Division of Surgical Oncology and Endocrine Surgery, Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
Herbert Wertheim School of Public Health & Human Longevity Science, University of California, San Diego, San Diego, CA, USA.
EBioMedicine. 2024 Aug;106:105233. doi: 10.1016/j.ebiom.2024.105233. Epub 2024 Jul 12.
Two important questions regarding the genetics of pancreatic adenocarcinoma (PDAC) are 1. Which germline genetic variants influence the incidence of this cancer; and 2. Whether PDAC causally predisposes to associated non-malignant phenotypes, such as type 2 diabetes (T2D) and venous thromboembolism (VTE).
In this study of 8803 patients with PDAC and 67,523 controls, we first performed a large-scale transcriptome-wide association study to investigate the association between genetically determined gene expression in normal pancreas tissue and PDAC risk. Secondly, we used Mendelian Randomization (MR) to analyse the causal relationships among PDAC, T2D (74,124 cases and 824,006 controls) and VTE (30,234 cases and 172,122 controls).
Sixteen genes showed an association with PDAC risk (FDR <0.10), including six genes not yet reported for PDAC risk (PPIP5K2, TFR2, HNF4G, LRRC10B, PRC1 and FBXL20) and ten previously reported genes (INHBA, SMC2, ABO, PDX1, MTMR6, ACOT2, PGAP3, STARD3, GSDMB, ADAM33). MR provided support for a causal effect of PDAC on T2D using genetic instruments in the HNF4G and PDX1 loci, and unidirectional causality of VTE on PDAC involving the ABO locus (OR 2.12, P < 1e). No evidence of a causal effect of PDAC on VTE was found.
These analyses identified candidate susceptibility genes and disease relationships for PDAC that warrant further investigation. HNF4G and PDX1 may induce PDAC-associated diabetes, whereas ABO may induce the causative effect of VTE on PDAC.
National Institutes of Health (USA).
关于胰腺导管腺癌（PDAC）的遗传学有两个重要问题：1. 哪些种系遗传变异会影响这种癌症的发病率；2. PDAC 是否会导致相关的非恶性表型，如 2 型糖尿病（T2D）和静脉血栓栓塞（VTE）。
在这项对 8803 名 PDAC 患者和 67523 名对照者的研究中，我们首先进行了一项大规模的转录组全基因组关联研究，以研究正常胰腺组织中遗传决定的基因表达与 PDAC 风险之间的关联。其次，我们使用孟德尔随机化（MR）分析 PDAC、T2D（74124 例和 824006 例对照）和 VTE（30234 例和 172122 例对照）之间的因果关系。
有 16 个基因与 PDAC 风险相关（FDR<0.10），包括 6 个以前未报道过与 PDAC 风险相关的基因（PPIP5K2、TFR2、HNF4G、LRRC10B、PRC1 和 FBXL20）和 10 个以前报道过的基因（INHBA、SMC2、ABO、PDX1、MTMR6、ACOT2、PGAP3、STARD3、GSDMB、ADAM33）。MR 提供了使用 HNF4G 和 PDX1 基因座中的遗传工具对 PDAC 与 T2D 之间因果关系的支持，并且涉及 ABO 基因座的 VTE 对 PDAC 的单向因果关系（OR 2.12，P<1e）。没有发现 PDAC 对 VTE 有因果关系的证据。
这些分析确定了候选易感性基因和 PDAC 的疾病关系，值得进一步研究。HNF4G 和 PDX1 可能会导致 PDAC 相关的糖尿病，而 ABO 可能会导致 VTE 对 PDAC 的因果作用。
美国国立卫生研究院（NIH）。
