DCC (Deleted in Colorectal Carcinoma) Gene Variants Confer Increased Susceptibility to Gallbladder Cancer (Ref. No.: GENE-D-12-01446).

Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow, India.
Gene (Impact Factor: 2.14). 01/2013; 518(2). DOI: 10.1016/j.gene.2013.01.019
Source: PubMed


Background and aim:
GBC is a lethal and multifaceted disease. Deleted in colorectal carcinoma (DCC) is a well known tumor suppressor gene. Recently a small genome-wide association study (GWAS) identified DCC to be significantly associated with gallbladder cancer (GBC) susceptibility in a Japanese population sample. However, the study sample size was small and lacked independent replication. Therefore, the present study was carried out to replicate the association of two GWAS identified DCC SNPs (A>Grs4078288, C>Trs7504990) and two other SNPs (C>Grs2229080 and A>Grs714) previously associated with various cancers.

The study was accomplished in 406 GBC cases and 260 healthy control samples from North India. Genotyping was carried out by PCR-RFLP and Taqman genotyping assays. Statistical analysis was performed by using SPSS ver16 and functional prediction of these variants was carried out using Bioinformatics tools (FAST-SNP, F-SNP).

We did not observe association with GWAS-identified SNPs of DCC but other SNPs showed significant association. In addition, a DCC haplotype Grs2229080-Ars4078288-Crs7504990-Ars714 conferred high risk of GBC in India. The haplotype associated risk was independent of gallstone, sex or tobacco usages which are well-known modifiers of GBC risk. Further analysis suggested DCC A>Grs714 as a major risk conferring SNP in the Indian population.

This study re-affirms the role of plausible tumor suppressor DCC variants, in gallbladder carcinogenesis and the risk haplotype may be explored as a useful marker for GBC susceptibility.

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    • "The healthy controls had no evidence of any personal history of gallstone, gallbladder cancer or other malignant conditions or chronic disease. The inclusion and exclusion criteria for the recruitment of the Patients and controls were as previously described [32]. The participation rate was 100%, and blood samples were available for all subjects. "
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    ABSTRACT: Defective apoptosis is a hallmark of cancer development and progression. Death receptors (DR4, FAS) and their ligands (TRAIL, FASL) are thought to mediate the major extrinsic apoptotic pathway in the cell. SNPs in these genes may lead to defective apoptosis. Hence, the present study aimed to investigate the association of functional SNPs of DR4 (rs20575, rs20576 and rs6557634), FAS (rs2234767) and FASL (rs763110) with gallbladder cancer (GBC) risk. This case-control study included 400 GBC and 246 healthy controls (HC). Genotyping was carried out by Taqman genotyping assays. Statistical analysis was performed by using SPSS ver16. Meta-analysis was performed using Comprehensive Meta-analysis software (Version 2.0, BIOSTAT, Englewood, NJ) to systematically summarize the possible association of SNP with cancer risk. Functional prediction of these variants was carried out using Bioinformatics tools (FAST-SNP, F-SNP). False discovery rate (FDR test) was used in multiple comparisons. The DR4 Crs20575Ars20576Ars6557634, Grs20575Ars20576Grs6557634 and Grs20575Crs20576Grs6557634 haplotypes conferred two-fold increased risk for GBC. Among these, the DR4 Crs20575Ars20576Ars6557634 haplotype emerged as main factor influencing GBC susceptibility as the risk was not modulated by gender or gallstone stratification. Our meta-analysis results showed significant association of DR4 rs6557634 with overall cancer risk, GI cancers as well as in Caucasians. We didn't find any association of FAS and FASL SNPs with GBC susceptibility. The DR4 haplotype Crs20575Ars20576Ars6557634 represents an important factor accounting the patients susceptibility to GBC probably due to decreased apoptosis. However, additional well-designed studies with larger sample size focusing on different ethnicities are required to further validate the results.
    PLoS ONE 02/2014; 9(2):e90264. DOI:10.1371/journal.pone.0090264 · 3.23 Impact Factor
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    • "The healthy controls were mean age, sex, ethnicity matched and free from any personal history of gallstone, gallbladder cancer or other malignant conditions. The recruitment of the patients and controls were based on the inclusion and exclusion criteria (Rai et al., 2013). The family history and general questionnaire of all the patients recruited for the study were taken to ensure their ethnicity. "
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    ABSTRACT: Background and aim PSCA is a tissue specific tumor suppressor or oncogene which has been found to be associated with several human tumors including gallbladder cancer. It is considered to be involved in the cell-proliferation inhibition and /or cell-death induction activity. Therefore, we aimed to investigate the role of PSCA gene polymorphisms in gallbladder cancer risk in North Indian population. Methodology A total of 405 gallbladder cancer patients and 247 healthy controls were included in the case-control study for risk prediction. We examined the association of two functional SNPs, rs2294008 and rs2978974 in PSCA gene by genotyping using Taqman allelic discrimination assays. Statistical analysis was done using SPSS software, version 17. Linkage disequilibrium and haplotype analysis was done with the help of SNPstats software. FDR test was used to correct for multiple comparisons. No significant associations of rs2294008 and rs2978974 genetic variants of the PSCA gene were found with GBC risk at allele, genotype or haplotype levels. Stratifying the subjects on the basis of gallstone also did not show any significant result. However, on gender stratification, we found a significant association of Trs2294008-Grs2978974 haplotype with higher risk of GBC in females (FDR Pcorr=0.021, OR=1.6). In contrary, Trs2294008-A rs2978974 haplotype conferred significant lower risk in males (FDR Pcorr=0.013; OR=0.25). These findings suggest that PSCA genetic variants may have a significant effect on GBC susceptibility in a gender specific manner.
    Gene 08/2013; 530(2). DOI:10.1016/j.gene.2013.08.058 · 2.14 Impact Factor
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    ABSTRACT: Genetic alterations in the deleted in colorectal carcinoma (DCC) gene have been a priori reported to associate with metastasis in variety of human cancers. We investigated the association between potentially functional SNPs in DCC and susceptibility to esophageal (EC) and gastric (GC) cancers in Kashmir Valley. We genotyped two SNPs DCC rs714 (A>G) and DCC rs2229080 (C>G) of DCC in 135 EC patients, 108 GC patients, and 195 controls matched by age and sex in Kashmir Valley by polymerase chain reaction-RFLP method. Risk for developing EC and GC was estimated by binary logistic regression by using SPSS. We also performed a meta-analysis on DCC rs714 (A>G) and evaluated the association between the DCC rs714 (A>G) polymorphisms and cancer risk. A significant difference in DCC rs714 (A>G) genotype distribution between EC and GC cases and corresponding control groups was observed (odds ratio (OR) = 1.92; P = 0.03; P-trend = 0.04; false discovery rate (FDR) Pcorr = 0.03: OR = 2.15; P = 0.02; P-trend = 0.01; FDR Pcorr = 0.03). But no such association was observed in DCC rs2229080 (C>G). Further, DCC rs714 (A>G) AA genotype showed significantly increased risk for both gastric squamous cell carcinoma (OR = 5.63; P = 0.02; FDR Pcorr = 0.01) and gastric adenocarcinoma (OR = 2.15; P = 0.02; FDR Pcorr = 0.01). Smoking and salted tea are independently associated with both EC and GC, but gene-environment interaction did not further modulate the risk. Meta-analysis also suggested both independent and overall association of DCC rs714 (A>G) polymorphism with cancer (P = 0.000). In conclusion, genetic variations in DCC rs714 (A>G) modulate risk of EC and GC in high-risk Kashmir population.
    Tumor Biology 06/2013; 34(5). DOI:10.1007/s13277-013-0870-4 · 3.61 Impact Factor
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