Circulating insulin-like growth factor I in relation to melanoma risk in the European prospective investigation into cancer and nutrition.

Insulin-like growth factor-I (IGF-I) regulates cell proliferation and apoptosis, and is thought to play a role in tumour development. Previous prospective studies have shown that higher circulating concentrations of IGF-I are associated with a higher risk of cancers at specific sites, including breast and prostate. No prospective study has examined the association between circulating IGF-I concentrations and melanoma risk. A nested case-control study of 1,221 melanoma cases and 1,221 controls was performed in the European Prospective Investigation into Cancer and Nutrition cohort, a prospective cohort of 520,000 participants recruited from 10 European countries. Conditional logistic regression was used to estimate odds ratios (ORs) for incident melanoma in relation to circulating IGF-I concentrations, measured by immunoassay. Analyses were conditioned on the matching factors and further adjusted for age at blood collection, education, height, BMI, smoking status, alcohol intake, marital status, physical activity and in women only, use of menopausal hormone therapy. There was no significant association between circulating IGF-I concentration and melanoma risk (OR for highest vs lowest fifth = 0.93 [95% confidence interval [CI]: 0.71 to 1.22]). There was no significant heterogeneity in the association between IGF-I concentrations and melanoma risk when subdivided by gender, age at blood collection, BMI, height, age at diagnosis, time between blood collection and diagnosis, or by anatomical site or histological subtype of the tumour (Pheterogeneity≥0.078). We found no evidence for an association between circulating concentrations of IGF-I measured in adulthood and the risk of melanoma.

Pre-diagnostic circulating insulin-like growth factor-I and bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition.

Previous in vitro and case-control studies have found an association between the insulin-like growth factor (IGF)-axis and bladder cancer risk. Circulating concentrations of IGF-I have also been found to be associated with an increased risk of several cancer types; however, the relationship between pre-diagnostic circulating IGF-I concentrations and bladder cancer has never been studied prospectively. We investigated the association of pre-diagnostic plasma concentrations of IGF-I with risk of overall bladder cancer and urothelial cell carcinoma (UCC) in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 843 men and women diagnosed with bladder cancer between 1992 and 2005 were matched with 843 controls by recruitment centre, sex, age at recruitment, date of blood collection, duration of follow-up, time of day and fasting status at blood collection using an incidence density sampling protocol. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression with adjustment for smoking status. No association was found between pre-diagnostic circulating IGF-I concentration and overall bladder cancer risk (adjusted OR for highest versus lowest fourth: 0.91, 95% CI: 0.66-1.24, ptrend = 0.40) or UCC (n of cases = 776; 0.91, 0.65-1.26, ptrend = 0.40). There was no significant evidence of heterogeneity in the association of IGF-I with bladder cancer risk by tumour aggressiveness, sex, smoking status, or by time between blood collection and diagnosis (pheterogeneity > 0.05 for all). This first prospective study indicates no evidence of an association between plasma IGF-I concentrations and bladder cancer risk.

Prediagnostic circulating concentrations of plasma insulin-like growth factor-I and risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition.

Insulin-like growth factor (IGF)-I has cancer promoting activities. However, the hypothesis that circulating IGF-I concentration is related to risk of lymphoma overall or its subtypes has not been examined prospectively. IGF-I concentration was measured in pre-diagnostic plasma samples from a nested case-control study of 1,072 cases of lymphoid malignancies and 1,072 individually matched controls from the European Prospective Investigation into Cancer and Nutrition. Odds ratios (ORs) and confidence intervals (CIs) for lymphoma were calculated using conditional logistic regression. IGF-I concentration was not associated with overall lymphoma risk (multivariable-adjusted OR for highest versus lowest third = 0.77 [95% CI = 0.57-1.03], ptrend = 0.06). There was no statistical evidence of heterogeneity in this association with IGF-I by sex, age at blood collection, time between blood collection and diagnosis, age at diagnosis, or body mass index (pheterogeneity for all ≥ 0.05). There were no associations between IGF-I concentration and risk for specific BCL subtypes, T-cell lymphoma or Hodgkin lymphoma, although number of cases were small. In this European population, IGF-I concentration was not associated with risk of overall lymphoma. This study provides the first prospective evidence on circulating IGF-I concentrations and risk of lymphoma. Further prospective data are required to examine associations of IGF-I concentrations with lymphoma subtypes.

The association of plasma IGF-I with dietary, lifestyle, anthropometric, and early life factors in postmenopausal women.

OBJECTIVE: Higher circulating concentrations of insulin like growth factor (IGF-I) are associated with an increased risk of breast cancer. The objective of this study was to investigate associations between circulating IGF-I concentrations and dietary factors (intakes of protein, dairy protein, and alcohol), lifestyle factors (smoking and HT use), anthropometric indices (height and adiposity) and factors in early life (birth weight, having been breastfed, body size at age 10, and at age 20) in postmenopausal women in the UK. DESIGN: An analysis of plasma IGF-I concentrations (measured by immunoassay) in 1883 postmenopausal women. Multivariate analysis was used to examine correlates of plasma IGF-I concentrations. RESULTS: Women in the highest quintile of total protein and dairy protein intakes had, respectively, 7.6% and 5.5% higher plasma IGF-I concentrations than women in the lowest quintile (p trend <0.05 for both). Other factors significantly (p<0.05) associated with reduced IGF-I concentrations were: consuming 14 or more vs 3-7 alcoholic drinks per week (8.8% lower IGF-I); current vs non-current HT users (9.9% lower IGF-I); current use of oestrogen alone vs oestrogen+progestagen (16.9% lower IGF-I); obese vs overweight (6.8% lower IGF-I); and women who reported wearing larger vs smaller clothes sizes at age 20 (4.9% lower IGF-I). CONCLUSIONS: This study in post-menopausal women identified several potentially modifiable determinants of circulating IGF-I concentrations. There is now strong evidence from this and other studies that IGF-I concentrations are associated with dietary protein intakes.

Insulin-like growth factor-i and risk of differentiated thyroid carcinoma in the European prospective investigation into cancer and nutrition.

BACKGROUND: Little is known about the causes of thyroid cancer, but insulin-like growth factor-I (IGF-I) might play an important role in its development due to its mitogenic and antiapoptotic properties. METHODS: This study prospectively investigated the association between serum IGF-I concentrations and risk of differentiated thyroid carcinoma in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition. The 345 incident cases of differentiated thyroid carcinoma were individually matched to 735 controls by study center, sex and age, date, time, and fasting status at blood collection, follow-up duration, and for women menopausal status, use of exogenous hormones, and phase of menstrual cycle at blood collection. Serum IGF-I concentrations were measured by immunoassay, and risk of differentiated thyroid cancer in relation to IGF-I concentration was estimated using conditional logistic regression. RESULTS: There was a positive association between IGF-I concentrations and risk of differentiated thyroid carcinoma: the OR for a doubling in IGF-I concentration was 1.48 (95% confidence interval, 1.06-2.08; Ptrend = 0.02). The positive association with IGF-I was stable over time between blood collection and cancer diagnosis. CONCLUSION: These findings suggest that IGF-I concentrations may be positively associated with risk of differentiated thyroid carcinoma. IMPACT: This study provides the first prospective evidence of a potential association between circulating IGF-I concentrations and risk of differentiated thyroid carcinoma and may prompt the further investigations needed to confirm the association.

First-morning urinary melatonin and breast cancer risk in the Guernsey Study.

It has been hypothesized that suppressed nocturnal melatonin production is associated with an increased risk of breast cancer, but results from several small prospective studies of the association have been inconclusive. We examined the association between nocturnal melatonin and breast cancer risk in a case-control study nested within the Guernsey III Study, a British prospective cohort study (1977-2009). Concentrations of 6-sulfatoxymelatonin were measured in prediagnostic first-morning urine samples from 251 breast cancer cases and 727 matched controls. Conditional logistic regression models were used to calculate odds ratios for breast cancer in relation to 6-sulfatoxymelatonin level. No significant association was found between 6-sulfatoxymelatonin level and breast cancer risk, either overall (for highest third vs. lowest, multivariable-adjusted odds ratio = 0.90, 95% confidence interval: 0.61, 1.33) or by menopausal status. However, in a meta-analysis of all published prospective data, including 1,113 cases from 5 studies, higher 6-sulfatoxymelatonin levels were associated with lower breast cancer risk (for highest fourth vs. lowest, odds ratio = 0.81, 95% confidence interval: 0.66, 0.99). In summary, we found no evidence that 6-sulfatoxymelatonin level in a first-morning urine sample was associated with breast cancer risk among British women. However, overall the published data suggest a modest inverse association between melatonin levels and breast cancer risk. Further data are needed to confirm this association.

Insulin-like growth factor-I concentration and risk of prostate cancer: results from the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: High circulating insulin-like growth factor-I (IGF-I) concentrations have been associated with increased risk for prostate cancer in several prospective epidemiological studies. In this study, we investigate the association between circulating IGF-I concentration and risk of prostate cancer over the long term in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. METHODS: In a nested case-control design, 1,542 incident prostate cancer cases from eight European countries were individually matched to 1,542 controls by study center, age at recruitment, duration of follow-up, time of day, and duration of fasting at blood collection. Conditional logistic regression models were used to calculate risk for prostate cancer associated with IGF-I concentration, overall and by various subgroups. RESULTS: Circulating IGF-I concentration was associated with a significant increased risk for prostate cancer [OR for highest vs. lowest quartile, 1.69; 95% confidence interval (CI), 1.35-2.13; P(trend) = 0.0002]. This positive association did not differ according to duration of follow-up [ORs for highest vs. lowest quartile were 2.01 (1.35-2.99), 1.37 (0.94-2.00), and 1.80 (1.17-2.77) for cancers diagnosed <4, 4-7, and >7 years after blood collection, respectively (P(heterogeneity) = 0.77)] or by stage, grade, and age at diagnosis or age at blood collection (all subgroups P(heterogeneity) >0.05). CONCLUSION: In this European population, high circulating IGF-I concentration is positively associated with risk for prostate cancer over the short and long term. IMPACT: As IGF-I is the only potentially modifiable risk factor so far identified, research into the effects of reducing circulating IGF-I levels on subsequent prostate cancer risk is warranted.

Incidence of breast cancer and its subtypes in relation to individual and multiple low-penetrance genetic susceptibility loci.

CONTEXT: There is limited evidence on how the risk of breast cancer and its subtypes depend on low-penetrance susceptibility loci, individually or in combination. OBJECTIVE: To analyze breast cancer risk, overall and by tumor subtype, in relation to 14 individual single-nucleotide polymorphisms (SNPs) previously linked to the disease, and in relation to a polygenic risk score. DESIGN, SETTING, AND PARTICIPANTS: Study of 10,306 women with breast cancer (mean age at diagnosis, 58 years) and 10,393 women without breast cancer who in 2005-2008 provided blood samples for genotyping in a large prospective study of UK women; and meta-analysis of these results and of other published results. MAIN OUTCOME MEASURES: Estimated per-allele odds ratio (OR) for individual SNPs, and cumulative incidence of breast cancer to age 70 years in relation to a polygenic risk score based on the 4, 7, or 10 SNPs most strongly associated with risk. RESULTS: Odds ratios for breast cancer were greatest for FGFR2-rs2981582 and TNRC9-rs3803662 and, for these 2 SNPs, were significantly greater for estrogen receptor (ER)-positive than for ER-negative disease, both in our data and in meta-analyses of all published data (pooled per-allele ORs [95% confidence intervals] for ER-positive vs ER-negative disease: 1.30 [1.26-1.33] vs 1.05 [1.01-1.10] for FGFR2; interaction P < .001; and 1.24 [1.21-1.28] vs 1.12 [1.07-1.17] for TNRC9; interaction P < .001). The next strongest association was for 2q-rs13387042, for which the per-allele OR was significantly greater for bilateral than unilateral disease (1.39 [1.21-1.60] vs 1.15 [1.11-1.20]; interaction P = .008) and for lobular than ductal tumors (1.35 [1.23-1.49] vs 1.10 [1.05-1.15]; interaction P < .001). The estimated cumulative incidence (95% confidence interval) of breast cancer to age 70 years among women in the top and bottom fifths of a polygenic risk score based on 7 SNPs was 8.8% (8.3%-9.4%) and 4.4% (4.2%-4.8%), respectively. For ER-positive disease the corresponding risks were 7.4% (6.9%-8.0%) and 3.4% (3.1%-3.8%), respectively; while for ER-negative disease they were 1.4% (1.2%-1.6%) and 1.0% (0.8%-1.2%). The findings did not differ materially according to the number of SNPs included in the polygenic risk model. CONCLUSIONS: The polygenic risk score was substantially more predictive of ER-positive than of ER-negative breast cancer, particularly for absolute risk.

Gene-environment interactions in 7610 women with breast cancer: prospective evidence from the Million Women Study.

BACKGROUND: Information is scarce about the combined effects on breast cancer incidence of low-penetrance genetic susceptibility polymorphisms and environmental factors (reproductive, behavioural, and anthropometric risk factors for breast cancer). To test for evidence of gene-environment interactions, we compared genotypic relative risks for breast cancer across the other risk factors in a large UK prospective study. METHODS: We tested gene-environment interactions in 7610 women who developed breast cancer and 10 196 controls without the disease, studying the effects of 12 polymorphisms (FGFR2-rs2981582, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, 2p-rs4666451, 5p12-rs981782, CASP8-rs1045485, LSP1-rs3817198, 5q-rs30099, TGFB1-rs1982073, and ATM-rs1800054) in relation to prospectively collected information about ten established environmental risk factors (age at menarche, parity, age at first birth, breastfeeding, menopausal status, age at menopause, use of hormone replacement therapy, body-mass index, height, and alcohol consumption). FINDINGS: After allowance for multiple testing none of the 120 comparisons yielded significant evidence of a gene-environment interaction. By contrast with previous suggestions, there was little evidence that the genotypic relative risks were affected by use of hormone replacement therapy, either overall or for oestrogen-receptor-positive disease. Only one of the 12 polymorphisms was correlated with any of the ten other risk factors: carriers of the high-risk C allele of MAP3K1-rs889312 were significantly shorter than non-carriers (mean height 162.4 cm [95% CI 162.1-162.7] vs 163.1 cm [162.9-163.2]; p=0.01 after allowance for multiple testing). INTERPRETATION: Risks of breast cancer associated with low-penetrance susceptibility polymorphisms do not vary significantly with these ten established environmental risk factors. FUNDING: Cancer Research UK and the UK Medical Research Council.

Association between endogenous plasma hormone concentrations and fracture risk in men and women: the EPIC-Oxford prospective cohort study.

Sex steroids have an important role in bone health, however previous studies on fracture risk have been carried out in older populations. The EPIC-Oxford study is a prospective cohort of men and women living in the UK. Five years after recruitment, participants self-reported previous fractures. Sex steroid concentrations (plasma estradiol, testosterone and sex hormone binding globulin) were measured in 436 cases (155 men, 46 premenopausal women and 235 postmenopausal women) with an incident fracture and 868 matched controls. Fracture risk was inversely related to concentrations of estradiol among men (RR for a doubling of estradiol 0.35, 95% CI 0.44-0.96) but there was no association between fracture risk and testosterone levels. There were no clear associations between fracture risk and hormone levels among postmenopausal women, however there was suggestion of an inverse association for both estradiol and testosterone as the RR in the highest compared with the lowest tertile for estradiol was 0.74 (95% CI 0.46, 1.18) and testosterone was 0.75 (95% CI 0.49, 1.16). Among premenopausal women fracture risk was inversely associated with levels of testosterone (RR for doubling of testosterone 0.46, 95% CI 0.26-0.81), with no association between estradiol and fracture risk. SHBG was not associated with risk of fracture among either men or women. In summary, this study finds evidence of an inverse association between endogenous estradiol and risk of fracture in men, and between endogenous testosterone and risk of fracture in premenopausal women but no clear associations among postmenopausal women.

Association between plasma 25-hydroxyvitamin D levels and fracture risk: the EPIC-Oxford study.

The importance of vitamin D for bone health is well established, but few data exist on the relation between plasma levels of 25-hydroxyvitamin D and risk of fracture. The authors examined this association within the EPIC-Oxford (European Prospective Investigation into Cancer and Nutrition-Oxford cohort) study of men and women in the United Kingdom (1993-1999). Five years after recruitment, participants completed a follow-up questionnaire where fracture incidence was self-reported. Plasma 25-hydroxyvitamin D concentration was measured in 730 incident fracture cases and 1,445 matched controls. There was a clear association between plasma 25-hydroxyvitamin D concentration and month of blood draw, the highest values being during the summer months. Among women, there were significant relations between 25-hydroxyvitamin D levels and age, body mass index, marital status, use of hormone therapy, physical activity, diet group, dietary intake of vitamin D, and alcohol. Similar relations were seen among men, although often they were nonsignificant because of smaller numbers. There was no evidence of an association between plasma 25-hydroxyvitamin D and fracture risk for men or women; the relative risks associated with a doubling of plasma 25-hydroxyvitamin D were 1.15 (95% confidence interval: 0.82, 1.61) and 0.95 (95% confidence interval: 0.80, 1.13), respectively. These results were not affected by adjustment for potential confounders and were consistent across a number of subgroups.