COVID-19 News: Scientists Warn That SARS-CoV-2 Infections Can Lead To Rapid Progression Of Cervical Intraepithelial Neoplasia To Cervix Cancers!

COVID-19 News: German scientists are warning that SARS-CoV-2 infections can possibly lead to rapid progression of cervical intraepithelial neoplasia to cervix cancers as a result of a dysregulated immune system! It is now being highly recommended that women who have been exposed to the SARS-CoV-2 virus to have regular health screenings especially for possible cervical issues.


 
The study team comprised of researchers from:
 
-University clinic of Gynaecology and Obstetrics, Carl von Ossietzky University Oldenburg, Wilhelmshaven, Germany
 
-University clinic of Gynaecology and Obstetrics, Klinikum Oldenburg, Rahel-Straus, Oldenburg, Germany
 
-Institute of Pathology, Hannover Medical School, Hannover, Germany
 
-The German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Germany
 
Cervical intraepithelial neoplasia (CIN) is a premalignant condition of the uterine cervix in which abnormal cells are found on the surface of the cervix. Cervical intraepithelial neoplasia is usually caused by certain types of human papillomavirus (HPV) and is found when a cervical biopsy is done. Cervical intraepithelial neoplasia is not cancer, but may become cancer and spread to nearby normal tissue.
 
Recently, cases of disease progression of HPV-infected CIN under SARS-CoV-2 infection were reported giving rise to the hypothesis of direct virus-infection induced pro-carcinogenic effect of SARS-CoV-2.
 
The study team presented a case of rapid progression from HPV-induced CIN 2 to microinvasive carcinoma within three months under COVID-19 without direct virus infection!
 
Detailed histopathologic evaluation, Fluorescence-in-situ hybridization and qRT-PCR against SARS-CoV-2 RNA as well as gene expression analysis were performed from the available FFPE-tissue and accompanied by an analysis of white blood cell differential.
 
Importantly, no signs of direct SARS-CoV-2 infection or COVID-19 typical alterations of cervical tissue were found.
 
However, as expected, p53 decreased in expression with progression of dysplasia, while APOBEC3A and VISTA showed a decrease in expression contrary to observations in dysplasia progression.
 
PD-L1 was expressed consistently or increased slightly but did not show the expected strong induction of expression.
 
DNMT1 showed an increase in expression in CIN III and a slight decrease in carcinoma, while DNMT3a is consistently expressed in CIN II and decreased in carcinoma.
 
Blood tests after COVID-19 showed substantial reduction of lymphocytes, eosinophils, T-cells, and NK-cells.
 
The study findings hint at an indirect effect of COVID-19 on the cervical neoplasm.
 
The study team concluded that the immune system might be preoccupied and exhausted by the concurring COVID-19 disease, leading to less immunological pressure on the HPV-infected cervical dysplasia enabling rapid disease progression. Further, indirect proangiogenic and proinflammatory micromilieu
due to the multisystemic effects of COVID-19 might play an additional role.
 
The study findings were published in the peer reviewed Journal of Reproductive Immunology.
https://www.sciencedirect.com/science/article/pii/S0165037822002923
 
Already Thailand Medical News in its various COVID-19 News coverages have been warning that SARS-CoV-2 infections will lead to an increase of various cancers.
 
https://www.thailandmedical.news/news/covid-19-news-while-lymphopenia-is-common-in-sars-cov-2-infections,-some-may-suffer-from-b-cell-lymphocytosis,-that-leads-to-lymphocytic-leukemia
 
https://www.thailandmedical.news/news/breaking-covid-19-news-sars-cov-2-infections-lead-to-increased-risk-of-breast-cancer,-recurrence-of-breast-cancer-and-also-breast-cancer-metastasis
 
https://www.thailandmedical.news/news/covid-19-news-will-sars-cov-2-infections-ultimately-lead-to-an-increased-incidence-of-head-and-neck-cancers
 
https://www.thailandmedical.news/news/covid-19-news-can-sars-cov-2-cause-reactivation-of-the-latent-sexually-transmitted-htlv-1-virus-that-causes-t-cell-leukemia-lymphoma-atl
 
https://www.thailandmedical.news/news/breaking-researchers-from-brazil-warn-sars-cov-2-induced-immunological-dysregulation-can-increase-the-risk-of-skin-and-blood-cancer-relapses
 
https://www.thailandmedical.news/news/breaking-covid-19-news-sars-cov-2-infections-lead-to-cellular-m6a-rna-methylation-loss-in-host-cells-possible-implications-for-cancer-and-other-issues
 
https://www.thailandmedical.news/news/spanish-study-discovers-that-sars-cov-2-infections-leads-to-downregulation-of-p53-a-critical-cancer-protective-gene
 
https://www.thailandmedical.news/news/breaking-study-finds-that-upregulated-interleukin-6-drives-development-of-rare-liver-cancers-covid-19-infections-causes-elevated-il-6-levels-in-many
 
https://www.thailandmedical.news/news/breaking-study-finds-that-cancer-causing-genes-are-upregulated-in-sars-cov-2-infected-individuals
 
https://www.thailandmedical.news/news/great-news-study-shows-that-sars-cov-2-protein-nsp13-is-able-to-cause-dna-damage-and-dysregulate-tumor-suppressor-gene-p53,-increasing-cancer-risk
 
https://www.thailandmedical.news/news/breaking-sars-cov-2-activates-epidermal-growth-factor-receptor-mediated-signaling,-inducing-survivin-expression-which-assists-in-cancer-progression
 
https://www.thailandmedical.news/news/post-covid-19-individuals-advised-to-take-probiotics-as-study-shows-sars-cov-2-induced-gut-microbiome-dysbiosis-increases-risk-for-colorectal-cancer
 
https://www.thailandmedical.news/news/breaking-study-discovers-sars-cov-2-could-be-carcinogenic-as-it-causes-mutagenesis,-telomere-dysregulation-and-impairs-dna-mismatch-repair
 
https://www.thailandmedical.news/news/breaking-research-reveals-that-tmprss2,-an-endothelial-cell-surface-protein-that-is-involved-in-sars-cov-2-cell-entry,-is-also-a-tumor-suppressor
 
https://www.thailandmedical.news/news/breaking-sars-cov-2-infection-induces-increase-of-gp73-that-causes-dysglycaemia-increased-gp73-could-also-imply-future-liver-disease-and-liver-cancer
 
https://www.thailandmedical.news/news/breaking-new-international-study-warns-that-sars-cov-2-infections-will-lead-to-cancers-especially-colorectal-cancers-due-to-disruption-in-autophagy
 
https://www.thailandmedical.news/news/breaking-news-chinese-researchers-discover-circrnas-encoded-by-sars-cov-2-virus-that-can-cause-cancer-millions-expected-to-get-cancer-eventually
 
https://www.thailandmedical.news/news/malaysian-researchers-discover-that-sars-cov-2-infections-and-lung-cancer-share-common-pathways-and-genes
 
https://www.thailandmedical.news/news/covid-19-and-cancer-study-shows-that-sars-cov-2-and-usage-of-anti-covid-19-drugs-can-reactivate-oncogenic-viruses-and-increase-risk-of-cancer
 
https://www.thailandmedical.news/news/must-read-covid-19-questions-can-the-sars-cov-2-coronavirus-ultimately-also-cause-cancer
 
It should be noted that interestingly, the incidence of cervical cancers is rising in the last 2 to 3 years.
https://www.cancer.org/cancer/cervical-cancer/about/key-statistics.html
 
https://ijgc.bmj.com/content/32/12/1635
 
https://moffitt.org/endeavor/archive/why-are-advanced-stage-cervical-cancer-cases-rising/
 
The study team found several indications that SARS-CoV-2 infection has effects on the immune system which can lead to the progression of cancers.
 
APOBEC3 or Apolipoprotein B mRNA editing enzyme catalytic polypeptide 3 proteins serve as antiviral defense against RNA virus infections such as HPV. Therefore, the proteins APOBEC3A and APOBEC3B are expected to be upregulated in HPV-positive patients as the disease progresses. This is observable in the study team’s control patients with progressing CIN dysplasia without SARS-CoV-2 infection despite minor individual differences, while the index patient showed a decreased expression of APOBEC3A with progression of dysplasia. The absence of high expression of a virus defense mechanism despite apparent virus infection of the cervix supports the hypothesis of an altered immune response to cervical infection with HPV during clinically manifest COVID-19 disease.
 
Numerous studies have investigated the expression of PD-L1 in cervical cancer. In 34–96% of peritumoral dendritic cells of cervical cancer tissues, PD-L1 expression was detected, while regular cervical tissue displayed a low-level expression of PD-L1 of 6,82% in dendritic cells. During high immune pressure, as seen in cervical neoplasms, increasing expression of PD-L1 is expected in order to evade the immune system.
 
Such an effect is observable in the control specimens with increasing PD-L1 levels, whereas the herein-reported case showed a stable up to a slightly increased expression of PD-L1 during the course of the disease.
 
These findings suggest lowered immune pressure as a potential sign of an exhausted immune system due to concomitant higher immune pressure in the epicentres of the SARS-CoV-2 infection.
 
V-domain immunoglobulin suppressor of T cell activation or VISTA, is an immune checkpoint inhibitor involved in the regulation of T cell activity and expressed on T cells and other myeloid cells (mainly monocytes, macrophages, and neutrophils.
 
VISTA has been detected in both cervical squamous cell carcinoma and clear cell carcinoma of the cervix. The structural similarity to PD-L1 leads to the assumption that there is likewise an increased expression in the case of a malignant event. In line with the study findings on PD-L1 and the hypothesis of lower immune pressure in the cervix during COVID-19, the study team detected a reduced expression of VISTA in the index patient.
 
Tumour suppressor protein 53 or p53 is a transcription factor. It is often referred to as the "guardian of the genome". After DNA damage, it regulates the expression of genes involved in cell cycle control, induction of apoptosis, and DNA repair.
 
P53 is inhibited by the HPV oncogene E6. Therefore, with increasing HPV oncogene E6, p53 expression is usually more and more inhibited, leading to progressing dysplasia.
 
As expected, p53 was decreased in the presented case suggesting that the general carcinogenesis pathway of HPV-associated cervix carcinoma proceeds in the same way as in comparative studies without concomitant symptomatic COVID-19.
 
An interesting aspect of COVID-19 effects discussed is the change in DNA methylation.
 
Several studies showed that COVID-19 can lead to hyper- but especially hypomethylation of promotors of several genes by DNA-methyltransferases (DNMTs).
 
A past study showed that DNMT1, 3a, and 3b are significantly decreased in SARS-CoV-2 transfected cells.
https://www.frontiersin.org/articles/10.3389/fgene.2021.622271/full
 
Interestingly, HPV also changes DNA methylation substantially leading to methylation of tumor suppressor genes during the development of dysplasia.
 
Hence, the study team, wanted to test if COVID-19 with expected contrary methylation effects compared to HPV can change the expression of DNMT1 and 3a in the cervix tissue.
 
In cervix carcinoma, DNMT1 and 3a are slightly but not significantly decreased. Nevertheless, the expected increase of DNMT3a expression, which is observable in both control patients, cannot be seen in the index patient, giving rise to the hypothesis that SARS-CoV-2 infection has a global impact on DNA methylation and might reduce DNMT expression in the cervix. However, the samples were taken three months after SARS-CoV-2 infection and showed no signs of direct virus infection, limiting the data interpretation. Further investigations in larger cohorts during and shortly after COVID-19 are needed to evaluate this aspect.
 
Importantly, blood tests three months after COVID-19 showed a substantial reduction of lymphocytes (14%, abs. 0.79x109/L; norm:22–49%, 1.05–2.87x109/L), eosinophils (0%, norm: 1–5%), T-cells (596/μl, norm: 700–2100/μl), NK-cells (57μl, norm: 90–600μl), and thrombocytes (137x109/L; norm: 171–388x109/L); a frequently described residual after COVID-19 and a sign of a high turnover of immune cells.
 
A low number of remaining immune cells can fuel the progression of malignant events, especially in immune-sensitive tumors, supporting the thesis of an exhausted immune system due to COVID-19 leading to disease progression.
 
In the case presented, symptomatic COVID-19 lead to a disease progression (in the malignant counterpart) of HPV-induced tumors.
 
The study team advocates that more detailed research in done in this field and that in the meantime, women exposed to the SARS-CoV-2 virus should go for frequent cancer screenings.
 
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