Genetic Variants in the SWI/SNF Complex and Smoking Collaborate to Modify the Risk of Pancreatic Cancer in a Chinese Population

Pancreatic cancer (PC) is an aggressive malignancy with extremely low 5-year survival rate (<5%). SWItch/Sucrose Non Fermentable (SWI/SNF) complex is a core factor for chromatin-remodeling that utilize energy of ATP hydrolysis to mobilize nucleosomes, and modulate gene transcription. Recent studies have identified recurrent mutations in major components of SWI/SNF in a variety of human cancers, including PC. We conducted a two-stage case-control study to investigate the associations between 14 common variants in 6 genes (SMARCA4, SMCRB1, PBRM1, BRD7, ARID1, and ARID2) encoding major components of the SWI/SNF complex and the risk of PC. Three promising variants, rs11644043, rs11085754, and rs2073389 in the discovery stage comprising 310 cases and 457 controls were further genotyped in the validation stage containing 429 cases and 585 controls. rs11644043 in BRD7 and rs11085754 in SMARCA4 showed consistent significant association with increased risk of PC in both stages, with odds ratios (ORs) and 95% confidence interval (CI) of 2.04 (1.17-3.56) and 1.64 (1.16-2.33) in stage one, and 1.97 (1.24-3.14) and 1.45 (1.04-2.02) in stage two, respectively in a recessive model. Furthermore, the accumulative effects of rs11644043, rs11085754, and rs2073389 in SMARCB1 were observed (P for trend <0.0001). Intriguingly, gene-environmental interactions analysis consistently revealed the potential interactions of rs2073389 (P-add-FDR=6.00x10(-4), P-mul-FDR=1.50x10(-2)) and rs11085754 (P-add-FDR=0.03) collaborating with smoking to modify the risk of PC. In conclusion, the current study provides evidence that genetic variants of SWI/SNF may contribute to the susceptibility of PC in the Chinese population. (c) 2014 Wiley Periodicals, Inc.