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

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 (P<1 × 10^-4) 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 7.46 × 10^-8 (OR6.95; 95% CI3.43-14.08). 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.