Melbourne School of Population and Global Health - Research Publications
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ItemIdentification of new breast cancer predisposition genes via whole exome sequencing(Springer Science and Business Media LLC, 2012-01)
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ItemIdentification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript(SPRINGER, 2011-06)Genome-wide association studies (GWAS) have identified more than 30 prostate cancer (PrCa) susceptibility loci. One of these (rs2735839) is located close to a plausible candidate susceptibility gene, KLK3, which encodes prostate-specific antigen (PSA). PSA is widely used as a biomarker for PrCa detection and disease monitoring. To refine the association between PrCa and variants in this region, we used genotyping data from a two-stage GWAS using samples from the UK and Australia, and the Cancer Genetic Markers of Susceptibility (CGEMS) study. Genotypes were imputed for 197 and 312 single nucleotide polymorphisms (SNPs) from HapMap2 and the 1000 Genome Project, respectively. The most significant association with PrCa was with a previously unidentified SNP, rs17632542 (combined P = 3.9 × 10(-22)). This association was confirmed by direct genotyping in three stages of the UK/Australian GWAS, involving 10,405 cases and 10,681 controls (combined P = 1.9 × 10(-34)). rs17632542 is also shown to be associated with PSA levels and it is a non-synonymous coding SNP (Ile179Thr) in KLK3. Using molecular dynamic simulation, we showed evidence that this variant has the potential to introduce alterations in the protein or affect RNA splicing. We propose that rs17632542 may directly influence PrCa risk.
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ItemNo Preview AvailableMeta-Analysis Combining New and Existing Data Sets Confirms that the TERT-CLPTM1L Locus Influences Melanoma Risk(NATURE PUBLISHING GROUP, 2012-02)
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ItemNo Preview AvailableGenome-wide association analysis identifies three new breast cancer susceptibility loci(NATURE PUBLISHING GROUP, 2012-03)Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.
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ItemEvaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk(NATURE PUBLISHING GROUP, 2011-12-06)BACKGROUND: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. METHODS: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). RESULTS: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139). CONCLUSION: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.
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ItemNo Preview AvailableGenome-wide association study identifies a new melanoma susceptibility locus at 1q21.3(NATURE PUBLISHING GROUP, 2011-11)We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.
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ItemLinkage to chromosome 2q32.2-q33.3 in familial serrated neoplasia (Jass syndrome)(SPRINGER, 2011-06)Causative genetic variants have to date been identified for only a small proportion of familial colorectal cancer (CRC). While conditions such as Familial Adenomatous Polyposis and Lynch syndrome have well defined genetic causes, the search for variants underlying the remainder of familial CRC is plagued by genetic heterogeneity. The recent identification of families with a heritable predisposition to malignancies arising through the serrated pathway (familial serrated neoplasia or Jass syndrome) provides an opportunity to study a subset of familial CRC in which heterogeneity may be greatly reduced. A genome-wide linkage screen was performed on a large family displaying a dominantly-inherited predisposition to serrated neoplasia genotyped using the Affymetrix GeneChip Human Mapping 10 K SNP Array. Parametric and nonparametric analyses were performed and resulting regions of interest, as well as previously reported CRC susceptibility loci at 3q22, 7q31 and 9q22, were followed up by finemapping in 10 serrated neoplasia families. Genome-wide linkage analysis revealed regions of interest at 2p25.2-p25.1, 2q24.3-q37.1 and 8p21.2-q12.1. Finemapping linkage and haplotype analyses identified 2q32.2-q33.3 as the region most likely to harbour linkage, with heterogeneity logarithm of the odds (HLOD) 2.09 and nonparametric linkage (NPL) score 2.36 (P = 0.004). Five primary candidate genes (CFLAR, CASP10, CASP8, FZD7 and BMPR2) were sequenced and no segregating variants identified. There was no evidence of linkage to previously reported loci on chromosomes 3, 7 and 9.
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ItemSecond to fourth digit ratio (2D: 4D) and prostate cancer risk in the Melbourne Collaborative Cohort Study(NATURE PUBLISHING GROUP, 2011-07-26)BACKGROUND: The ratio of the lengths of index and ring fingers (2D:4D) is a marker of prenatal exposure to sex hormones, with low 2D:4D being indicative of high prenatal androgen action. Recent studies have reported a strong association between 2D:4D and risk of prostate cancer. METHODS: A total of 6258 men participating in the Melbourne Collaborative Cohort Study had 2D:4D assessed. Of these men, we identified 686 incident prostate cancer cases. Hazard ratios (HRs) and confidence intervals (CIs) were estimated for a standard deviation increase in 2D:4D. RESULTS: No association was observed between 2D:4D and prostate cancer risk overall (HRs 1.00; 95% CIs, 0.92-1.08 for right, 0.93-1.08 for left). We observed a weak inverse association between 2D:4D and risk of prostate cancer for age <60, however 95% CIs included unity for all observed ages. CONCLUSION: Our results are not consistent with an association between 2D:4D and overall prostate cancer risk, but we cannot exclude a weak inverse association between 2D:4D and early onset prostate cancer risk.
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ItemDietary patterns and risk of breast cancer(SPRINGERNATURE, 2011-02-01)BACKGROUND: Evidence is emerging that prudent/healthy dietary patterns might be associated with a reduced risk of breast cancer. METHODS: Using data from the prospective Melbourne Collaborative Cohort Study, we applied principal factor analysis to 124 foods and beverages to identify dietary patterns and estimated their association with breast cancer risk overall and by tumour characteristics using Cox regression. RESULTS: During an average of 14.1 years of follow-up of 20 967 women participants, 815 invasive breast cancers were diagnosed. Among the four dietary factors that we identified, only that characterised by high consumption of fruit and salad was associated with a reduced risk, with stronger associations observed for tumours not expressing oestrogen (ER) and progesterone receptors (PR). Compared with women in the lowest quintile of the factor score, the hazard ratio for women in the highest quintile was 0.92 (95% confidence interval (CI)=0.70-1.21; test for trend, P=0.5) for ER-positive or PR-positive tumours and 0.48 (95% CI=0.26-0.86; test for trend, P=0.002) for ER-negative and PR-negative tumours (test for homogeneity, P=0.01). CONCLUSION: Our study provides additional support for the hypothesis that a dietary pattern rich in fruit and salad might protect against invasive breast cancer and that the effect might be stronger for ER- and PR-negative tumours.
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ItemNo Preview AvailableCommon variants in ZNF365 are associated with both mammographic density and breast cancer risk(NATURE PUBLISHING GROUP, 2011-03)High-percent mammographic density adjusted for age and body mass index is one of the strongest risk factors for breast cancer. We conducted a meta analysis of five genome-wide association studies of percent mammographic density and report an association with rs10995190 in ZNF365 (combined P = 9.6 × 10(-10)). Common variants in ZNF365 have also recently been associated with susceptibility to breast cancer.