Meta Association of Colorectal Cancer Confirms Risk Alleles at 8q24 and 18q21

Genetic Epidemiology, University of Utah School of Medicine, Salt Lake City, UT 84109, USA.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.13). 02/2009; 18(2):616-21. DOI: 10.1158/1055-9965.EPI-08-0690
Source: PubMed


Genome-wide association studies of colorectal cancer (CRC) have identified genetic variants that reproducibly associate with CRC. Associations of 12 single nucleotide polymorphisms at 8q24, 9p24, and 18q21 (SMAD7) and CRC were investigated in a three-center collaborative study including two U.K. case-control cohorts (Sheffield and Leeds) and a U.S. case-control study of CRC cases from high-risk Utah pedigrees.
Our combined resource included 1,092 CRC case subjects and 1,060 age- and sex-matched controls. Meta statistics and Monte Carlo significance testing using Genie software provided a valid combined analysis of our mixed independent and related case-control resource. We also evaluated whether these associations differed by sex, age at diagnosis, family history, or tumor site.
At 8q24, we observed two independent significant associations at single nucleotide polymorphisms located in two different risk regions of 8q24: rs6983267 in region 3 [P(trend) = 0.01; per allele odds ratio (OR), 1.17; 95% confidence intervals (95% CI), 1.03-1.32] and rs10090154 in region 5 (P(trend) = 0.05; per allele OR, 1.24; 95% CI, 1.01-1.51). At 18q21, associations were observed in distal colon tumors but not in proximal or rectal cancers: rs4939827 (P(trend) = 0.007; per allele OR, 0.77; 95% CI, 0.64-0.93; case-case p(diff) = 0.03) and rs12953717 (P(trend) = 0.01; per allele OR, 1.27; 95% CI, 1.06-1.52). We were unable to detect any associations at 9p24 with CRC.
Our investigation confirms that variants across multiple risk regions of 8q24 are associated with CRC, and that associations at 18q21 differ by tumor site.

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Available from: Lisa A Cannon-Albright
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    ABSTRACT: Genome-wide association studies have identified that genetic variants in 8q24 confer susceptibility to colorectal cancer (CRC). Recently, a novel lncRNA (PRNCR1) that located in the 8q24 was discovered. Single nucleotide polymorphisms (SNPs) in the lncRNAs may influence the process of splicing and stability of mRNA conformation, resulting in the modification of its interacting partners. We hypothesized that SNPs in the lncRNA PRNCR1 may be related to the risk of CRC. We conducted a case-control study and genotyped five tag SNPs in the lncRNA PRNCR1 in 908 subjects including 313 cases with CRC and 595 control subjects using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. In overall analyses, we found that the rs13252298 and rs1456315 were associated with significantly decreased risks of CRC. In stratification analyses, we found that CRC patients carrying the rs1456315G were likely to have a tumor size of greater than 5 cm (G vs. A: adjusted OR = 1.56, 95% CI: 1.10-2.23). Additionally, patients with the rs7007694C and rs16901946G had decreased risks to develop poorly differentiated CRC, whereas patients with the rs1456315G had an increased risk to develop poorly differentiated CRC. These findings suggest that SNPs in the lncRNA PRNCR1 may contribute to susceptibility to CRC.
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    • "Recent genome-wide association studies (GWASs) have consistently identified genetic variants in SMAD7 as being modestly associated with the risk of developing CRC (Broderick et al., 2007; Tenesa et al., 2008; Tomlinson et al., 2008; Curtin et al., 2009). In a pooled analysis across four populations, Broderick et al. (2007) estimated a 15% (95% confidence interval (CI): 11-19%) decrease in CRC risk per minor allele of rs4939827 and a 15% (CI: 9-21%) increase in risk per minor allele of rs4464148. "
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