Melbourne School of Population and Global Health - Research Publications
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ItemNo Preview AvailableGWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer(NATURE PUBLISHING GROUP, 2013-04)Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10(-9)) and 10p12 (rs1243180, P = 1.8 × 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.
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ItemNo Preview AvailableIdentification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31(NATURE RESEARCH, 2013-03)Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.
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ItemConfirmation of the reduction of hormone replacement therapy-related breast cancer risk for carriers of the HSD17B1_937_G variant(SPRINGER, 2013-04)17β-hydroxysteroid dehydrogenase type 1 (HSD17B1) plays an important role in the biosynthesis of 17β-estradiol. The current study aimed at confirming the reduced risk of breast cancer in carriers of the non-synonymous HSD17B1_937_A>G (rs605059) polymorphism who used any hormone replacement therapy (HRT) for 10 years or longer. We performed an independent association study using four breast cancer case-control studies from Australia, Germany, and Sweden. In all, 5,777 cases and 8,189 age-matched controls of European descent were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and TaqMan. Risk estimates were calculated by interaction analysis and main effect analysis adjusted for age and study. Main effect analyses for women using any HRT for 10 years or longer (1,428 cases versus 1,724 controls) revealed a protective effect of the HSD17B1_937_G allele on breast cancer risk (OR 0.86, 95 % CI: 0.73-0.99; p = 0.048). Thus, our previous finding of a protective effect of the HSD17B1_937_G allele on HRT-associated breast cancer risk has now been confirmed both in independent large patient cohorts and a comprehensive pooled analysis supporting the hypothesis that a HSD17B1-mediated decreased conversion of estrone to the more potent 17β-estradiol may reduce the estrogenic effects, thereby reducing the risk of developing breast cancer during long-term HRT use.
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ItemDietary intake of B vitamins and methionine and breast cancer risk(SPRINGER, 2013-08)PURPOSE: We investigated prospectively the relationship between dietary intakes of methionine and B vitamins associated with one-carbon metabolism and breast cancer risk, including modification by age, hormone receptor status and alcohol consumption. Interactions between different B vitamins and methionine were also examined. METHODS: During follow-up of 20,756 women from the Melbourne Collaborative Cohort Study for an average of 16 years, we ascertained 936 incident breast cancers. Dietary intakes were estimated using a 121-item food frequency questionnaire. Hazard ratios (HR) and 95 % confidence intervals were estimated using Cox regression. RESULTS: We found weak evidence for an inverse association between breast cancer risk and riboflavin intake (fourth versus first quartile, HR Q4 vs. Q1 = 0.84 (0.69, 1.01); p linear trend = 0.05) and a positive association for vitamin B12 (HR Q4 vs. Q1 = 1.21 (1.00, 1.46); p linear trend = 0.06). We did not find any significant interactions between alcohol consumption and any of the B vitamins or methionine intake (all p interaction > 0.17) or between methionine or folate intake and any other B vitamins (all p interaction > 0.07). No association varied by tumor hormone receptor status (all p homogeneity > 0.14). CONCLUSIONS: We found weak evidence of an inverse association between breast cancer risk and riboflavin intake and a positive association with vitamin B12.
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ItemReply to comment on: 'Second to fourth digit ratio (2D:4D), breast cancer risk factors, and breast cancer risk: a prospective cohort study'(NATURE PUBLISHING GROUP, 2013-02-19)
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ItemPopulation-Based Estimate of Prostate Cancer Risk for Carriers of the HOXB13 Missense Mutation G84E(PUBLIC LIBRARY SCIENCE, 2013-02-15)The HOXB13 missense mutation G84E (rs138213197) is associated with increased risk of prostate cancer, but the current estimate of increased risk has a wide confidence interval (width of 95% confidence interval (CI) >200-fold) so the point estimate of 20-fold increased risk could be misleading. Population-based family studies can be more informative for estimating risks for rare variants, therefore, we screened for mutations in an Australian population-based series of early-onset prostate cancer cases (probands). We found that 19 of 1,384 (1.4%) probands carried the missense mutation, and of these, six (32%) had a family history of prostate cancer. We tested the 22 relatives of carriers diagnosed from 1998 to 2008 for whom we had a DNA sample, and found seven more carriers and one obligate carrier. The age-specific incidence for carriers was estimated to be, on average, 16.4 (95% CI 2.5-107.2) times that for the population over the time frame when the relatives were at risk prior to baseline. We then estimated the age and birth year- specific cumulative risk of prostate cancer (penetrance) for carriers. For example, the penetrance for an unaffected male carrier born in 1950 was 19% (95% CI 5-46%) at age 60 years, 44% (95% CI 18-74%) at age 70 years and 60% (95% CI 30-85%) at age 80 years. Our study has provided a population-based estimate of the average risk of prostate cancer for HOXB13 missense mutation G84E carriers that can be used to guide clinical practice and research. This study has also shown that the majority of hereditary prostate cancers due to the HOXB13 missense mutation are 'sporadic' in the sense that unselected cases with the missense mutation do not typically report having a family history of prostate cancer.
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ItemEpigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer(NATURE RESEARCH, 2013-03)HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.
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ItemNo Preview AvailableGenetic modifiers of menopausal hormone replacement therapy and breast cancer risk: a genome-wide interaction study(BIOSCIENTIFICA LTD, 2013-12)Women using menopausal hormone therapy (MHT) are at increased risk of developing breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-analysis of four genome-wide case-only studies followed by replication in 11 case-control studies. We used a case-only design to assess interactions between single-nucleotide polymorphisms (SNPs) and current MHT use on risk of overall and lobular BC. The discovery stage included 2920 cases (541 lobular) from four genome-wide association studies. The top 1391 SNPs showing P values for interaction (Pint) <3.0 × 10(-3) were selected for replication using pooled case-control data from 11 studies of the Breast Cancer Association Consortium, including 7689 cases (676 lobular) and 9266 controls. Fixed-effects meta-analysis was used to derive combined Pint. No SNP reached genome-wide significance in either the discovery or combined stage. We observed effect modification of current MHT use on overall BC risk by two SNPs on chr13 near POMP (combined Pint≤8.9 × 10(-6)), two SNPs in SLC25A21 (combined Pint≤4.8 × 10(-5)), and three SNPs in PLCG2 (combined Pint≤4.5 × 10(-5)). The association between lobular BC risk was potentially modified by one SNP in TMEFF2 (combined Pint≤2.7 × 10(-5)), one SNP in CD80 (combined Pint≤8.2 × 10(-6)), three SNPs on chr17 near TMEM132E (combined Pint≤2.2×10(-6)), and two SNPs on chr18 near SLC25A52 (combined Pint≤4.6 × 10(-5)). In conclusion, polymorphisms in genes related to solute transportation in mitochondria, transmembrane signaling, and immune cell activation are potentially modifying BC risk associated with current use of MHT. These findings warrant replication in independent studies.
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ItemNo Preview AvailableAssociations between Weight in Early Adulthood, Change in Weight, and Breast Cancer Risk in Postmenopausal Women(AMER ASSOC CANCER RESEARCH, 2013-08)BACKGROUND: Adult weight is positively associated with postmenopausal breast cancer but few studies have investigated whether there are associations with weight and body mass index (BMI) in early adulthood, or subsequent weight change. METHODS: A total of 14,441 postmenopausal women from the Melbourne Collaborative Cohort Study (MCCS) were followed for 16.5 years (mean) and 668 incident breast cancers were identified. Hazard ratios (HRs) were estimated using Cox regression. RESULTS: Weight and BMI at 18 to 21 years were not associated with risk of any type of breast cancer and there was no variation by age. Women with the greatest increase in weight and BMI had higher risk at older ages [HR per 5 kg/m(2) gain in BMI = 1.24; 95% confidence interval (CI), 1.11-1.40], although the test for homogeneity by age was not significant. At older ages, the association was stronger for progesterone (PR) positive disease compared with PR negative disease (HR per 5 kg/m(2) gain in BMI, 1.43; 95% CI, 1.23-1.66; test for homogeneity by PR status, P < 0.01) and for diseases that were positive for both estrogen (ER) and PR (HR per 5 kg/m(2) gain in BMI, 1.45; 95% CI, 1.24-1.69; test for homogeneity by ER/PR status, P = 0.02). HRs were also greater for HER2- and luminal A tumors, but the P values for homogeneity by tumor subgroups were not significant. CONCLUSION: Early adulthood weight is not associated with risk of postmenopausal breast cancer. Greater weight gain during adulthood might be associated with increased risk for older women (>69 years) and this association might vary by tumor hormone receptor status. IMPACT: Further studies need to investigate the impact of increase in weight during adulthood on postmenopausal breast cancer risk and the potential variation by age or tumor characteristics.
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ItemThe use of DNA from archival dried blood spots with the Infinium HumanMethylation450 array(BIOMED CENTRAL LTD, 2013-03-15)BACKGROUND: Dried blood (Guthrie card) spots provide an efficient way to collect and store blood specimens. DNA from this source has been utilised for a number of molecular analyses including genome-wide association studies, but only few studies have tested the feasibility of using it for epigenetic applications, particularly at a genome-wide level. RESULTS: In this study, we demonstrate the successful use of DNA isolated from archived dried blood spots for the Infinium HumanMethylation450 Beadchip, along with DNA from matched frozen buffy coats. We obtained high quality and reproducible genome-wide DNA methylation profiles using both sample types. We also report high correlations (r > 0.9907) between DNA obtained from matched dried blood spots and frozen buffy coats, sufficient to distinguish between unrelated individuals. CONCLUSIONS: We, thus, demonstrate that DNA from archived dried blood spots is suitable for genome-wide DNA methylation profiling.