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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ItemHOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG)(SPRINGER, 2013-01)Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P = 9.9 × 10(-8) [odds ratio 4.42 (95 % confidence interval 2.56-7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (P = 6.5 × 10(-6)). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer.
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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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ItemAssociations between congenital malformations and childhood cancer. A register based case-control study(CHURCHILL LIVINGSTONE, 1998-11)This report describes a population-based case-control study that aimed to assess and quantify the risk of children with congenital malformations developing cancer. Three sources of data were used: the Victorian Cancer Register, the Victorian Perinatal Data Register (VPDR) and the Victorian Congenital Malformations/Birth Defects Register. Cases included all Victorian children born between 1984 and 1993 who developed cancer. Four controls per case, matched on birth date, were randomly selected from the VPDR. Record linkage between registers provided malformation data. A matched case-control analysis was undertaken. Of the 632 cancer cases, 570 (90.2%) were linked to the VPDR. The congenital malformation prevalence in children with cancer was 9.6% compared with 2.5% in the controls [odds ratio (OR) 4.5, 95% CI 3.1-6.7]. A strong association was found with chromosomal defects (OR=16.7, 95% CI 6.1-45.3), in particular Down's syndrome (OR=27.1, 95% CI 6.0-122). Most other birth defect groups were also associated with increased cancer risk. The increased risk of leukaemia in children with Down's syndrome was confirmed, and children with central nervous system (CNS) defects were found to be at increased risk of CNS tumours. The report confirms that children with congenital malformations have increased risks of various malignancies. These findings may provide clues to the underlying aetiology of childhood cancer, as congenital malformations are felt to be a marker of exposures or processes which may increase cancer risk. The usefulness of record linkage between accurate population-based registers in the epidemiological study of disease has also been reinforced.
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ItemHave increases in solar ultraviolet exposure contributed to the rise in incidence of non-Hodgkin's lymphoma?(NATURE PUBLISHING GROUP, 1996-04)The incidence of non-Hodgkin's lymphoma (NHL) has increased substantially in many countries over recent decades. The aetiology of this cancer is poorly understood, and this rise is largely unexplained. The incidence of NHL is known to increase markedly following immune suppression. In the light of evidence that exposure to ultraviolet radiation (UVR) may cause systemic immune suppression, part of the recent increase in NHL incidence may reflect population-based increases in UVR exposure. That such exposure increases have occurred is inferred from the widespread increases in skin cancer incidence in fair-skinned populations, especially malignant melanoma (MM), over recent decades. Epidemiological evidence presented here in support of the proposed UVR-NHL relationship includes the following: in Caucasian populations there is a moderate positive correlation between ambient UVR level, by latitude, and NHL incidence; there is also a positive correlation between time trends in MM incidence and NHL; there is some evidence that migration across latitude gradients induces concordant shifts in risks of NHL and MM. Data from two historical cancer patient registers show that, in individuals, these two cancers concurred a little more often than expected. These findings support recent suggestions that UVR-induced impairment of immune functioning contributes to the aetiology of NHL.
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ItemCERVICAL CYTOLOGY REPORTED AS NEGATIVE AND RISK OF ADENOCARCINOMA OF THE CERVIX - NO STRONG EVIDENCE OF BENEFIT(NATURE PUBLISHING GROUP, 1995-04)The relationship between negative cervical cytology reports and risk of adenocarcinoma of the cervix was evaluated in a case-control study of 113 cases and 452 controls. All cases and controls had received at least two negative cytology reports. There was no significant difference between the cases and controls in the number of negative cytology reports or in history of cervical abnormality; while a test for trend in the time since last negative cytology report was significant (P < 0.001), the estimated benefit was very modest. Although the estimates of relative protection were higher in women aged less than 35 years than in women aged 35-69 years, this difference was not statistically significant. These results suggest that cervical screening as practised in the 1970s and 1980s was much less effective in preventing adenocarcinoma than squamous carcinoma of the cervix.
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ItemMortality from cutaneous melanoma: evidence for contrasting trends between populations(NATURE PUBLISHING GROUP, 2000-06)In recent years several reports have been published concerning trends in melanoma mortality in different countries, some of which have indicated that rates are beginning to fall. Many of these reports, however, have been based on small populations and have used different forms of statistical analysis. Our objective was to analyse systematically to what degree the epidemic of melanoma mortality had evolved similarly in different populations and whether there were any divergent trends that might increase our understanding. Instead of using all available data, we focused on countries with a minimum time series of 30 years and a minimum of 100 deaths annually in at least one sex from melanoma. We first inspected sex-specific age-standardized mortality rates and then performed age-period-cohort modelling. We found that the increase in mortality observed after 1950 was more pronounced in the age group 60-79. Statistical modelling showed a general increase in mortality rates in generations born after the turn of the century. Downturns in mortality, essentially in women and starting with generations born just before World War II, were found in Australia (where the earliest decreases were noted), the Nordic countries and the USA. Small decreases in rates in more recent generations were found in the UK and Canada. However, in France, Italy and Czechoslovakia, mortality rates were seen to be still increasing in recent cohorts. Our analysis suggests that populations are at different places on the melanoma mortality epidemic curve. The three trend patterns we observed are in agreement with time differences between populations with respect to the promotion of sun protection and the surveillance of pigmented skin lesions.
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ItemNo Preview AvailableGenome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia(NATURE PUBLISHING GROUP, 2013-08)Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P=1.22×10(-14)), 18q21.33 (BCL2, P=7.76×10(-11)), 11p15.5 (C11orf21, P=2.15×10(-10)), 4q25 (LEF1, P=4.24×10(-10)), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P=2.50×10(-9)), 9p21.3 (CDKN2B-AS1, P=1.27×10(-8)), 18q21.32 (PMAIP1, P=2.51×10(-8)), 15q15.1 (BMF, P=2.71×10(-10)) and 2p22.2 (QPCT, P=1.68×10(-8)), as well as an independent signal at an established locus (2q13, ACOXL, P=2.08×10(-18)). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P=5.40×10(-8)) and 5p15.33 (TERT, P=1.92×10(-7)). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism.
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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 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.