Molecular Characterization and Clinical Relevance of ALDH2 in Human Cancers.

Bo Ma,Hui Xu,Zaoqu Liu,Libo Wang,Long Liu,Lifeng Li,Xinwei Han,Lingfang Meng,Tao Huang,Yuyuan Zhang

doi:10.3389/fmed.2021.832605

Abstract

Background: Aldehyde dehydrogenase 2 (ALDH2) is well-known to be a key enzyme in alcohol metabolism. However, a comprehensive understanding of ALDH2 across human cancers is lacking.Methods: A systematic and comprehensive analysis of the molecular alterations and clinical relevance for ALDH2 in more than 10,000 samples from 33 cancer types was performed. qRT-PCR was performed on 60 cancer and 60 paired nontumor tissues.Results: It was observed that ALDH2 was generally downregulated in most cancers, which was mainly driven by DNA hypermethylation rather than mutations or copy number variations. Besides, ALDH2 was closely related to the inhibition and activation of tumor pathways and a variety of potential targeted agents had been discovered in our research. Last but not least, ALDH2 had the best prediction efficacy in assessing immunotherapeutic response compared with PD-L1, PD-1, CTLA4, CD8, and tumor mutation burden (TMB) in cutaneous melanoma. According to the analysis of large-scale public data and 60 pairs of clinical cancer samples, we found the downregulation of ALDH2 expression tends to suggest the malignant phenotypes and adverse prognosis, which might enhance the precise diagnosis and timely intervention of cancer patients.Conclusion: This study advanced the understanding of ALDH2 across cancers, and provided important insight into chemotherapy, immunotherapy and prognosis of patients with cancer.

Highlights

Aldehyde dehydrogenase 2 (ALDH2) is one of the aldehyde dehydrogenase family of enzymes
It was observed that ALDH2 was generally downregulated in most cancers, which was mainly driven by DNA hypermethylation rather than mutations or copy number variations
According to the analysis of large-scale public data and 60 pairs of clinical cancer samples, we found the downregulation of ALDH2 expression tends to suggest the malignant phenotypes and adverse prognosis, which might enhance the precise diagnosis and timely intervention of cancer patients

Summary

Introduction

Aldehyde dehydrogenase 2 (ALDH2) is one of the aldehyde dehydrogenase family of enzymes. ALDH2 is well-known to be a key enzyme in alcohol metabolism and has a major contribution in oxidizing endogenous aldehydic products arising from lipid peroxidation such as 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde under oxidative stress [2]. As the ratelimiting enzyme of alcohol metabolism, ALDH2 has a profound impact on the clearance process of toxic acetaldehyde. Low expression or genetic polymorphism of ALDH2 dramatically reduce its enzyme activity, and the accumulation of acetaldehyde can further damage normal cells and lead to cancers [4]. Aldehyde dehydrogenase 2 (ALDH2) is well-known to be a key enzyme in alcohol metabolism. A comprehensive understanding of ALDH2 across human cancers is lacking

Methods

Results

Conclusion