A Transcriptome-Wide Association Study Identifies Candidate Susceptibility Genes for Pancreatic Cancer Risk.
A Transcriptome-Wide Association Study Identifies Candidate Susceptibility Genes for Pancreatic Cancer Risk.
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DOI：
10.1158/0008-5472.can-20-1353
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发表时间：
2020-10-15
期刊：
影响因子：
11.2
通讯作者：
Wu L
中科院分区：
文献类型：
--
作者：
Liu D;Zhou D;Sun Y;Zhu J;Ghoneim D;Wu C;Yao Q;Gamazon ER;Cox NJ;Wu L
胰腺癌是特征最为明确的癌症类型之一，但胰腺癌风险的大部分遗传力仍不清楚。在此，我们进行了一项大规模的全转录组关联研究（TWAS），以系统地探究正常胰腺组织中基因预测的基因表达与胰腺癌风险之间的关联。利用基因型 - 组织表达项目中大多为欧洲血统的305名受试者的数据，我们构建了综合的遗传模型来预测正常胰腺组织的基因表达，对UTMOST（分子特征的统一检验）进行了改进。这些预测模型被应用于8275例胰腺癌病例和6723例欧洲血统对照的遗传数据。13个基因在错误发现率（FDR）≤0.05的情况下显示出基因预测表达与胰腺癌风险之间的关联，包括7个先前报道过的基因（抑制素βA（INHBA）、染色体结构维持蛋白2（SMC2）、血型糖蛋白A（ABO）、胰腺十二指肠同源盒蛋白1（PDX1）、RCCD1、CFDP1和PGAP3）以及6个尚未报道与胰腺癌风险相关的新基因（6q27：SFT2D1（比值比（OR）（95%置信区间（CI））：1.54（1.25 - 1.89））；13q12.13：肌管素相关蛋白6（MTMR6）（OR（95% CI）：0.78（0.70 - 0.88））；14q24.3：酰基辅酶A硫酯酶2（ACOT2）（OR（95% CI）：1.35（1.17 - 1.56））；17q12：类固醇生成急性调节蛋白相关脂质转运结构域蛋白3（STARD3）（OR（95% CI）：6.49（2.96 - 14.27））；17q21.1：含gasdermin结构域蛋白B（GSDMB）（OR（95% CI）：1.94（1.45 - 2.58））；以及20p13：解整合素金属蛋白酶33（ADAM33）（OR（95% CI）：1.41（1.20 - 1.66）））。即使在对先前全基因组关联研究（GWAS）中确定的风险单核苷酸多态性（SNP）进行调整后，其中10个基因（SFT2D1、MTMR6、ACOT2、STARD3、GSDMB、ADAM33、SMC2、RCCD1、CFDP1和PGAP3）的关联仍然具有统计学意义。总体而言，这项分析确定了胰腺癌的新的候选易感基因，值得进一步研究。
Pancreatic cancer is among the most well characterized cancer types, yet a large proportion of the heritability of pancreatic cancer risk remains unclear. Here we performed a large transcriptome-wide association study (TWAS) to systematically investigate associations between genetically predicted gene expression in normal pancreas tissue and pancreatic cancer risk. Using data from 305 subjects of mostly European descent in the Genotype-Tissue Expression Project, we built comprehensive genetic models to predict normal pancreas tissue gene expression, modifying the UTMOST (unified test for molecular signatures). These prediction models were applied to the genetic data of 8,275 pancreatic cancer cases and 6,723 controls of European ancestry. Thirteen genes showed an association of genetically predicted expression with pancreatic cancer risk at a false discovery rate (FDR) ≤ 0.05, including seven previously reported genes (INHBA, SMC2, ABO, PDX1, RCCD1, CFDP1, and PGAP3) and six novel genes not yet reported for pancreatic cancer risk (6q27: SFT2D1 (odds ratio (OR) (95% confidence interval (CI)): 1.54 (1.25–1.89)); 13q12.13: MTMR6 (OR (95% CI): 0.78 (0.70–0.88)); 14q24.3: ACOT2 (OR (95% CI): 1.35 (1.17–1.56)); 17q12: STARD3 (OR (95% CI): 6.49 (2.96–14.27)); 17q21.1: GSDMB (OR (95% CI): 1.94 (1.45–2.58)); and 20p13: ADAM33 (OR (95% CI): 1.41 (1.20–1.66))). The associations for ten of these genes (SFT2D1, MTMR6, ACOT2, STARD3, GSDMB, ADAM33, SMC2, RCCD1, CFDP1, and PGAP3) remained statistically significant even after adjusting for risk SNPs identified in previous GWAS. Collectively, this analysis identified novel candidate susceptibility genes for pancreatic cancer that warrant further investigation.