Journal Title
Title of Journal: Hum Genet
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Abbravation: Human Genetics
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Publisher
Springer-Verlag
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Authors: Z KoteJarai A Amin Al Olama D Leongamornlert M Tymrakiewicz E Saunders M Guy G G Giles G Severi M Southey J L Hopper K C Sit J M Harris J Batra A B Spurdle J A Clements F Hamdy D Neal J Donovan K Muir P D P Pharoah S J Chanock N Brown S Benlloch E Castro N Mahmud L O’Brien A Hall E Sawyer R Wilkinson D F Easton R A Eeles
Publish Date: 2011/04/05
Volume: 129, Issue: 6, Pages: 687-
Abstract
Genomewide 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 prostatespecific 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 twostage 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 = 39 × 10−22 This association was confirmed by direct genotyping in three stages of the UK/Australian GWAS involving 10405 cases and 10681 controls combined P = 19 × 10−34 rs17632542 is also shown to be associated with PSA levels and it is a nonsynonymous 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 riskProstate cancer PrCa is the most common cancer in men living in the Western world with a lifetime risk of approximately 1 in 8 for men in Europe and the USA http//wwwinfocancerresearchukorg/cancerstats/types/prostate/ Its aetiology remains poorly understood The increased risk of PrCa for men with a family history is consistent with variation in genetic susceptibility to the disease Edwards and Eeles 2004 Genomewide association studies GWAS are a proven way to identify common disease susceptibility alleles Thus far such studies have identified SNPs associated with prostate cancer in more than 30 independent regions Liu et al 2010 We previously conducted a GWAS in two stages and identified SNPs in seven regions associated with PrCa risk Eeles et al 2008 One of these SNPs rs2735839 on 19q133 lies within an LD block of 34 kb containing the kallikrein genes KLK3 and KLK2 combined stage 1 and 2 P = 23 × 10−17 This SNP was also shown to be associated with serum PSA level however an association with PrCa has been demonstrated using samples not ascertained by PSA screening suggesting that the association is not solely due to selection of cases with elevated PSA and controls with a low PSA level Ahn et al 2008KLK3 encodes prostatespecific antigen PSA a member of the kallikrein family of serine proteases Its main physiological function is to cleave semenogelins in the seminal coagulum thereby regulating sperm motility Like other kallikreins it might also participate in the process of neoplastic growth and metastasis of PrCa Lawrence et al 2010 Paliouras et al 2007 The expression of PSA is highly restricted to normal and malignant prostate epithelial cells in men During tumorigenesis however serum PSA levels tend to be elevated probably due to the loss of normal architecture of the gland For this reason PSA is extensively used as a biomarker to screen for and monitor treatment of PrCaThe association with rs2735839 implies that one or more variants in the KLK3 region correlated with rs2735839 are directly associated with PrCa risk In an attempt to identify such variants we performed a comprehensive analysis of SNPs across the region using a combination of imputation and further genotypingAnalyses were based on the samples genotyped in first and second stages of an UK/Australian GWAS collected as previously described Eeles et al 2008 2009 together with a third stage involving a further 4901 cases and 4847 controls Stage 3 samples were selected from UKGPCS as for stages 1 and 2 from Studies of Epidemiology and Risk factors in Cancer Heredity SEARCH a case–control study based on the region covered by the Eastern UK Cancer Registry and Information Centre ECRIC and from the Australian epidemiological studies as in stage 2 Supplementary Table 1 We also included data from the Cancer Genetic Markers of Susceptibility CGEMS study a GWAS of 1117 PrCa cases and 1105 controls drawn from the PLCO study http//wwwcgemscancergov/To evaluate associations with PrCa for SNPs not included in genotyping arrays used in the GWAS we defined a 34 kb LD region that included all SNPs in the region correlated with the original best hit rs2735839 at r 2 01 according to the HapMap Phase II CEU dataset We then identified all SNPs in the interval from the HapMap Phase II as well as SNPs identified through sequencing of European CEU samples in the 1000 Genomes study at a frequency of at least 2 Genotypes for these SNPs in stages 1 and 2 of the UK/Australian GWAS and the CGEMS study were then imputed using MACH 10 http//wwwsphumichedu/csg/abecasis/MACH/ and 50 rounds of imputation We included SNPs with quality score r 2 03 in the analysis
Keywords:
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