Visalini Nair-Shalliker

Sun exposure may increase risk of prostate cancer in the high UV environment of New South Wales, Australia: A case–control study

Ultraviolet (UV) radiation in sunlight may influence risk of prostate cancer. In New South Wales (NSW), Australia, we examined the relationship between sun exposure at 30 and 50 years of age and risk of prostate cancer in a case–control study combining the NSW prostate cancer care and outcome study (cases) and the NSW non‐Hodgkins lymphoma study (controls). Prostate cancer risk increased with increasing estimated sun exposure (adjusted OR for highest vs. lowest quartiles of average weekly sun exposure in the warmer months 2.07 95% CI: 1.36–3.15) and this increase was most evident with weekend sun exposure (adjusted OR = 5.55, 95% CI: 2.94–10.48). High sun sensitivity was also positively associated with risk for prostate cancer (adjusted OR = 1.63, 95% CI: 1.09–2.44). The apparent effects of weekly sun exposure did not vary by disease aggressiveness. Our results suggest that increasing sun exposure in mid‐adult years increases prostate cancer risk in a high ambient solar UV environment. Given that previous studies, conducted mainly in low solar UV environments, have generally found evidence of a negative association, our findings suggest there may be a U‐shaped relationship between solar UV exposure and prostate cancer. Further studies are needed to test the hypothesis that high solar UV exposure is a risk factor for prostate cancer and to explore possible mechanisms for such an association.

Adult body size, sexual history and adolescent sexual development, may predict risk of developing prostate cancer: Results from the New South Wales Lifestyle and Evaluation of Risk Study (CLEAR)

Prostate cancer (PC) is the most common non‐cutaneous cancer in men worldwide. The relationships between PC and possible risk factors for PC cases (n = 1,181) and male controls (n = 875) from the New South Wales (NSW) Cancer, Lifestyle and Evaluation of Risk Study (CLEAR) were examined in this study. The associations between PC risk and paternal history of PC, body mass index (BMI), medical conditions, sexual behaviour, balding pattern and puberty, after adjusting for age, income, region of birth, place of residence, and PSA testing, were examined. Adjusted risk of PC was higher for men with a paternal history of PC (OR = 2.31; 95%CI: 1.70–3.14), personal history of prostatitis (OR = 2.30; 95%CI: 1.44–3.70), benign prostatic hyperplasia (OR = 2.29; 95%CI: 1.79–2.93), being overweight (vs. normal; OR = 1.24; 95%CI: 0.99–1.55) or obese (vs. normal; OR = 1.44; 95%CI: 1.09–1.89), having reported more than seven sexual partners in a lifetime (vs. < 3 partners; OR = 2.00; 95%CI: 1.49–2.68), and having reported more than 5 orgasms a month prior to PC diagnosis (vs. ≤3 orgasms; OR = 1.59; 95%CI: 1.18–2.15). PC risk was lower for men whose timing of puberty was later than their peers (vs. same as peers; OR = 0.75; 95%CI: 0.59–0.97), and a smaller risk reduction of was observed in men whose timing of puberty was earlier than their peers (vs. same as peers; OR = 0.85; 95%CI: 0.61–1.17). No associations were found between PC risk and vertex balding, erectile function, acne, circumcision, vasectomy, asthma or diabetes. These results support a role for adult body size, sexual activity, and adolescent sexual development in PC development.

Obesity, physical activity and cancer risks: Results from the Cancer, Lifestyle and Evaluation of Risk Study (CLEAR)

INTRODUCTION Physical activity (PA) has been associated with lower risk of cardiovascular diseases, but the evidence linking PA with lower cancer risk is inconclusive. We examined the independent and interactive effects of PA and obesity using body mass index (BMI) as a proxy for obesity, on the risk of developing prostate (PC), postmenopausal breast (BC), colorectal (CRC), ovarian (OC) and uterine (UC) cancers. METHODS We estimated odds ratios (OR) and 95% confidence intervals (CI), adjusting for cancer specific confounders, in 6831 self-reported cancer cases and 1992 self-reported cancer-free controls from the Cancer Lifestyle and Evaluation of Risk Study, using unconditional logistic regression. RESULTS For women, BMI was positively associated with UC risk; specifically, obese women (BMI≥30kg/m2) had nearly twice the risk of developing UC compared to women with healthy-BMI-range (<25kg/m2) (OR=1.99;CI:1.31-3.03). For men, BMI was also positively associated with the risk of developing any cancer type, CRC and PC. In particular, obese men had 37% (OR=1.37;CI:1.11-1.70), 113% (OR=2.13;CI:1.55-2.91) and 51% (OR=1.51;CI:1.17-1.94) higher risks of developing any cancer, CRC and PC respectively, when compared to men with healthy-BMI-range (BMI<25kg/m2). Among women, PA was inversely associated with the risks of CRC, UC and BC. In particular, the highest level of PA (versus nil activity) was associated with reduced risks of CRC (OR=0.60;CI:0.44-0.84) and UC (OR=0.47;CI:0.27-0.80). Reduced risks of BC were associated with low (OR=0.66;CI:0.51-0.86) and moderate (OR=0.72;CI:0.57-0.91) levels of PA. There was no association between PA levels and cancer risks for men. We found no evidence of an interaction between BMI and PA in the CLEAR study. CONCLUSION These findings suggest that PA and obesity are independent cancer risk factors.

The association between personal sun exposure, serum vitamin D and global methylation in human lymphocytes in a population of healthy adults in South Australia

BACKGROUND There is a positive association between solar UV exposure and micronucleus frequency in peripheral blood lymphocytes (PBL) and this association may be stronger when serum vitamin D (25(OH)D) levels are insufficient (<50 nmol/L). Micronucleus formation can result from global hypomethylation of DNA repeat sequences. The aim of this analysis was to evaluate the relationship between solar UV exposure and methylation pattern in LINE-1 repetitive elements in PBL DNA and to see if serum 25(OH)D levels modify it. METHOD Personal solar UV exposure was estimated from hours of outdoor exposure over 6 weeks recalled at the time of blood collection in 208 male and female participants living in South Australia. Methylation in LINE-1 repetitive elements was assessed in PBL using pyrosequencing. RESULTS Methylation in LINE-1 decreased with increasing solar UV exposure (% decrease = 0.5% per doubling of sUV; 95%CI: -0.7 to -0.2 p(value) = 0.00003). Although there was no correlation between LINE-1 methylation and micronucleus frequency, there was a 4.3% increase (95%CI: 0.6-8.1 p-value = 0.02) in nucleoplasmic bridges and a 4.3% increase in necrosis (CI: 1.9-6.8 p-value = 0.0005) for every 1% increase in LINE-1 methylation. Serum 25(OH)D was not associated with DNA methylation; or did it modify the association of solar UV with DNA methylation. CONCLUSION Exposure to solar UV radiation may reduce DNA methylation in circulating lymphocytes. This association does not appear to be influenced or mediated by vitamin D status.

Sunlight and vitamin D affect DNA damage, cell division and cell death in human lymphocytes: a cross-sectional study in South Australia

The ultraviolet (UV)-B spectrum in solar UV radiation is essential for stimulating the epidermal production of vitamin D but also damages DNA and causes cancer in exposed cells. We examined the role of solar UV in inducing DNA damage in blood lymphocytes and the possible modulation of this damage by serum 25-hydroxy vitamin D (25(OH)D) in 207 male and female participants from South Australia. Personal solar UV exposure was estimated from hours of outdoor exposure recalled at the time of blood collection for analysis of DNA damage in lymphocytes, using the cytokinesis-block micronucleus cytome (CBMN-cyt) assay and of serum 25(OH)D. We examined the association between solar UV exposure, serum 25(OH)D and DNA damage using multiple linear regression, with age, sex, body mass index and alcohol consumption as covariates. The frequency of cells with micronuclei (a biomarker of chromosome breakage or loss) increased with increasing sun exposure [% increase = 5.24; 95% confidence interval (CI): 0.35 to 10.37 P-value = 0.04] but cells with nucleoplasmic bridges (a biomarker of misrepair of DNA strand breaks or telomere end fusions) decreased (% increase = -8.38; 95% CI: -14.32 to -2.03 P-value = 0.01). There was also a fall in the nuclear division index (NDI) (% increase = -1.01; 95% CI: -2.00 to 0.00 P-value = 0.05), suggesting diminished mitogenic response and, possibly, immune suppression. There was no overall relationship between 25(OH)D and DNA damage. There were, however, weak modulating effects of 25(OH)D on the associations of solar UV exposure with micronucleus formation and with NDI (P-interaction = 0.03 and 0.05, respectively), where the increase in micronuclei and fall in NDI with increasing solar UV were greater at serum 25(OH)D levels <50 nmol/l. Thus, the influence of solar UV exposure in causing DNA damage or immune suppression in internal tissues may be stronger when vitamin D levels are low.

The Cancer, Lifestyle and Evaluation of Risk Study (CLEAR): Rationale and design of an unmatched "case-spouse control" study of over 10,000 participants in New South Wales, Australia

INTRODUCTION The New South Wales (NSW) Cancer, Lifestyle and Evaluation of Risk Study (CLEAR) is an open epidemiological bioresource, using an all cancer unmatched case-spouse control design. Participant characteristics and selected confirmed associations are compared to published estimates: current smoking and lung cancer; country of birth and melanoma; body mass index (BMI) and bowel cancer; and paternal history of prostate cancer and prostate cancer, to illustrate the validity of this design. MATERIAL AND METHODS Cases are NSW residents, ≥18 years, with an incident cancer of any type. Controls are cancer-free spouses of cases. Participants complete a consent form, a questionnaire, and provide an optional blood sample. For analyses, odds ratios for males and females are calculated for cancers and exposures of interest, by sex-matching controls to cases. RESULTS 10,816 participants (8569 cases, 2247 controls, 54% female) recruited to-date, median age: 61.6 y cases, 61.3 y controls. The top five cancer types are female breast (n=1691), prostate (n=1102), bowel (n=888), melanoma (n=608), and lung (n=265). Adjusted odds ratios (OR) were: 20.65 (95% CI: 13.25-32.19) for lung cancer in current versus never smokers; 1.16 (1.05-1.28) for bowel cancer per 5 kg/m(2) increment in BMI; 1.41 (1.01-1.96) for melanoma in Australian-born compared to those born in UK/Ireland; and 2.47 (1.82-3.37) for prostate cancer in men with versus without a paternal history of prostate cancer. DISCUSSION This study design, where controls are the spouses of cases diagnosed with a variety of cancers and which are analysed unmatched, avoids potential biases due to overmatching, considered problematic in standard case-spouse control studies, and illustrates that risk estimates analysed are consistent with the published literature. CLEAR methodology provides a practical design to advance local knowledge on the causes of various leading and emerging cancers.

An initial melanoma diagnosis may increase the subsequent risk of prostate cancer: Results from the New South Wales Cancer Registry

Emerging evidence suggests that a diagnosis of cutaneous melanoma (CM) may be associated with prostate cancer (PC) incidence. We examined if the incidence of CM was associated with an increased subsequent risk of PC. We used data from the New South Wales Cancer Registry for all CM and PC cases diagnosed between January 1972 and December 2008. We calculated the age standardized incidence ratio (SIR) and 95% confidence intervals (95% CI) for PC incidence following a CM diagnosis, applying age- and calendar- specific rates to the appropriate person years at risk. We determined rate ratio (RR) and 95% CI of PC incidence according to specified socio-demographic categories and disease related characteristics, using a negative binomial model. There were 143,594 men diagnosed with PC or CM in the study period and of these 101,198 and 42,396 were diagnosed with PC and CM, respectively, as first primary cancers. Risk of PC incidence increased following CM diagnosis (n = 2,114; SIR = 1.25; 95% CI:1.20.8-1.31: p < 0.0001), with the increased risk apparent in men diagnosed with localised CM (n = 1,862;SIR = 1.26; 95% CI:1.20–1.32). CM diagnosis increased the subsequent risk of PC incidence. This raises the potential for future PC risk to be discussed with newly diagnosed males with CM.

Factors associated with prostate specific antigen testing in Australians: Analysis of the New South Wales 45 and Up Study

Australia has one of the highest incidence rates of prostate cancer (PC) worldwide, due in part to widespread prostate specific antigen (PSA) testing. We aimed to identify factors associated with PSA testing in Australian men without a diagnosis of prostate cancer or prior prostate disease. Participants were men joining the 45 and Up Study in 2006–2009, aged ≥45 years at recruitment. Self-completed questionnaires were linked to cancer registrations, hospitalisations, health services data and deaths. Men with a history of PC, radical prostatectomy or a “monitoring” PSA test for prostate disease were excluded. We identified Medicare reimbursed PSA tests during 2012–2014. Multivariable logistic regression was used to estimate adjusted odds ratios (OR) for the association between having PSA tests and factors of interest. Of the 62,765 eligible men, 51.8% had at least one screening PSA test during 2012–2014. Factors strongly associated with having a PSA test included having 27+ general practitioner consultations (versus 3–9 consultations; OR = 2.00; 95%CI = 1.90–2.11), benign prostatic hyperplasia treatment (versus none; OR = 1.59(95%CI = 1.49–1.70), aged 60–69 years (versus 50–59 years; OR = 1.54; 95%CI = 1.48–1.60). These results emphasise the important role of primary care in decision making about PSA testing.

Associations between sun sensitive pigmentary genes and serum prostate specific antigen levels

Background Melanoma and prostate cancer may share risk factors. This study examined the association between serum PSA levels, which is a risk factor for prostate cancer, and variants in some melanoma-associated pigmentary genes. Methods We studied participants, all aged 70+ years, in the Concord Health and Ageing in Men Project who had no history of prostatitis or received treatment for prostate disease (n = 1033). We genotyped variants in MC1R (rs1805007, rs1805008), ASIP (rs4911414, rs1015362), SLC45A2 (rs28777, rs16891982), IRF4 (rs12203592), TYRP1 (rs1408799), TYR (rs1126809, rs1042602), SLC24A2 (rs12896399), and OCA2 (rs7495174). Generalised linear dominant models with Poisson distribution, log link functions and robust variance estimators estimated adjusted percentage differences (%PSA) in mean serum PSA levels (ng/mL) between variant and wildtype (0%PSA = reference) genotypes, adjusting for age, body mass index, serum 25OHD levels and birth regions (Australia or New Zealand (ANZ), Europe or elsewhere). Results Serum PSA levels were strongly associated with advancing age and birth regions: mean PSA levels were lower in Europe-born (-29.7%) and elsewhere-born (-11.7%) men than ANZ-born men (reference). Lower %PSA was observed in men with variants in SLC45A2: rs28777 (-19.6;95%CI: -33.5, -2.7), rs16891982 (-17.3;95%CI:-30.4,-1.7) than in wildtype men (reference). There were significant interactions between birth regions and PSA levels in men with variants in MC1R (rs1805007; p-interaction = 0.0001) and ASIP (rs4911414; p-interaction = 0.007). For these genes %PSA was greater in ANZ-born men and lower in Europe- and elsewhere-born men with the variant than it was in wildtype men. In a post hoc analysis, serum testosterone levels were increased in men with MC1R rs1805007 and serum dihydrotestosterone in men with ASIP rs1015362. Conclusion Men with SNPs in SLC45A2, who have less sun sensitive skin, have lower PSA levels. Men with SNPs in MC1R and ASIP, who have more sun sensitive skin, and were born in ANZ, have higher PSA levels. Androgens may modify these apparent associations of pigmentary genes and sun exposure with PSA levels. Impact PSA levels and possibly prostate cancer risk may vary with sun sensitivity and sun exposure, the effects of which might be modified by androgen levels.

Abstract 2514: The association between personal sun exposure, serum vitamin D and global methylation in human lymphocytes, in a population of healthy adults in South Australia.

A positive association between solar UV exposure and micronuclei (MN) frequency (biomarker of chromosome breakage or loss) was previously reported with the effect of solar UV exposure on DNA damage greater when serum vitamin D (25(OH)D) levels were insufficient ( value =0.00003). There was no correlation between LINE-1 methylation and MN frequency, however for every 1% increase in LINE-1 methylation there was a corresponding 4.3% (95% CI:0.6-8.1 p-value=0.02) increase in nucleoplasmic bridges (biomarker of dicentric chromosome formation) and a 4.3% increase in necrosis (CI:1.9-6.8 p-value=0.0005). This suggests that the reduction in LINE-1 methylation with increased solar exposure may be too small to explain increases in MN frequency and therefore other mechanisms must be considered. There was no clear relationship between 25(OH)D and DNA methylation. In conclusion, the inverse relationship between solar UV radiation and LINE-1 DNA methylation status suggests a role for solar UV exposure in influencing genomic methylation patterns, which in turn appears to be associated with specific biomarkers of cell death (necrosis) and chromosomal stability (NPBs). If this holds true, then the use of LINE-1 hypomethylation, and possibly methylation of other sequences such as Alu repeats, as a biomarker for studying the role of UV in inducing both skin and internal cancers (and other diseases) might deserve further consideration. Citation Format: Visalini Nair-Shalliker, Varinderpal Dhillon, Mark Clements, Bruce K. Armstrong, Michael Fenech. The association between personal sun exposure, serum vitamin D and global methylation in human lymphocytes, in a population of healthy adults in South Australia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2514. doi:10.1158/1538-7445.AM2013-2514