Predicting Pancreatic Cancer in the UK Biobank Cohort Using Polygenic Risk Scores and Diabetes Mellitus,Gastroenterology

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Predicting Pancreatic Cancer in the UK Biobank Cohort Using Polygenic Risk Scores and Diabetes Mellitus
Gastroenterology ( IF 29.4 ) Pub Date : 2022-01-21 , DOI: 10.1053/j.gastro.2022.01.016
Shreya Sharma ₁ , William J Tapper ₁ , Andrew Collins ₂ , Zaed Z R Hamady ₃

Affiliation

Background & Aims

Diabetes mellitus (DM) is known to be associated with pancreatic ductal adenocarcinoma (PDAC), particularly new-onset DM (NODM). Others have developed polygenic risk scores (PRS) associated with PDAC risk. We aimed to compare the performance of these PRS in an independent cohort to determine if they can discriminate between NODM and long-standing DM patients with PDAC.

Methods

Cases (1042) and matched cancer-free controls (10,420) were drawn from the UK Biobank. Five PRS models were calculated using single nucleotide polymorphisms (SNPs) from previous studies (Nakatochi, Galeotti, Molina, Jia, and Rashkin) and a combination of these. Regression models were used to assess the association between PDAC and PRS adjusted for ancestry, smoking, DM, waist circumference, and family history of digestive cancer. Receiver operator characteristic curves and area under the curve metrics (AUC) were used to assess the performance of each PRS for classifying PDAC risk.

Results

The combined PRS model achieved the highest AUC (0.605), and significantly improved a clinical risk model in this cohort (AUC = 0.83; P = .0002). Individuals within the fifth quintile have a 2.74-fold increased risk of developing PDAC vs those in the first quintile (P < .001), and have a 3.05-fold increased risk of developing PDAC if they have DM vs those without DM (P < .001). The positive predictive value was 11.9% in participants without DM, 23.9% with long-standing DM, and 86.7% with NODM.

Conclusions

The PDAC-related common genetic variants are more strongly associated with DM. This PRS has the potential for targeting individuals with NODM for PDAC secondary screening measures.

中文翻译：

使用多基因风险评分和糖尿病预测英国生物银行队列中的胰腺癌

背景与目标

已知糖尿病 (DM) 与胰腺导管腺癌 (PDAC) 相关，尤其是新发 DM (NODM)。其他人开发了与 PDAC 风险相关的多基因风险评分 (PRS)。我们的目的是比较这些 PRS 在独立队列中的表现，以确定它们是否可以区分 NODM 和患有 PDAC 的长期 DM 患者。

方法

病例 (1042) 和匹配的无癌对照 (10,420) 来自英国生物银行。使用先前研究（Nakatochi、Galeotti、Molina、Jia 和 Rashkin）的单核苷酸多态性 (SNP) 及其组合计算了五个 PRS 模型。回归模型用于评估根据血统、吸烟、糖尿病、腰围和消化道癌症家族史调整后的 PDAC 和 PRS 之间的关联。接受者操作员特征曲线和曲线下面积 (AUC) 用于评估每个 PRS 对 PDAC 风险分类的性能。

结果

联合 PRS 模型实现了最高的 AUC (0.605)，并显着改善了该队列中的临床风险模型（AUC = 0.83；P = .0002）。与第一个五分位数的人相比，第五个五分位数的人患 PDAC 的风险增加 2.74 倍 ( P < .001)，如果他们患有 DM 与没有 DM 的人相比，他们患 PDAC 的风险增加 3.05 倍 ( P < .001 ) .001）。阳性预测值在没有 DM 的参与者中为 11.9%，在有长期 DM 的参与者中为 23.9%，在有 NODM 的参与者中为 86.7%。