Marina Kvaskoff

IRF4 Variants Have Age-Specific Effects on Nevus Count and Predispose to Melanoma

High melanocytic nevus count is a strong predictor of melanoma risk. A GWAS of nevus count in Australian adolescent twins identified an association of nevus count with the interferon regulatory factor 4 gene (IRF4 [p = 6 x 10(-9)]). There was a strong genotype-by-age interaction, which was replicated in independent UK samples of adolescents and adults. The rs12203592(*)T allele was associated with high nevus counts and high freckling scores in adolescents, but with low nevus counts and high freckling scores in adults. The rs12203592(*)T increased counts of flat (compound and junctional) nevi in Australian adolescent twins, but decreased counts of raised (intradermal) nevi. In combined analysis of melanoma case-control data from Australia, the UK, and Sweden, the rs12203592(*)C allele was associated with melanoma (odds ratio [OR] 1.15, p = 4 x 10(-3)), most significantly on the trunk (OR = 1.33, p = 2.5 x 10(-5)). The melanoma association was corroborated in a GWAS performed by the GenoMEL consortium for an adjacent SNP, rs872071 (rs872071(*)T: OR 1.14, p = 0.0035; excluding Australian, the UK, and Swedish samples typed at rs12203592: OR 1.08, p = 0.08).

Endometriosis: a high-risk population for major chronic diseases?

BACKGROUND Despite an estimated prevalence of 10% in women, the etiology of endometriosis remains poorly understood. Over recent decades, endometriosis has been associated with risk of several chronic diseases, such as cancer, autoimmune diseases, asthma/atopic diseases and cardiovascular diseases. A deeper understanding of these associations is needed as they may provide new leads into the causes or consequences of endometriosis. This review summarizes the available epidemiological findings on the associations between endometriosis and other chronic diseases and discusses hypotheses for underlying mechanisms, potential sources of bias and methodological complexities. METHODS We performed a comprehensive search of the PubMed/Medline and ISI Web of Knowledge databases for all studies reporting on the associations between endometriosis and other diseases published in English through to May 2014, using numerous search terms. We additionally examined the reference lists of all identified papers to capture any additional articles that were not identified through computer searches. RESULTS We identified 21 studies on the associations between endometriosis and ovarian cancer, 14 for breast cancer, 8 for endometrial cancer, 4 for cervical cancer, 12 for cutaneous melanoma and 3 for non-Hodgkins lymphoma, as well as 9 on the links between endometriosis and autoimmune diseases, 6 on the links with asthma and atopic diseases, and 4 on the links with cardiovascular diseases. Endometriosis patients were reported to be at higher risk of ovarian and breast cancers, cutaneous melanoma, asthma, and some autoimmune, cardiovascular and atopic diseases, and at decreased risk of cervical cancer. CONCLUSIONS Increasing evidence suggests that endometriosis patients are at higher risk of several chronic diseases. Although the underlying mechanisms are not yet understood, the available data to date suggest that endometriosis is not harmless with respects to womens long-term health. If these relationships are confirmed, these findings may have important implications in screening practices and in the management and care of endometriosis patients.

Prediagnostic circulating vitamin D levels and risk of hepatocellular carcinoma in European populations: A nested case-control study

The association between vitamin D status and hepatocellular carcinoma (HCC) has not been well investigated, despite experimental evidence supporting an important role of vitamin D in liver pathophysiology. Our objective was to investigate the association between prediagnostic circulating 25‐hydroxyvitamin D [25(OH)D] serum levels and the risk of HCC in a prospective, nested case‐control study among 520,000 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Each case (n = 138) diagnosed between 1992 and 2010 was matched to one control by age, sex, study center, date and time of blood collection, and fasting status. Serum baseline levels of 25(OH)D were measured by liquid chromatography/tandem mass spectrometry. Multivariable incident rate ratios (IRRs) of HCC associated with continuous (per 10 nmol/L) or categorical levels (tertiles or a priori‐defined categories) of prediagnostic 25(OH)D were calculated using conditional logistic regression. Higher 25(OH)D levels were associated with a 49% reduction in the risk of HCC (highest versus lowest tertile: multivariable IRR = 0.51, 95% confidence interval [CI], 0.26 to 0.99; Ptrend = 0.04; per 10 nmol/L increase: IRR = 0.80, 95% CI, 0.68‐0.94). The finding did not vary substantially by time from enrolment to diagnosis, and did not change after adjustment for biomarkers of preexisting liver damage, nor chronic infection with hepatitis B or C viruses. The findings were not modified by body size or smoking status. Conclusion: In this prospective study on western European populations, serum levels of 25(OH)D were inversely associated with the risk of HCC. Given the rising incidence of this cancer in low‐risk developed countries and the strong public health interest surrounding the potentially cancer‐protective roles of vitamin D, additional studies in different populations are required. (Hepatology 2014;60:1222–1230)

The Queensland Study of Melanoma: Environmental and Genetic Associations (Q-MEGA); Study Design, Baseline Characteristics, and Repeatability of Phenotype and Sun Exposure Measures

Cutaneous malignant melanoma (CMM) is a major health issue in Queensland, Australia, which has the worlds highest incidence. Recent molecular and epidemiologic studies suggest that CMM arises through multiple etiological pathways involving gene-environment interactions. Understanding the potential mechanisms leading to CMM requires larger studies than those previously conducted. This article describes the design and baseline characteristics of Q-MEGA, the Queensland Study of Melanoma: Environmental and Genetic Associations, which followed up 4 population-based samples of CMM patients in Queensland, including children, adolescents, men aged over 50, and a large sample of adult cases and their families, including twins. Q-MEGA aims to investigate the roles of genetic and environmental factors, and their interaction, in the etiology of melanoma. Three thousand, four hundred and seventy-one participants took part in the follow-up study and were administered a computer-assisted telephone interview in 2002-2005. Updated data on environmental and phenotypic risk factors, and 2777 blood samples were collected from interviewed participants as well as a subset of relatives. This study provides a large and well-described population-based sample of CMM cases with follow-up data. Characteristics of the cases and repeatability of sun exposure and phenotype measures between the baseline and the follow-up surveys, from 6 to 17 years later, are also described.

Plasma 25-hydroxyvitamin D and the risk of breast cancer in the European prospective investigation into cancer and nutrition: A nested case–control study

Experimental evidence suggests that vitamin D might play a role in the development of breast cancer. Although the results of case–control studies indicate that circulating 25‐hydroxyvitamin D [25(OH)D] is inversely associated with the risk of breast cancer, the results of prospective studies are inconsistent. A case–control study embedded in the European Prospective Investigation into Cancer and Nutrition (EPIC) was carried out comprising 1,391 incident breast cancer cases and 1,391 controls. Multivariable conditional logistic regression models did not reveal a significant overall association between season‐standardized 25(OH)D levels and the risk of breast cancer (ORQ4–Q1 [95% CI]: 1.07 [0.85–1.36], ptrend = 0.67). Moreover, 25(OH)D levels were not related to the risks of estrogen receptor positive tumors (ORQ4–Q1 [95% CI]: 0.97 [0.67–1.38], ptrend = 0.90) and estrogen receptor negative tumors (ORQ4–Q1 [95% CI]: 0.97 [0.66–1.42], ptrend = 0.98). In hormone replacement therapy (HRT) users, 25(OH)D was significantly inversely associated with incident breast cancer (ORlog2 [95% CI]: 0.62 [0.42–0.90], p = 0.01), whereas no significant association was found in HRT nonusers (ORlog2 [95% CI]: 1.14 [0.80–1.62], p = 0.48). Further, a nonsignificant inverse association was found in women with body mass indices (BMI) < 25 kg/m2 (ORlog2 [95% CI]: 0.83 [0.67–1.03], p = 0.09), as opposed to a borderline significant positive association in women with BMI ≥ 25 kg/m2 (ORlog2 [95% CI]: 1.30 [1.0–1.69], p = 0.05). Overall, prediagnostic levels of circulating 25(OH)D were not related to the risk of breast cancer in the EPIC study. This result is in line with findings in the majority of prospective studies and does not support a role of vitamin D in the development of breast cancer.

Flavonoid and lignan intake in relation to bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study

Background:There is growing evidence of the protective role of dietary intake of flavonoids and lignans on cancer, but the association with bladder cancer has not been thoroughly investigated in epidemiological studies. We evaluated the association between dietary intakes of total and subclasses of flavonoids and lignans and risk of bladder cancer and its main morphological type, urothelial cell carcinoma (UCC), within the European Prospective Investigation into Cancer and Nutrition (EPIC) study.Methods:A cohort of 477 312 men and women mostly aged 35–70 years, were recruited in 10 European countries. At baseline, dietary flavonoid and lignan intakes were estimated using centre-specific validated questionnaires and a food composition database based on the Phenol-Explorer, the UK Food Standards Agency and the US Department of Agriculture databases.Results:During an average of 11 years of follow-up, 1575 new cases of primary bladder cancer were identified, of which 1425 were UCC (classified into aggressive (n=430) and non-aggressive (n=413) UCC). No association was found between total flavonoid intake and bladder cancer risk. Among flavonoid subclasses, significant inverse associations with bladder cancer risk were found for intakes of flavonol (hazard ratio comparing fifth with first quintile (HRQ5–Q1) 0.74, 95% confidence interval (CI): 0.61–0.91; P-trend=0.009) and lignans (HRQ5–Q1 0.78, 95% CI: 0.62–0.96; P-trend=0.046). Similar results were observed for overall UCC and aggressive UCC, but not for non-aggressive UCC.Conclusions:Our study suggests an inverse association between the dietary intakes of flavonols and lignans and risk of bladder cancer, particularly aggressive UCC.

Determinants of age at menarche and time to menstrual cycle regularity in the French E3N cohort

PURPOSE Early menarche has been associated with a greater risk of several major chronic diseases. Although largely genetically determined, age at menarche also has been related to environmental and lifestyle factors. METHODS Using linear regression models, we explored simultaneously several pre- and postnatal factors as potential determinants of age at menarche and time to menstrual cycle regularity in 96,493 women participating, since 1990, in the French E3N prospective cohort. RESULTS Younger age at recruitment, greater fathers income index, urban birth place, greater birth length, and larger body silhouette during childhood were associated with an earlier age at menarche (from -1.3 to -4.6 months, P(trend) < .0001) whereas greater family size, food deprivation during childhood, and greater birth weight resulted in a delayed menarche (from +1.5 months to +5.3 months, P(trend) < .0001). Fathers income index, urban birth place, and prematurity predicted a shorter time to menstrual cycle regularity (from -1.1 to -1.9 months, P(trend) < .04), whereas birth cohort, larger body silhouette at menarche, and childhood exposure to passive smoking were associated with a longer time to menstrual cycle regularity (from +1.1 months to +8.6 months, P(trend) < .006). CONCLUSIONS Age at menarche and menstrual cycle regularity are significantly influenced by several individual, environmental and lifestyle factors.

Risk of second primary malignancies in women with breast cancer: Results from the European prospective investigation into cancer and nutrition (EPIC).

Women with a diagnosis of breast cancer are at increased risk of second primary cancers, and the identification of risk factors for the latter may have clinical implications. We have followed‐up for 11 years 10,045 women with invasive breast cancer from a European cohort, and identified 492 second primary cancers, including 140 contralateral breast cancers. Expected and observed cases and Standardized Incidence Ratios (SIR) were estimated using Aalen‐Johansen Markovian methods. Information on various risk factors was obtained from detailed questionnaires and anthropometric measurements. Cox proportional hazards regression models were used to estimate the role of risk factors. Women with breast cancer had a 30% excess risk for second malignancies (95% confidence interval—CI 18–42) after excluding contralateral breast cancers. Risk was particularly elevated for colorectal cancer (SIR, 1.71, 95% CI 1.43–2.00), lymphoma (SIR 1.80, 95% CI 1.31–2.40), melanoma (2.12; 1.63–2.70), endometrium (2.18; 1.75–2.70) and kidney cancers (2.40; 1.57–3.52). Risk of second malignancies was positively associated with age at first cancer, body mass index and smoking status, while it was inversely associated with education, post‐menopausal status and a history of full‐term pregnancy. We describe in a large cohort of women with breast cancer a 30% excess of second primaries. Among risk factors for breast cancer, a history of full‐term pregnancy was inversely associated with the risk of second primary cancer.

High residential sun exposure is associated with a low risk of incident Crohn's disease in the prospective E3N cohort.

Background:Vitamin D insufficiency has been suggested to be associated with high risk of Crohns disease (CD). In France, where food fortification is limited, the major source of vitamin D is through sun exposure. The aim of this work was to analyze the relationship between residential sun exposure and the risk of incident CD or ulcerative colitis (UC). Methods:The E3N cohort consists of women living in France, aged 40 to 65 years and free of major diseases at inclusion in 1990. Among the 91,870 women included in the study, we identified 123 incident cases (45 CD, 71 UC, and 7 indeterminate colitis). To assess residential sun exposure, we used a database containing mean daily ultraviolet radiation (UVR) dose for each French county. The relationship between residential sun exposure and risk of incident inflammatory bowel diseases was explored using Cox models. Results:Higher levels of residential sun exposure were associated with a significant decreased risk of CD (hazard ratio [HR] for the third versus the first tertile of UVR dose, 0.49; 95% confidence interval (CI), 0.23–1.01; P for trend = 0.04), but not of UC (HR, 1.21; CI, 0.61–2.11). In women with available data on dietary vitamin D intake, we observed a lower risk of CD with higher residential UVR (HR, 0.29; 95% CI, 0.11–0.80; P for trend = 0.01). Dietary vitamin D intake was neither associated with the risk of CD (HR, 0.41; 95% CI, 0.14–1.24; P for trend = 0.14) nor UC (HR, 1.61; CI, 0.61–4.23). Conclusions:In this prospective cohort of women, high residential sunlight exposure was associated with decreased incidence of CD, but not UC.

A Population-Based Study of Australian Twins with Melanoma Suggests a Strong Genetic Contribution to Liability

Melanoma runs within families, but this may be due to either shared genetic or shared environmental influences within those families. The concordance between pairs of non-identical twins compared to that between identical twins can be used to determine whether familial aggregation is due to genetic or environmental factors. Mandatory reporting of melanoma cases in the state of Queensland yielded approximately 12,000 cases between 1982 and 1990. Twins in this study and from the adjacent state of New South Wales (125 pairs in total) were used to partition variation in liability to melanoma into genetic and environmental factors. Identical twins were more concordant for melanoma (4 of 27 pairs) than non-identical twins (3 of 98 pairs; P-value approximately 0.04). Identical co-twins of affected individuals were 9.8 times more likely to be affected than by chance. However, non-identical co-twins of affected individuals were only 1.8 times more likely to be affected than by chance. An MZ:DZ recurrence risk ratio of 5.6 suggests that some of the genetic influences on melanoma are due to epistatic (gene-gene) interactions. Using these data and population prevalences, it was estimated that 55% of the variation in liability to melanoma is due to genetic influences.