Death receptor 4 variants enhanced prostate cancer risk in North Indian population

Abstract

Death receptor 4 (DR4) is a tumor suppressor gene and plays an important mediator of apoptosis. Polymorphism in DR4 gene may reduce apoptotic capacity and provoke proliferation of cell and cancer. We evaluated genetic polymorphisms of DR4 gene in association with risk of prostate cancer (PCa) in Northern Indian population. We have recruited 192 PCa patients and 225 cancer-free ages matched unrelated healthy control of similar ethnicity. They were genotyped for DR4, 141 (G > A), 209 (C > G), and 228 (A > C) polymorphisms using amplification refractory mutation system (ARMS) method. Variant genotype AA (OR = 2.54; p = 0.007) and A allele (OR = 1.51; p = 0.015) of DR4 141 demonstrated significant increased risk for PCa. Similarly, variant genotype GG (OR = 2.58; p = 0.003) and G allele carrier (CG + GG) (OR = 1.50; p = 0.043) of DR4 209 conferred increased risk. G allele (OR = 1.50, p = 0.005) was also statistically associated with PCa risk. High risk for PCa was also observed with respect to haplotypes A-G-A (OR = 2.86; Bonferroni correction Pc = 0.008) and A-G-C (OR = 3.18, Pc = 0.008). We observed significantly enhanced risk for PCa due to interaction between DR4 209 and 228 gene polymorphisms. Furthermore, a significantly increased risk of high Gleason grade tumor was found in the combined variant allele carrier (GA + AA) of DR4 141 compared with the GG genotype (OR = 2.27, Pc = 0.052). Interaction of smoking and genotypes did not further modulate the risk of PCa. Our observations suggested that genetic variants of the DR4 gene significantly influence the risk of PCa in North Indian population and might be involved in the etiology of PCa.

DR4 mediates the progression, invasion, metastasis and survival of colorectal cancer through the Sp1/NF1 switch axis on genomic locus

“…Recent studies have shown that the SNPs in the DR4 gene are associated with different types of cancers, such as colorectal cancer, 13 prostate cancer, 14 ovarian cancer, 15 lung cancer and head and neck cancer. 16 To the best of our knowledge, the findings reported herein establish for the first-time decreased risk and increased survival times in colorectal cancer patients carrying the rs13278062 GT/TT genotype.…”

“…[7][8][9] Death receptor 4(DR4) contains a cytoplasmic death domain that activates apoptosis by interacting with tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) through the extrinsic death receptor pathway. 12 Several functional single nucleotide polymorphisms (SNPs) in the DR4 gene are associated with different types of diseases, such as colorectal cancer, 13 prostate cancer, 14 ovarian cancer, 15 lung cancer and head and neck cancer, 16 However, the minor allele frequency (MAF) of these SNPs was low in Han Chinese individuals from Beijing, China (CHB populations), suggesting that other variants in DR4 might play an important role in the development of cancer. 11 Furthermore, it has been reported that abnormal expression of DR4 was also correlated with the prognosis of colorectal cancer 10 and lung squamous cell carcinoma.…”

“…11 Furthermore, it has been reported that abnormal expression of DR4 was also correlated with the prognosis of colorectal cancer 10 and lung squamous cell carcinoma. 12 Several functional single nucleotide polymorphisms (SNPs) in the DR4 gene are associated with different types of diseases, such as colorectal cancer, 13 prostate cancer, 14 ovarian cancer, 15 lung cancer and head and neck cancer, 16 However, the minor allele frequency (MAF) of these SNPs was low in Han Chinese individuals from Beijing, China (CHB populations), suggesting that other variants in DR4 might play an important role in the development of cancer. Wang et al first reported that the SNP 2397G > T polymorphism in the promoter of DR4, which has a high MAF, was associated with a significantly increased risk of bladder cancer in a Chinese population.…”

The The Frigging Kinship Between Prostate Carcinogenesis and the Genomic Landscape of Indian Males

“…Significant association was reported for two SNPs of tumor suppressor gene P53 by Mittal et al 2011; with the heterozygous GA genotype of intron-6 polymorphism rs1625895, c.13494G>A (P value=0.051, OR=1.48, 95%CI=0.999-2.220) and heterozygous GC genotype of exon-4 non-synonymous polymorphism rs1042522 (c.215G>C; Arg72Pro) (P value=0.050, OR=1.5, 95%CI=1-2.199) showed an increased risk of PCa [54]. The team also reported 2 missense variants of DR4, rs6557634 (G>A; His141Arg) and rs4871857 (C>G; Thr209Arg) whose homozygous variant genotypes conferred higher PCa risk (P value=0.007, OR(95%CI)=2.54(1.29-5.00) and P value=0.003, OR(95%CI)=2.58 (1.38-4.81), respectively) [55].…”