarkers Prev 2006;15:1688-95.
156. Stolzenberg-Solomon RZ, Vieth R, Azad A, et al. A prospective nested case-control
study of vitamin D status and pancreatic cancer risk in male smokers. Cancer Research
2006;66:10213-10219.
157. Stolzenberg-Solomon RZ, Hayes RB, Horst RL, et al. Serum vitamin D and risk of
pancreatic cancer in the prostate, lung, colorectal, and ovarian screening trial. Cancer
Recearch 2009;69:1439-47.

158. Launoy G, Milan C, Day NE, Pienkowski MP, Gignoux M, Faivre J. Diet and squamous-
cell cancer of the oesophagus: a French multicentre case-control study. Int J Cancer
1998;76:7-12.


                                                                                           42
159. Bosetti C, Scotti L, Dal Maso L, et al. Micronutrients and the risk of renal cell cancer: A
case-control study from Italy. Int. J. Cancer 2006;120:892–896.
160. IARC: Solar and ultraviolet radiation. Lyon: International agency for Research on
cancer, 1992. IARC monographs on the evaluation of carcinogenic risks to humans, vol.55.
161. English DR, Armstrong BK, Kricker A, Fleming C. Sunlight and cancer. Cancer Causes
Control 1997;8:271-83.
162. Armstrong BK, Kricker A. The epidemiology of UV induced skin cancer. J Photochem
Photobiol 2001;63:8-18.
163. Elwood JM, Jopson J. Melanoma and sun exposure: an overview of published studies.
Int J Cancer 1997;73:198-203.
164. Gandini S, Sera F, Cattaruzza MF, et al. Meta-analysis of risk factors for cutaneous
melanoma: 2. Sun exposure. Eur J Cancer 2005;41:45-60.
165. Berwick M, Armstrong BK, Ben-Porat L, et al. Sun exposure and mortality from
melanoma. J Natl Cancer Inst 2005;97:195-9.

166. Heenan PJ, English DR, Holman CD, Armstrong BK. Survival among patients with
clinical stage 1 cutaneous malignant melanoma diagnosed in Western Australia in 1975/1976
and 1980/1981. Cancer 1991;68:2079-87.
167. Barnhill RL, Fine JA, Roush GC, Berwick M. Predicting five-year outcome for patients
with cutaneous melanoma in a population-based study. Cancer 1996;78:427-32.
168. Vollmer RT. Solar elastosis in cutaneous melanoma. Am J Clin Pathol 2007;128:260-64.
169. Boniol M, Armstrong BK, Dore JF. Variation in Incidence and fatality of melanoma by
season of diagnosis in New South Wales, Australia. Cancer Epidemiol Biomarkers Prev
2006; 15:524-28.
170. Rosso S, Sera F, Segnan N, Zanetti R. Sun exposure prior to diagnosis is associated with
improved survival in melanoma patients: results from a long-term follow-up study of Italian
patients. Eur J Cancer 2008;44:1275-81.
171. Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart
disease, and osteoporosis. Am J Clin Nutr 2004;79:362-71.
172. IARC. Vitamin D and Cancer. IARC Working Group Reports Vol.5, International
Agency for research on Cancer, Lyon, 25 November 2008.
173. Giovannucci E. Strengths and limitations of current epidemiologic studies: Vitamin D as
a modifier of colon and prostate cancer risk. Nutrition News 2007;65:77-79.




                                                                                              43
174. Bizzarri M, Cucina A, Valente MG, et al. Melatonin and vitamin D3 increase TGF-beta1
release and induce growth inhibition in breast cancer cell cultures. J Surg Res 2003;110:332-
7.
175. Schwartz GG. Vitamin D and the epidemiology of prostate cancer. Semin Dial
2005;18:276–89.
176. Harris DM, Go VL. Vitamin D and colon carcinogenesis. J Nutr 2004;134:3463S–71S.
177. Welsh J. Vitamin D and breast cancer: insights from animal models. Am J Clin Nutr
2004;80:1721S–4S.
178. Chen TC, Holick MF. Vitamin D and prostate cancer prevention and treatment. Trends
Endocrinol Metab 2003;14:423–30.
179. Dutch Cancer Registry. http://www.kankerregistratie.nl




                                                                                            44

								
To top