ABSTRACT: SARS-CoV-2 infection results in a broad spectrum of COVID-19 disease, from mild or no symptoms to hospitalization and death. The degree of the adaptive immune response to SARS-CoV-2 and some pre-existing diseases has been linked to the severity of COVID-19 disease, and a recent genome-wide association study (GWAS) of the risk of critical illness found a strong genetic component. Many assume that the diversity of HLA increases the likelihood that a species can survive pandemics. The requirement for a species to have a diversified immune system to survive a pandemic is believed to be the cause of the HLA system’s widespread polymorphism. Two genomic regions are associated with severe COVID-19: one region on chromosome 3, which contains six genes, and one region on chromosome 9 that determines ABO blood groups. Numerous ACE2 and TMPRSS2 polymorphisms that affect the expression of COVID-19-related receptors have been linked to risk factors and disease susceptibility. Differential cytokine production in COVID-19 patients may be linked to genetic variations in the regulatory regions of cytokine genes. The plasma miRNA expression profile at an early stage of COVID-19 is profoundly disrupted by SARS-CoV-2 infection, which makes miRNAs extremely useful as early indicators of severity and mortality. An inflammatory outburst and lymphopenia are associated with severe COVID-19, which may worsen the prognosis for cancer. Through mechanisms including cytokine storm, tissue hypoxia, poor T-cell responses, autophagy, neutrophil activation, and oxidative stress, SARS-CoV-2 infection may increase cancer susceptibility and speed cancer progression.

Impact statement:  This review clarifies how genetic and epigenetic factors shaper COVID-19 susceptibility, severity, and outcomes, offering a framework to improve risk stratification, personalized care, and oncology-oriented research in future clinical studies.

Key words: COVID-19; HLA; ACE2; ABO blood group; microRNAs; cancer.