Are female-specific cancers long-term sequelae of COVID-19? Evidence from a large-scale genome-wide cross-trait analysis

Abstract

Background: Little is known regarding the long-term adverse effects of COVID-19 on female-specific cancers due to the restricted length of observational time, nor the shared genetic influences underlying these conditions. Methods: Leveraging summary statistics from the hitherto largest genome-wide association studies conducted in each trait, we performed a comprehensive genome-wide cross-trait analysis to investigate the shared genetic architecture and the putative genetic associations between COVID-19 with three main female-specific cancers: breast cancer (BC), epithelial ovarian cancer (EOC), and endometrial cancer (EC). Three phenotypes were selected to represent COVID-19 susceptibility (SARS-CoV-2 infection) and severity (COVID-19 hospitalization, COVID-19 critical illness). Results: For COVID-19 susceptibility, we found no evidence of a genetic correlation with any of the female-specific cancers. For COVID-19 severity, we identified a significant genome-wide genetic correlation with EC for both hospitalization (r_g=0.19, P=0.01) and critical illness (r_g=0.29, P=3.00*10-4). Mendelian randomization demonstrated no valid association of COVID-19 with any cancer of interest, except for suggestive associations of genetically predicted hospitalization (ORIVW=1.09, 95%CI=1.01-1.18, P=0.04) and critical illness (ORIVW=1.06, 95%CI=1.00-1.11, P=0.04) with EC risk, none withstanding multiple correction. No reverse association was found. Cross-trait meta-analysis identified multiple pleiotropic SNPs between COVID-19 and female-specific cancers, including 20 for BC, 15 for EOC, and 5 for EC. Transcriptome-wide association studies revealed shared genes, mostly enriched in the hematologic, cardiovascular, and nervous systems. Conclusions: Our genetic analysis highlights an intrinsic link underlying female-specific cancers and COVID-19 - while COVID-19 is not likely to elevate the immediate risk of the examined female-specific cancers, it appears to share mechanistic pathways with these conditions. These findings may provide implications for future therapeutic strategies and public health actions.

Should We Expect an Increase in the Number of Cancer Cases in People with Long COVID?

“…According to the TCGA database results, these four genes were upregulated in pancreatic adenocarcinoma [ 89 ]. In a similar way, Zhao et al [ 90 ] performed a genome-wide cross-trait analysis to investigate the shared genetic architectures and putative genetic associations between COVID-19 and the three main female-specific cancers (breast cancer, epithelial ovarian cancer and endometrial cancer). Although the authors did not find any evidence of genetic correlations between COVID-19 and the female-specific cancers, the cross-trait meta-analysis found that these conditions shared multiple mechanistic pathways (connecting the hematologic system, immune system and cell proliferation), especially in breast cancer and ovarian cancer [ 90 ].…”