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 (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 (OR=6.95; 95% CI=3.43–14.08). 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.
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Acknowledgements
We express our heartfelt gratitude to all the subjects who participated in this study, and the members of the Rotary Club of Osaka-Midosuji District 2660 Rotary International in Japan for supporting our study. We would also like to acknowledge members of the Laboratory for Genotyping Development, RIKEN Center for Genomic Medicine for their excellent technical assistance, and the BioBank Japan for providing DNA samples and clinical information for this study. We also thank Drs Jin-Young Jang, Yoon-Sup Song, Jae-Hyun Park and Siew-Kee Low for their kind support and helpful discussion. This work was supported by Leading Project for Personalized Medicine in Ministry of Education, Culture, Sports, Science and Technology, Japan.
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Cha, PC., Zembutsu, H., Takahashi, A. et al. A genome-wide association study identifies SNP in DCC is associated with gallbladder cancer in the Japanese population. J Hum Genet 57, 235–237 (2012). https://doi.org/10.1038/jhg.2012.9
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DOI: https://doi.org/10.1038/jhg.2012.9
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