Cancer Susceptibility In Population Research Articles

Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer

Pancreatic cancer is the fourth leading cause of cancer-related deaths in Japan. To identify risk loci, we perform a meta-analysis of three genome-wide association studies comprising 2,039 pancreatic cancer patients and 32,592 controls in the Japanese population. Here, we identify 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P < 5.0 × 10−8), of which 16p12.3 has not been reported in the Western population. The lead single nucleotide polymorphism (SNP) at 16p12.3 is rs78193826 (odds ratio = 1.46, 95% confidence interval = 1.29-1.66, P = 4.28 × 10−9), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant. Associations between selected GP2 gene variants and pancreatic cancer are replicated in 10,822 additional cases and controls of East Asian origin. Functional analyses using cell lines provide supporting evidence of the effect of rs78193826 on KRAS activity. These findings suggest that GP2 gene variants are probably associated with pancreatic cancer susceptibility in populations of East Asian ancestry.

A systematic analysis of the association studies between CASP8 D302H polymorphisms and breast cancer risk.

Caspase 8 (CASP8) is a regulator of apoptosis, whose genetic variation has been reported to be associated with the risk of various cancers. Especially, the single-nucleotide polymorphism (SNP) rs1045485, which generates the substitution D302H in CASP8, is likely to be associated with breast cancer. Several previous studies have reported the association of CASP8 D302H polymorphism with breast cancer; however, the results are inconsistent. To validate the association between CASP8 D302H polymorphism and breast cancer risk, we performed an updated meta-analysis of 18 studies including 27,807 cases and 32,332 controls. We tested the overall association between this SNP and breast cancer susceptibility and stratified subgroups based on countries where cases are from. We confirmed a significant correlation between CASP8 D302H polymorphism and the reduced breast cancer susceptibility in population from UK, Germany and Poland, but no significant association was observed in other countries, such as Finland or USA. Our findings indicate the relationship of SNP CASP8 D302H and breast cancer would not be universal but only be sensitive in some particular European countries. The genetic difference for diverse countries may be useful in individual and precision medicine or health.

Association of glutathione S-transferase T1 and M1 polymorphisms with prostate cancer susceptibility in populations of Asian descent: a meta-analysis.

Genetic polymorphism was hypothesized to be reason of variation in prostate cancer incidence among different racial group. Based on that published data on the association of prostate cancer susceptibility with polymorphisms in genes encoding Glutathione S-transferases (GSTs) were inconclusive, the aim of this study was to more precisely address the role of GSTs polymorphisms (especially, GSTT1 and GSTM1 deletions) on prostate cancer risk in Asian descent. A meta-analysis including 8 articles with 711 cases and 1122 controls for GSTT1 and 1098 cases and 1588 controls for GSTM1 was performed. Significantly increased prostate cancer risk was found among subjects carrying GSTM1 null genotype (odds ratio (OR) = 1.403; 95% confidence interval (CI) = 1.088 - 1.808) but not among subjects carrying GSTT1 deletion genotype (OR = 0.959; 95%CI = 0.709 - 1.297). When stratified by country, the null genotype of GSTT1 neither increased nor decreased prostate cancer risk significantly in China (OR = 1.355; 95%CI = 0.895 - 2.049), Japan (OR = 0.812; 95%CI = 0.545 - 1.211), and Korea (OR = 1.056; 95%CI = 0.727 - 1.534). While significant association of elevated prostate cancer risk with GSTM1 deletion were found in China (OR = 1.665; 95%CI = 1.324 - .094) and Korea (OR = 1.914; 95%CI = 1.311 - 2.793) but not in Japan (OR = 0.980; 95%CI = 0.726 - 1.321). In summary, this meta-analysis suggested that the null genotype of GSTM1 rather than GSTT1 may be involved in the etiology of prostate cancer in Asian population.

Association between p53 Gene Variants and Oral Cancer Susceptibility in Population from Gujarat, West India

p53 gene variants i.e. 16 bp duplication in intron 3, Arg72Pro in exon 4 and G>A in intron 6 have been reported to modulate susceptibility to various malignancies. Therefore, the present study evaluated the role of these p53 polymorphisms in oral cancer susceptibility in a population from Gujarat, West India. Genotype frequencies at the three p53 loci in 110 controls and 79 oral cancer cases were determined by the PCR-RFLP method. Heterozygous individuals at exon 4 showed protection from developing oral cancer. Homozygous wild and heterozygous individuals at intron 3 and those heterozygous at exon 4 in combination appeared to be at lowered risk. Furthermore, carriers of the 16 bp duplication allele at intron 3, proline allele at exon 4 and G allele at intron 6 were protected from oral cancer development. p53 polymorphisms, especially Arg72Pro in exon 4 could significantly modify the risk of oral cancer development in Gujarat, West Indian population.

A two-stage association study identifies methyl-CpG-binding domain protein 2 gene polymorphisms as candidates for breast cancer susceptibility

Genome-wide association studies for breast cancer have identified over 40 single-nucleotide polymorphisms (SNPs), a subset of which remains statistically significant after genome-wide correction. Improved strategies for mining of genome-wide association data have been suggested to address heritable component of genetic risk in breast cancer. In this study, we attempted a two-stage association design using markers from a genome-wide study (stage 1, Affymetrix Human SNP 6.0 array, cases=302, controls=321). We restricted our analysis to DNA repair/modifications/metabolism pathway related gene polymorphisms for their obvious role in carcinogenesis in general and for their known protein–protein interactions vis-à-vis, potential epistatic effects. We selected 22 SNPs based on linkage disequilibrium patterns and high statistical significance. Genotyping assays in an independent replication study of 1178 cases and 1314 controls were attempted using Sequenom iPLEX Gold platform (stage 2). Six SNPs (rs8094493, rs4041245, rs7614, rs13250873, rs1556459 and rs2297381) showed consistent and statistically significant associations with breast cancer risk in both stages, with allelic odds ratios (and P-values) of 0.85 (0.0021), 0.86 (0.0026), 0.86 (0.0041), 1.17 (0.0043), 1.20 (0.0103) and 1.13 (0.0154), respectively, in combined analysis (N=3115). Of these, three polymorphisms were located in methyl-CpG-binding domain protein 2 gene regions and were in strong linkage disequilibrium. The remaining three SNPs were in proximity to RAD21 homolog (S. pombe), O-6-methylguanine-DNA methyltransferase and RNA polymerase II-associated protein 1. The identified markers may be relevant to breast cancer susceptibility in populations if these findings are confirmed in independent cohorts.

Relationship between CYP1A1 and GSTM1 genetic polymorphisms and lung cancer susceptibility in population of Inner Mongolia

Lung cancer is one of malignant tumors to hurt human health. It has been known that the development of lung cancer may be associated with genetic polymorphism of some lung cancer related genes. The aim of this study is to explore the susceptibility to lung cancer in relation to CYP1A1 and GSTM1 genetic polymorphisms in population of Inner Mongolia. CYP1A1 and GSTM1 genetic polymorphisms were determined by PCR-RFLP in 163 lung cancer cases and healthy controls respectively. The frequencies of CYP1A1 variation genotype (vt/vt) and GSTM1(-) were 36.8% and 65.0% in lung cancer cases and 19.0% and 48.9% in healthy controls respectively. Statistical tests showed significant difference in the frequencies between the two groups (Chi-Square =12.82, P=0.0001; Chi-Square = 9.78, P=0.002). The risk of lung cancer with CYP1A1 variation genotype was significantly higher than those of controls (OR= 2.48, 95% CI=1.51-4.08). The individuals who carried with GSTM1-null genotype had a high risk of lung cancer (OR=2.03, 95% CI=1.30-3.17). Combined analysis of the polymorphisms showed that percentage of CYP1A1(vt/vt)/GSTM1(-) in lung cancer and control groups was 28.8% and 8.0% respectively (Chi-Square = 23.883, P=0.0001). The people who carried with CYP1A1(vt/vt)/GSTM1(-) had a high risk of lung cancer (OR=4.90, 95% CI=2.50-9.83). Pearson Chi-Square of sex differential showed there was no significance between the homozygous variation genotype of CYP1A1/GSTM1(-) and the other genotypes of CYP1A1/GSTM1(-) neither in lung cancer group (Chi-Square=0.797, P=0.372) nor in control group (Chi-Square=0.670, P=0.761). Statistical tests showed that susceptibility to lung cancer was related to smoking (Chi-Square = 14.197, P=0.000), the risk of lung cancer in smoking individuals raised remarkably (OR=2.33, 95% CI=1.50-3.62). There may be a synergetic interaction between CYP1A1 variation genotype (vt/vt) and smoking on the elevated susceptibility to lung cancer (Chi-Square = 23.843, P=0.000), the smokers who carried with CYP1A1 (vt/vt) had a significantly higher risk of lung cancer (OR=4.44, 95% CI=2.40-8.32, Chi-Square = 23.843, P= 0.000). So did the GSTM1(-) and smoking on the elevated susceptibility to lung cancer, the significantly higher risk of lung cancer had also been found in those smokers who carried with GSTM1(-) (OR=7.32, 95% CI=3.39-15.50, Chi-Square = 36.708,P=0.000). The polymorphisms of CYP1A1 vt/vt and GSTM1(-) are the risk factors in lung cancer of Inner Mongolia. Smoking is also related to the susceptibility to lung cancer. There may be a synergetic interaction between CYP1A1 (vt/vt) and GSTM1(-) on the elevated susceptibility of lung cancer. So do the CYP1A1 (vt/vt), GSTM1(-) and smoking.