Genomic and transcriptomic alterations associated with drug vulnerabilities and prognosis in adenocarcinoma at the gastroesophageal junction

Yuan Lin,Xuan Zhao,Chen Wu,Wen Tan,Wenjia Guo,Yuling Ma,Ge Gao,Yiyi Xi,Yanxia Sun,Mingming Shao,Yingying Luo,Dongxin Lin

doi:10.1038/s41467-020-19949-6

Abstract

Adenocarcinoma at the gastroesophageal junction (ACGEJ) has dismal clinical outcomes, and there are currently few specific effective therapies because of limited knowledge on its genomic and transcriptomic alterations. The present study investigates genomic and transcriptomic changes in ACGEJ from Chinese patients and analyzes their drug vulnerabilities and associations with the survival time. Here we show that the major genomic changes of Chinese ACGEJ patients are chromosome instability promoted tumorigenic focal copy-number variations and COSMIC Signature 17-featured single nucleotide variations. We provide a comprehensive profile of genetic changes that are potentially vulnerable to existing therapeutic agents and identify Signature 17-correlated IFN-α response pathway as a prognostic marker that might have practical value for clinical prognosis of ACGEJ. These findings further our understanding on the molecular biology of ACGEJ and may help develop more effective therapeutic strategies.

Highlights

Adenocarcinoma at the gastroesophageal junction (ACGEJ) has dismal clinical outcomes, and there are currently few specific effective therapies because of limited knowledge on its genomic and transcriptomic alterations
In a previous study conducted in Caucasian patients by the Cancer Genome Atlas (TCGA) project8, 65% of ACGEJ were categorized as the chromosomal instability (CIN) subtype of gastric cancer, characterized by preponderating focal copynumber variations (CNVs) in the tumor genome
These results suggest that focal CNVs are the major genomic alterations of ACGEJ in Chinese patients

Summary

Introduction

Adenocarcinoma at the gastroesophageal junction (ACGEJ) has dismal clinical outcomes, and there are currently few specific effective therapies because of limited knowledge on its genomic and transcriptomic alterations. We provide a comprehensive profile of genetic changes that are potentially vulnerable to existing therapeutic agents and identify Signature 17-correlated IFN-α response pathway as a prognostic marker that might have practical value for clinical prognosis of ACGEJ. These findings further our understanding on the molecular biology of ACGEJ and may help develop more effective therapeutic strategies. We deliver a comprehensive profile of genetic alterations potentially vulnerable to existing treatments, and identify genomic and transcriptomic prognostic markers of potential clinical values These findings may improve current knowledge about ACGEJ and contribute to its precision diagnosis and treatment

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Conclusion