Pan-cancer analysis of RNA expression of ANGIOTENSIN-I-CONVERTING ENZYME 2 reveals high variability and possible impact on COVID-19 clinical outcomes

Michelle Saul,Edward S Kim,Heinz-Josef Lenz,Jia Zeng,Jim Abraham,David Spetzler,Andrew Elliott,Lee Schwartzberg,John L Marshall,Joanne Xiu,W Michael Korn,Misako Nagasaka,Phillip Stafford

doi:10.1038/s41598-021-84731-7

Abstract

Patients with cancer demonstrate particularly poor outcomes from COVID-19. To provide information essential for understanding the biologic underpinnings of this association, we analyzed whole-transcriptome RNA expression data obtained from a large cohort of cancer patients to characterize expression of ACE2, TMPRSS2, and other proteases that are involved in viral attachment to and entry into target cells. We find substantial variability of expression of these factors across tumor types and identify subpopulations expressing ACE2 at very high levels. In some tumor types, especially in gastrointestinal cancers, expression of ACE2 and TMPRSS2 is highly correlated. Furthermore, we found infiltration with T-cell and natural killer (NK) cell infiltration to be particularly pronounced in ACE2-high tumors. These findings suggest that subsets of cancer patients exist with gene expression profiles that may be associated with heightened susceptibility to SARS-CoV-2 infection, in whom malignant tumors function as viral reservoir and possibly promote the frequently detrimental hyper-immune response in patients infected with this virus.

Highlights

The new severe acute respiratory syndrome coronavirus, SARS-CoV-2, has led to a devastating pandemic affecting large segments of the global population with 70,111,812 confirmed cases and at least 1,591,595 deaths as of December 11, 2 0201
Understanding how the tumor microenvironment changes in Non-small cell lung cancer (NSCLC) as ANGIOTENSIN-I-CONVERTING ENZYME 2 (ACE2) expression increases may provide additional insight into the associated immune system deregulation that may underlie the severe comorbidities observed in NSCLC patients and may provide additional insight into an effective treatment for those suffering from COVID-19
Average ACE2 expression was significantly increased in patients under 65 years compared to patients 65 years and older (5.8 vs 4.8 transcripts per million molecules (TPM), p < 0.0001), and male patients exhibited significantly higher average ACE2 expression compared to female patients (6.0 vs 4.8 TPM, p < 0.0001)

Summary

Introduction

The new severe acute respiratory syndrome coronavirus, SARS-CoV-2, has led to a devastating pandemic affecting large segments of the global population with 70,111,812 confirmed cases and at least 1,591,595 deaths as of December 11, 2 0201. Understanding how the tumor microenvironment changes in NSCLC as ACE2 expression increases may provide additional insight into the associated immune system deregulation that may underlie the severe comorbidities observed in NSCLC patients and may provide additional insight into an effective treatment for those suffering from COVID-19. Initial data suggest that some cancers express high levels of ACE216,17 In such cases, malignant masses could function as viral reservoirs, similar to observations related to other viruses, sustaining and amplifying SARS-CoV-2 infection in patients with cancer[18,19]. We hypothesized that ACE2 and protease gene expression would vary across tumor types, with high expression presumed to associate with increased risk of infection and severe course of disease. We found that ACE2 expression varies and correlates with expression of proteases in a tumor type-specific manner, which may underlie the severe disease progression observed in subsets of patients with cancer

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