Cancer and COVID-19 Susceptibility and Severity: A Two-Sample Mendelian Randomization and Bioinformatic Analysis.

Yiyin Zhang,Yuelong Liang,Qiming Xia,Duguang Li,Peng Chen,Jing Yang,Jiaxi Cheng,Yirun Li,Qijiang Mao,Shengxi Jin,Guoqiao Chen,Xiaoxiao Fan,Hui Lin,Cheng Zhong

doi:10.3389/fcell.2021.759257

Abstract

The clinical management of patients with COVID-19 and cancer is a Gordian knot that has been discussed widely but has not reached a consensus. We introduced two-sample Mendelian randomization to investigate the causal association between a genetic predisposition to cancers and COVID-19 susceptibility and severity. Moreover, we also explored the mutation landscape, expression pattern, and prognostic implications of genes involved with COVID-19 in distinct cancers. Among all of the cancer types we analyzed, only the genetic predisposition to lung adenocarcinoma was causally associated with increased COVID-19 severity (OR = 2.93, β = 1.074, se = 0.411, p = 0.009) with no obvious heterogeneity (Q = 17.29, p = 0.24) or symmetry of the funnel plot. In addition, the results of the pleiotropy test demonstrated that instrument SNPs were less likely to affect COVID-19 severity via approaches other than lung adenocarcinoma cancer susceptibility (p = 0.96). Leave-one-out analysis showed no outliers in instrument SNPs, whose elimination rendered alterations in statistical significance, which further supported the reliability of the MR results. Broad mutation and differential expression of these genes were also found in cancers, which may provide valuable information for developing new treatment modalities for patients with both cancer and COVID-19. For example, ERAP2, a risk factor for COVID-19-associated death, is upregulated in lung squamous cancer and negatively associated with patient prognosis. Hence, ERAP2-targeted treatment may simultaneously reduce COVID-19 disease severity and restrain cancer progression. Our results highlighted the importance of strengthening medical surveillance for COVID-19 deterioration in patients with lung adenocarcinoma by showing their causal genetic association. For these patients, a delay in anticancer treatment, such as chemotherapy and surgery, should be considered.

Highlights

Coronavirus disease 2019 (COVID-19), which arises from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, can result in severe illnesses such as acute respiratory distress syndrome, multiorgan dysfunction syndrome, and consequent death, and it has become a public health emergency of international concern (Huang et al, 2020).During the COVID-19 pandemic, the clinical management of patients with cancer is a Gordian knot that has been discussed broadly but has not reached a consensus (Moujaess et al, 2020)
The E-values for the observed association between cancer and COVID-19-induced mortality, rates of ICU admission, severe or critical symptoms, and deterioration were 4.11, 2.76, 2.73, and 4.18, respectively, which were not large enough to eliminate the possibility of bias on the causality derived from unmeasured confounders
We demonstrated that a genetic predisposition to lung adenocarcinoma as opposed to lung squamous cancer is causally related to COVID-19 severity but not susceptibility, suggesting that increased surveillance for severe COVID-19associated complications should be conducted among hospitalized patients with lung adenocarcinoma

Summary

Introduction

Coronavirus disease 2019 (COVID-19), which arises from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, can result in severe illnesses such as acute respiratory distress syndrome, multiorgan dysfunction syndrome, and consequent death, and it has become a public health emergency of international concern (Huang et al, 2020).During the COVID-19 pandemic, the clinical management of patients with cancer is a Gordian knot that has been discussed broadly but has not reached a consensus (Moujaess et al, 2020). Two observational studies from China revealed that patients with cancer were more susceptible to COVID-19 and its relevant severe complications (Dai et al, 2020; Liang et al, 2020). ICIs could induce immunerelated pneumonitis followed by lung injury, which could enhance the risk of developing severe COVID-19 pneumonia. Some studies reported that CoV-2 infection causes functional exhaustion of CTLs and NK cells with significantly higher levels of exhaustion markers such as programmed death-1 (PD-1) than healthy controls (Zheng et al, 2020), suggesting that the use of ICIs may activate the anti-COVID-19 ability in the host and improve the patient prognosis. Two ongoing clinical trials will demonstrate the pros and cons of adopting ICIs in COVID19 treatment (NCT04343144 and NCT04333914)

Methods

Results

Conclusion