解析胃癌的遗传异质性。

Dissecting the genetic heterogeneity of gastric cancer.

机构信息

Institute of Human Genetics, University of Marburg, Marburg, Germany; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.

Institute of Human Genetics, University of Marburg, Marburg, Germany; Medical Faculty, Institute for Genomic Statistics and Bioinformatics, University of Bonn, Bonn, Germany.

出版信息

EBioMedicine. 2023 Jun;92:104616. doi: 10.1016/j.ebiom.2023.104616. Epub 2023 May 18.

DOI:10.1016/j.ebiom.2023.104616

PMID:37209533

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10212786/

Abstract

BACKGROUND

Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture.

METHODS

We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO.

FINDINGS

Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level.

INTERPRETATION

Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO.

FUNDING

German Research Foundation (DFG).

摘要

背景

胃癌（GC）根据部位（贲门/非贲门）和组织病理学（弥漫性/肠型）在临床上存在异质性。我们旨在根据其亚型描述 GC 的遗传风险结构。另一个目的是检查贲门癌和食管腺癌（OAC）及其前体病变巴雷特食管（BO）是否共享多基因风险结构，这些癌症均位于胃食管交界处（GOJ）。

方法

我们对 10 项欧洲全基因组关联研究（GWAS）的 GC 及其亚型进行了荟萃分析。所有患者均经组织病理学证实为胃腺癌。为了在 GWAS 位点中识别风险基因，我们对胃体和胃窦黏膜进行了全转录组关联研究（TWAS）和表达数量性状基因座（eQTL）研究。为了测试贲门癌和 OAC/BO 是否具有遗传病因，我们还使用了具有 OAC/BO 的欧洲 GWAS 样本。

结果

我们的 GWAS 包括 5816 名患者和 10999 名对照，根据其亚型突出了 GC 的遗传异质性。我们新发现了两个并复制了五个 GC 风险位点，所有这些位点都与亚型特异性相关。包含 361 个胃体和 342 个胃窦黏膜样本的胃转录组数据表明，四个 GWAS 位点中 MUC1、ANKRD50、PTGER4 和 PSCA 的表达上调可能是 GC 的发病机制。在另一个风险位点上，我们发现血型 O 对非贲门和弥漫性 GC 具有保护作用，而血型 A 则增加了两种 GC 亚型的风险。此外，我们对贲门癌和 OAC/BO 的 GWAS（10279 名患者，16527 名对照）表明，这两种癌症实体在多基因水平上具有遗传病因，并在单标记水平上确定了两个新的风险位点。