Case–control, kin-cohort and meta-analyses provide no support for STK15 F31I as a low penetrance colorectal cancer allele

Abstract

Recently, homozygosity for T91A single-nucleotide polymorphism (SNP) in the serine/threonine kinase (STK15) gene, which generates the substitution F31I has been proposed to increase the risk of a number of tumours including colorectal cancer (CRC). To further evaluate the relationship between STK15 F31I and risk of CRC, we genotyped 2558 CRC cases and 2680 controls for this polymorphism. We found no evidence that homozygosity for the STK15 31I genotype confers an increased risk of CRC (odds ratio ¼ 0.95, 95% confidence interval (CI): 0.74 -1.24). We also conducted a kin-cohort analysis to assess risk among first-degree relatives of the CRC cases. The hazard ratio for I/I homozygotes compared to F/F homozygotes was 1.65 (95% CI: 0.39 -3.17). A meta-analysis of our case -control data and three previous studies also provided no evidence of an elevated risk of CRC associated with homozygosity. These data provide no support for the hypothesis that sequence variation in STK15 defined by SNP F31I per se confers an elevated risk of CRC. (Dutertre et al, 2002) and plays a role in the development of malignancy (Bischoff et al, 1998;Zhou et al, 1998;Ewart-Toland et al, 2003). Recently, the T91A singlenucleotide polymorphism (SNP) in STK15, which generates the substitution F31I, and has been reported to influence genomic instability (Ewart-Toland et al, 2003;Kimura et al, 2005), has been proposed as a low penetrance variant for a number of tumours including colorectal cancer (CRC) (Ewart-Toland et al, 2003. To further evaluate the relationship between STK15 F31I and risk of CRC, we genotyped 2558 CRC cases and 2680 controls for this polymorphism. We also conducted a kin-cohort analysis to assess risk among first-degree relatives of the CRC cases. MATERIALS AND METHODSUnselected CRC cases with histologically confirmed colorectal adenocarcinomas (1471 men; 1087 women; mean age at diagnosis 61 years; standard deviation (s.d.)711.4) were ascertained through over 100 centres in the UK. Detailed family histories were obtained from cases by previously validated questionnaire. Controls (836 men; 1844 women; mean age 59 years; s.d.710.9) were the spouses or friends of patients with malignancies ascertained as part of ongoing National Cancer Research Network genetic epidemiological studies (1999 -2004; n ¼ 1067), the Royal Marsden Hospital Trust/Institute of Cancer Research Family History and DNA Registry (1999 -2004; n ¼ 1021) and UK Study of Breast Cancer Genetics (1999 -2004; n ¼ 592) all established within the UK. None of the controls had a personal history of malignancy at time of ascertainment. As we are not seeking to evaluate environmental interactive effects, the theoretical possibility of 'overmatching' on environmental factors by using spouse and friend controls is unlikely to impact on study findings. All cases and controls were British Caucasians, and there were no obvious differences in the demography of cases and controls in terms of place of residence within the UK. Blood samples were obtained with informed consent a...

Common genetic polymorphisms of AURKA and prostate cancer risk

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Efficient distribution estimation for data with unobserved sub-population identifiers

“…We inspect two types of widely used NPMLEs and report a surprising finding that they are either inefficient or even inconsistent. Although commonly applied in clinical studies (Sigurdson et al, 2004; Hauptmann et al, 2003; Webb et al, 2006a,b; Hartge et al, 2002), the inconsistency of the second type of NPMLE has not been discovered in the literature before.…”

Serine/threonine kinase 15 gene polymorphism and risk of digestive system cancers: A meta-analysis

“…Since the study by Ewart-Toland et al ( 16 ) included two populations, these populations were treated separately in the current meta-analysis ( Tables I and II ); as such, there were 15 case-control studies from 14 publications with 7,619 cases and 7,196 controls concerning the 91T>A polymorphism and four studies with 826 cases and 713 controls concerning the 169G>A polymorphism. Of the 15 eligible studies, 10 studies ( 11 , 12 , 14 , 10 , 16 – 19 , 22 ) were written in English and five studies ( 13 , 15 , 20 , 21 , 23 ) in Chinese; nine studies ( 12 , 13 , 15 , 10 , 18 – 21 , 23 ) were conducted on Asian populations, five studies ( 11 , 14 , 16 , 17 , 22 ) on Caucasian populations and one study ( 16 ) on a mixed population. Four tumor types were addressed: Six studies ( 12 , 15 , 10 , 19 – 21 ) focused on esophageal cancer; six studies ( 14 , 16 , 17 , 22 , 23 ) on colorectal cancer; two studies ( 13 , 18 ) on gastric cancer and one study ( 11 ) on hepatocellular carcinoma.…”