ACE2 and TMPRSS2 expression by clinical, HLA, immune, and microbial correlates across 34 human cancers and matched normal tissues: implications for SARS-CoV-2 COVID-19

  1. Riyue Bao
  2. Kyle Hernandez
  3. Lei Huang
  4. Jason John Luke

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Abstract

Pandemic COVID-19 by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) infection is facilitated by the ACE2 receptor and protease TMPRSS2. Modestly sized case series have described clinical factors associated with COVID-19, while ACE2 and TMPRSS2 expression analyses have been described in some cell types. Patients with cancer may have worse outcomes to COVID-19.

Methods

We performed an integrated study of ACE2 and TMPRSS2 gene expression across and within organ systems, by normal versus tumor, across several existing databases (The Cancer Genome Atlas, Census of Immune Single Cell Expression Atlas, The Human Cell Landscape, and more). We correlated gene expression with clinical factors (including but not limited to age, gender, race, body mass index, and smoking history), HLA genotype, immune gene expression patterns, cell subsets, and single-cell sequencing as well as commensal microbiome.

Results

Matched normal tissues generally display higher ACE2 and TMPRSS2 expression compared with cancer, with normal and tumor from digestive organs expressing the highest levels. No clinical factors were consistently identified to be significantly associated with gene expression levels though outlier organ systems were observed for some factors. Similarly, no HLA genotypes were consistently associated with gene expression levels. Strong correlations were observed between ACE2 expression levels and multiple immune gene signatures including interferon-stimulated genes and the T cell-inflamed phenotype as well as inverse associations with angiogenesis and transforming growth factor-β signatures. ACE2 positively correlated with macrophage subsets across tumor types. TMPRSS2 was less associated with immune gene expression but was strongly associated with epithelial cell abundance. Single-cell sequencing analysis across nine independent studies demonstrated little to no ACE2 or TMPRSS2 expression in lymphocytes or macrophages. ACE2 and TMPRSS2 gene expression associated with commensal microbiota in matched normal tissues particularly from colorectal cancers, with distinct bacterial populations showing strong associations.

Conclusions

We performed a large-scale integration of ACE2 and TMPRSS2 gene expression across clinical, genetic, and microbiome domains. We identify novel associations with the microbiota and confirm host immunity associations with gene expression. We suggest caution in interpretation regarding genetic associations with ACE2 expression suggested from smaller case series.

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  1. Version published to 10.1136/jitc-2020-001020
  2. ScreenIT

    SciScore for 10.1101/2020.04.29.20082867: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Datasets: Sample metadata tables were downloaded from The Cancer Genome Atlas (TCGA) (Genomic Data Commons (GDC) portal: https://portal.gdc.cancer.gov).
    https://portal.gdc.cancer.gov
    suggested: (Genomic Data Commons Data Portal (GDC Data Portal, RRID:SCR_014514)
    ACE2 and TMPRSS2 gene expression correlation and percentile calculation: The gene expression of ACE2 (Entrez Gene ID 59272) and TMPRSS2 (Entrez Gene ID 7113) was retrieved from the RSEM-quantified RNAseq data and used for all analyses described in this study.
    Entrez Gene
    suggested: (Entrez Gene, RRID:SCR_002473)
    Those analyses were performed using R (v3.6.1) and Bioconductor (release 3.10).
    Bioconductor
    suggested: (Bioconductor, RRID:SCR_006442)

    Results from OddPub: Thank you for sharing your code and data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    We note limitations to our report with the acknowledgment that the use of pre-existing data does not fully capture the complexity of active infection by SARS-CoV-2. Rather we sought to investigate factors correlated with viral cell engagement via ACE2 and viral entry via TMPRSS2 as possible associative risk factors that might be entertained on a clinical or translational level when considering risk for patients with cancer and otherwise of COVID-19. Certainly, there may be virus infection-induced changes that are dynamic. However, we believe our analysis to be the most comprehensive catalog of ACE2 and TMPRSS2 correlates to date (34 tumor types from 15 tissue types across 10,038 subjects including both tumor samples and matched normal tissues as well as scRNAseq databases consisting of patients with cancer and healthy donors). We also acknowledge that the microbiota we analyzed were identified from tissue RNAseq data, and the sample collection and preparation of tissue RNAseq was not designed originally to completely rule out potential contamination or confirm the vitality of identified microbes. However, these source data constitute the largest collection of microbiota communities identified from patients with cancer, have previously been used in this manner to build prediction algorithms, and the data were optimized via rigorous methodology to control for noise across the data set [30]. We also note that we are unable in this analysis to comment on respiratory or fecal samp...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • No funding statement was detected.
    • No protocol registration statement was detected.

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  3. Version published to 10.1101/2020.04.29.20082867v1 on medRxiv