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.

Download full-text


Available from: Lisa A Cannon-Albright,
  • Source
    • "SNPs in the lncRNA PRNCR1 gene might influence the predicted secondary structure of PRNCR1 mRNA, alter the stability of the lncRNA PRNCR1 or the mRNA conformation, and result in the modification of its interacting partners [19]. Since the lncRNA PRNCR1 located in 8q24 which was a susceptibility locus to CRC [2-17,59], we hypothesized that SNPs in this region may have roles in the development of CRC. Our findings confirmed our hypothesis. "
    [Show abstract] [Hide abstract]
    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.
    Journal of Experimental & Clinical Cancer Research 12/2013; 32(1):104. DOI:10.1186/1756-9966-32-104 · 4.43 Impact Factor
  • Source
    • "Studies investigating more than one type of cancer with the same or overlapping controls were regarded as individual data sets in subgroup analyses by cancer type [13,19.20]. These 14 studies included 2 breast cancer studies [11], [17], 1 renal cancer study [16], 1 colorectal cancer, gastric cancer, and lung cancer study [13], 1 chronic lymphocytic leukemia study [19], and 11 colorectal cancer studies [12], [14], [15], [17], [18], [20]. Of these, there were 3 studies of Asians [12], [13], [16], 9 studies of Caucasians [14], [17]–[20], and 2 studies of mixed ethnicity [11], [15]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Accumulating evidence has suggested that Mothers against decapentaplegic homolog 7 (SMAD7) rs12953717 polymorphism might be related to cancer risk. However, epidemiologic findings have been inconsistent. We therefore performed a meta-analysis to clarify the association between the SMAD7 rs12953717 polymorphism and cancer risk. A comprehensive search was conducted to identify all eligible studies of SMAD7 rs12953717 polymorphism and cancer risk. We used odds ratios (ORs) to assess the strength of the association, and 95% confidence intervals (CIs) to give a sense of the precision of the estimate. Heterogeneity, publication bias, and sensitivity analysis were also explored. A total of 14 case-control studies, including 16928 cases and 14781 controls, were included in the present meta-analysis. The overall results showed that the variant genotypes were associated with a significantly increased risk of all cancer types (homozygote comparison, OR = 1.23, 95%CI = 1.10-1.38, P<0.01; heterozygote comparison, OR = 1.12, 95%CI = 1.02-1.22, P = 0.02; recessive model, OR = 1.17, 95%CI = 1.07-1.29, P<0.01; dominant model, OR = 1.15, 95%CI = 1.06-1.25, P<0.01; allelic model, OR = 1.12, 95%CI = 1.06-1.18, P<0.01). Further sensitivity analysis confirmed the significant association. In the subgroup analysis by ethnicity, SMAD7 rs12953717 polymorphism was significantly associated with cancer risk in both Caucasians and Asians. In the subgroup analysis by cancer types, SMAD7 rs12953717 polymorphism was significantly associated with colorectal cancer. Our investigations demonstrate that rs12953717 polymorphism is associated with the susceptibility of cancer. Large-scale and well-designed case-control studies are necessary to validate the risk identified in the present meta-analysis.
    PLoS ONE 03/2013; 8(3):e58170. DOI:10.1371/journal.pone.0058170 · 3.23 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Common single nucleotide polymorphisms (SNPs) in SMAD7 (18q21) have been linked to colorectal cancer (CRC) risk in genome-wide association studies, but little is known about their effects on survival. SMAD7 regulates gastrointestinal inflammation by inhibiting transforming growth factor-β (TGFB), which can act as both a tumor suppressor and a promoter of metastasis. Regular use of cyclooxygenase-2 (COX2) inhibitors, such as nonsteroidal anti-inflammatory drugs (NSAIDs), reduces the risk of developing CRC. Because COX2 overexpression reduces the growth suppressing effects of TGFB, we hypothesized that survival may depend on both SMAD7 genotype and prediagnostic NSAID use. Postmenopausal women, ages 50-74, diagnosed with incident invasive CRC from 1997 to 2002 were identified using the Seattle-Puget Sound Surveillance, Epidemiology, and End Results (SEER) cancer registry. Information on prediagnostic NSAID use and other risk factors was ascertained by interview, and women were followed-up for survival through December 31, 2009. Seven hundred and twenty-seven cases were genotyped for two GWAS hits in SMAD7 with minor allele frequency > 30%, one with minor allele associated with decreased risk (rs4939827) and one with minor allele associated with increased risk (rs4464148). Two hundred and forty-two deaths occurred, 160 attributable to CRC. Among those without distant disease at diagnosis, CRC-specific survival differed by genotype only for NSAID users: each minor allele of rs4939827 was associated with worse survival [hazard ratio (HR) = 2.67, 95% confidence interval (CI): 1.33-5.37] and each minor allele of rs4464148 was associated with better survival (HR = 0.41, CI 0.18-0.94). SMAD7 variants known to be important for CRC risk were associated with disease-specific survival among prediagnostic NSAID users.
    Genes Chromosomes and Cancer 11/2011; 50(11):875-86. DOI:10.1002/gcc.20913 · 4.04 Impact Factor
Show more