A genome-wide association study identifies SNP in DCC is associated with gallbladder cancer in the Japanese population

Abstract

Gallbladder cancer (GC) is a relatively uncommon cancer with higher incidence in certain areas including Japan. Because of the difficulty in diagnosis, prognosis of GC is very poor. To identify genetic determinants of GC, we conducted a genome-wide association study (GWAS) in 41 GC patients and 866 controls. Association between each single-nucleotide polymorphism (SNP) with GC susceptibility was evaluated by multivariate logistic regression analysis conditioned on age and gender of subjects. SNPs that showed suggestive association (Po1Â10 À4 ) with GC were further examined in 30 cases and 898 controls. SNP rs7504990 in the DCC (deleted in colorectal cancer, 18q21.3) that encodes a netrin 1 receptor achieved a combined P-value of 7.46Â10 À8 (OR¼6.95; 95% CI¼3.43-14.08). Subsequent imputation analysis identified multiple SNPs with similarly strong associations in an adjacent genomic region, where loss of heterozygosity was reported in GC and other cancers. Reduced expression of DCC was indicated to be associated with the poorly differentiated histological type, increased proliferation and metastasis through loss of adhesiveness. However, due to the limited sample size investigated here, further replication study and functional analysis would be necessary to further confirm the result of the association. INTRODUCTIONGallbladder cancer (GC) is the most common malignancy of the biliary tract and the fifth most common cancer of the gastrointestinal tract. 1 With an overall 5-year survival rate of o5%, GC is a highly lethal malignancy with very poor prognosis. 2 Most of GCs were diagnosed at a very late stage because of the lack of symptoms and non-specific symptoms of early-stage tumors. 1,3 Although the incidence of GC is relatively rare compared with other cancers, higher incidences of GC have been reported in certain geographical regions including India, Pakistan, Ecuador, Korea and Japan. 4 In addition, the prevalence of GC is known to be three times higher in women than in men. 5 Although several clinical risk factors of GC such as gallstones, cholecystitis, porcelain gallbladder, gallbladder polyps, anomalous panreatobiliary duct junction and obesity have been indicated, 1,6 etiology of GC is largely unknown. Only few somatic genetic changes including mutations in K-ras, TP53 and p16 Ink4 /CDKN2 as well as loss of heterozygosity at several chromosomal regions harboring known or putative tumor-suppressor genes have been reported in GCs. 5,7 Hence, identification of novel genetic factors associated with susceptibility to GC should

Association of gastrointestinal gland cancer susceptibility loci with esophageal carcinoma among the Chinese Han population: a case–control study

“…Of the six EC susceptibility loci, we identified and found that only the minor allele of rs10953615 was a similar risk factor for gallbladder and esophageal carcinoma and this allele was associated with increased risk for both cancers [21]. The other five SNPs showed results that were inconsistent with previous studies.…”

“…Twenty SNPs (rs6736997, rs401681, rs6879627, rs9502893, rs9363918, rs4269383, rs3016539, rs7832232, rs10088262, rs10788473, rs12413624, rs10500715, rs1000589, rs1585440, rs9573163, rs9543325, rs4924935, rs225190, rs372883, and rs1547374) were selected from previous research of pancreatic cancer [15][16][17][18][19][20]. Four SNPs (rs975334, rs10953615, rs13294589, and rs7504990) were selected from previous research of gallbladder cancer [21]. All of the SNPs in this study had minor allele frequencies (MAFs) of >5 % in the Asian Population HapMap and had previously been reported to be associated with gastrointestinal cancer.…”

Modifiable Factors and Genetic Predisposition Associated with Gallbladder Cancer. A Concise Review

“…As mentioned above, according to our knowledge, only a single, small GWAS has been performed in patients with this tumor yet [68]. Although GWAS analyses can identify only common variants (i.e.…”

“…Finally, genome-wide association analyses and functional studies have identified the p. D19H variant of the hepatic cholesterol hemitransporter (ABCG8) associated with susceptibility for human gallstones [55,66,67]. To our knowledge the only genome-wide association study (GWAS) of patients with gallbladder cancer published to date (https://www.ebi.ac.uk/gwas/) was conducted in a relatively small Japanese discovery cohort of 41 GC patients and 866 controls, and a subsequent validation cohort of 30 cases and 898 controls [68]. A strong positive signal (combined P = 7.46 × 10 -8 OR=6.95; 95% CI=3.43-14.08) was detected for rs7504990 within the DCC gene (deleted in colorectal cancer) on chromosome 18q21.3.…”

DCC (deleted in colorectal carcinoma) gene variants confer increased susceptibility to gallbladder cancer (Ref. No.: Gene-D-12-01446)

“…Using candidate gene association studies, we have previously identified several genetic variants in cholesterol metabolism, inflammation, hormonal and DNA-repair pathway as playing a significant role in vulnerability to GBC Srivastava et al, 2010Srivastava et al, , 2011aSrivastava et al, ,b, 2012. Recently, a genome-wide association study (GWAS) showed a significant association between DCC gene polymorphisms and GBC susceptibility in a Japanese population sample (Cha et al, 2012). However, the sample size of the study was very low and the study lacked independent replication.…”