Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci (original) (raw)
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Genome-wide association study identifies new prostate cancer susceptibility loci
2011
Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade ≥ 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P < 0.02) in two published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P 5 4.3 3 10 28). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P 5 8.6 3 10 29). The estimated per-allele odds ratios for these loci (1.14 for rs2292884 and 1.17 for rs902774) did not differ between advanced and non-advanced PrCa (case-only test for heterogeneity P 5 0.72 and P 5 0.61, respectively). Further studies will be needed to assess whether these or other loci are differentially associated with PrCa subtypes.
Nature genetics, 2009
Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we have previously conducted a genome-wide association study in which 541, 129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and 1,894 controls. We have now evaluated promising associations in a second stage, in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls, and a third stage, involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to previously identified loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11, and 22 (P=1.6×10 −8 to P=2.7×10 −33 ).
Genome-wide association study of prostate cancer identifies a second risk locus at …
Nature genetics, 2007
In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study (GWAS), with 1,047,986 single nucleotide polymorphism (SNP) markers examined in 3,425 African American prostate cancer cases and 3,290 African American male controls. The most significant 17 novel associations in stage 1 were followed-up in 1,844 cases and 3,269 controls of African ancestry. We identified a novel risk variant on chromosome 17q21 (rs7210100; odds ratio per allele=1.51; p=3.4×10 −13). The frequency of the risk allele is ~5% in men of African descent while it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting GWAS in diverse populations. Genome-wide association studies (GWAS) of prostate cancer have identified more than 30 risk associated variants, which in aggregate are estimated to account for approximately 20% of the familial risk of prostate cancer 1-12. Aside from admixture, and fine-mapping studies which identified multiple independent risk variants at 8q24 13,14 , and a more recent GWAS among Japanese men which identified five novel loci 9 , discoveries in prostate cancer have come from studies in men of European ancestry. However, prostate cancer incidence in men of African ancestry is greater than in non-African populations 15 , with the disparity presumably reflecting both differences in prevalence of environmental risk factors and susceptibility alleles that are shared among men of African descent. For example, the risk variants at 8q24, many of which are more common in men of African ancestry 14 , could contribute partly to the greater incidence of prostate cancer in this population, and provide some support for the hypothesis of a genetic contribution underlying racial/ethnic disparities in disease risk. Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Multiple loci identified in a genome-wide association study of prostate cancer
Nature Genetics, 2008
We followed our initial genome-wide association study (GWAS) of 527,869 SNPs on 1,172 individuals with prostate cancer and 1,157 controls of European origin-nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial prospective study-by testing 26,958 SNPs in four independent studies (total of 3,941 cases and 3,964 controls). In the combined joint analysis, we confirmed three previously reported loci (two independent SNPs at 8q24 and one in HNF1B (formerly known as TCF2 on 17q); P o 10 À10 ). In addition, loci on chromosomes 7, 10 (two loci) and 11 were highly significant (between P o 7.31 Â 10 À13 and P o 2.14 Â 10 À6 ). Loci on chromosome 10 include MSMB, which encodes b-microseminoprotein, a primary constituent of semen and a proposed prostate cancer biomarker, and CTBP2, a gene with antiapoptotic activity; the locus on chromosome 7 is at JAZF1, a transcriptional repressor that is fused by chromosome translocation to SUZ12 in endometrial cancer. Of the nine loci that showed highly suggestive associations (P o 2.5 Â 10 À5 ), four best fit a recessive model and included candidate susceptibility genes: CPNE3, IL16 and CDH13. Our findings point to multiple loci with moderate effects associated with susceptibility to prostate cancer that, taken together, in the future may predict high risk in select individuals.
Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study
Nature Genetics, 2011
Author contribution RAE and DFE designed the study, and are joint PIs on the GWAS. RAE is PI of the UKGPCS and project managed the overall study. ZKJ, RAE, DFE and AA wrote the paper, ZKJ coordinated and managed the Stage 3 and the PRACTICAL Stage 4 genotyping. ZKJ, DAL, MT, EJS, NM coordinated sample collation for Stage 3 and the PRACTICAL Stage 4 set genotyped in the UK. AA and DFE performed the statistical analyses; SB collated the dataset. GGG, JH, DRE, and GS are PIs of the Australian studies; and MS manages the molecular work. JS is PI of the Tampere study; TW collected clinical data, performed sample selection, and collated data. TLT coordinated sample collection. MW is the PI of the CPCS1 and 2 studies, PK, BGE, MAR, ATH and SEB have collected samples data and contributed to genotyping of this study. FCH, DN and JD are joint PIs of ProtecT; AL is study coordinator and MD the data base manager. AC assisted with sample selection, retrieval and processing. DA and JV are PIs of the ATBC Study, and were responsible for the original collection of the ATBC DNA samples. SC was responsible for assembly and genotyping. SIB is the PI of the PLCO study, AG is the PI for St. Louis screening centre for PLCO, and MY oversaw the genotyping for PLCO. HB is PI of the ESTHER study; DR, CS contributed to design and data collection; HM is study coordinator. CC and JL of the Poland study coordinated sample collection. CC and DWgenotyped the samples. CM and WV are PIs of the Ulm study. AER identified and collected clinical material/processed samples/undertook genotyping/ collated data for Ulm. TD is PI of the Hannover Prostate Cancer Study; AM and JS coordinated sample collation, provided molecular advice and conducted molecular work. JLD is PI of the Tasprac study: JRM led the Tasmanian genotyping and collated data; BP provided molecular advice assistance with collating data. PK coordinated data collection and management for the HPFS. TØ and KDS are PIs of the Aarhus study. MB coordinated sample collection and registration of clinical data. KDS led the sample genotyping. TK is PI of the EPIC-Oxford cohort and collected clinical material. RT collated data. SMG and MJT are PIs of the ACS CPS-II study, WRD is the data manager for this study. BEH and LL are PIs of the MEC; CH and FS are CI. YJL and HWZ are joint PIs of CHSH; YJL is study coordinator and HWZ participates and closely supervised the CHSH study. JLS is PI of the Fred Hutchinson study and EAO is PI of the NHGRI genotyping for PROGRESS; LMF and JSK coordinated data collation. SAI is PI of the USC study, EMJ is PI of the NCCC study; MCS and RC led the genotyping of both studies. SNT and DS are PIs of the Mayo clinic study; SKD coordinated data collation. JYP is PI of the Moffitt study, TAS and HYL are contributors to this study. JAC, ABS are PIs of the molecular genetics arm of the ProsCan study, and with JB and FL co-ordinated all risk factor data and genetic data collection for prostate cancer cases from Proscan, the Brisbane Retrospective Study, the Australian Prostate Cancer BioResource Brisbane node, and controls from two Queensland control sets. SC, JA and RAG are PIs of the Proscan study and were responsible for the original platform study initiation, conceptualisation and collection of the Proscan study cases. 60 , Vanio Mitev 45 , The UK Genetic Prostate Cancer Study Collaborators/British Association of Urological Surgeons' Section of Oncology 61 , The UK ProtecT Study Collaborators 61 , The PRACTICAL Consortium 61 ,