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Coronavirus disease 2019 (COVID-19) advances to affect every part of the globe and remains a challenge to the human race. Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) was shown to affect many organs and organ systems including the thyroid gland as these parts highly express angiotensin-converting enzyme 2 (ACE2) protein, which functions as a receptor for initially entering the virus into the cells. Furthermore, some categories of the population including older people and persons with comorbidities are prone to be more vulnerable to COVID-19 and its complications. Recent reports showed that SARS-CoV-2 infection could cause Graves’ disease (autoimmune hyperthyroidism) in post-COVID-19 patients. Factors that may boost the mortality risk of COVID-19 patients are not completely known yet and a clear perception of the group of vulnerable people is also essential. This review briefly summarizes the features of Graves’ disease such as symptoms, risk factors, including environmental, genetic, immunological, and other factors, associated disorders, and therapeutic options. It comprehensively describes the recent advances in SARS-CoV-2-induced Graves’ disease and the pivotal role of autoimmune factors in inducing the disease. The review also discusses the possible risks of SARS-CoV-2 infection and associated COVID-19 in people with hyperthyroidism. Furthermore, it explains thyroid disease and its association with the severity of COVID-19.

Coronavirus disease-2019 (COVID-19) is asymptomatic in most cases, but it is impartible and fatal in fragile and elderly people. Heretofore, more than four million people succumbed to COVID-19, while it spreads to every part of the globe. Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) induces various dysfunctions in many vital organs including the thyroid by utilizing ACE2 as a receptor for cellular entry. Emerging reports clearly show the involvement of SARS-CoV-2 in diverse thyroid disorders. Thus, this review article aims to review comprehensively all the recent developments in SARS-CoV-2-induced pathogenesis of thyroid diseases. The review briefly summarizes the recent key findings on the mechanism of SARS-CoV-2 infection, the role of ACE2 receptor in viral entry, SARS-CoV-2-activated molecular signaling in host cells, ACE2 expression in the thyroid, cytokine storm, and its vital role in thyroid dysfunction and long-COVID in relation to thyroid and autoimmunity. Further, it extensively discusses rapidly evolving knowledge on the potential part of SARS-CoV-2 in emerging various thyroid dysfunctions during and post-COVID-19 conditions which include subacute thyroiditis, Graves' diseases, Hashimoto's thyroiditis, thyrotoxicosis, and other recent advances in further discerning the implications of this virus within thyroid dysfunction. Unraveling the pathophysiology of SARS-CoV-2-triggered thyroid dysfunctions may aid pertinent therapeutic options and management of these patients in both during and post-COVID-19 scenarios. Keywords: thyroid, COVID-19, hyperthyroidism, hypothyroidism, SARS-CoV-2, ACE2, inflammation, IL6, subacute thyroiditis, Graves' disease, Hashimoto's thyroiditis, thyrotoxicosis, p38/MAPK, thyroid cancer

Mammalian target of rapamycin (mTOR) signaling is often aberrantly activated, particularly when genetically altered, in human cancers. mTOR inhibitors targeting the activated mTOR signaling are highly promising anti-cancer drugs. Knowing the activating genetic change in mTOR can help guide the use of mTOR inhibitors for cancer treatment. This study was conducted to identify and characterize novel oncogenic mTOR mutations that can potentially be therapeutic targets in human cancer. We sequenced 30 exons of the mTOR gene in 12 thyroid cancer cell lines, 3 melanoma cell lines, 20 anaplastic thyroid cancer (ATC) tumors, and 23 melanoma tumors and functionally characterized the identified novel mTOR mutations in vitro and in vivo. We identified a novel point mutation A1256G in ATC cell line and G7076A in melanoma tumor in exon 9 and exon 51 of the mTOR gene, respectively. Over-expression of the corresponding mTOR mutants H419R and G2359E created through induced mutagenesis showed markedly elevated protein kinase activities associated with the activation of mTOR/p70S6K signaling in HEK293T cells. Stable expression of the two mTOR mutants in NIH3T3 cells strongly activated the mTOR/p70S6K signaling pathway and induced morphologic transformation, cell focus formation, anchorage-independent cell growth, and invasion. Inoculation of these mutant-expressing cells in athymic nude mice induced rapid tumor development, showing their driving oncogenicity. We also demonstrated that transfection with the novel mutants conferred cells high sensitivities to the mTOR inhibitor temsirolimus. We speculate that human cancers harboring these mTOR mutations, such as ATC and melanoma, may be effectively treated with inhibitors targeting mTOR.

Graves' disease (GD) is an autoimmune disorder that results in hyperthyroidism, in which the immune system mistakenly targets the thyroid gland, causing it to produce excessive amounts of thyroid hormones. Genetic predisposition, environmental factors such as infections and stress, disruptions in the gut microbiome, excessive iodine intake, and epigenetic changes have all been implicated in the development of GD. The recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) posed a serious global health crisis. The emergence of COVID-19 vaccines has been pivotal in combating the viral infection and its spread. However, reports of rare adverse events, including the development of autoimmune disorders such as GD following vaccination, have raised concerns. Autoimmune factors play a critical role in the pathogenesis of GD, particularly through the production of autoantibodies targeting the thyroid gland. In this review, reported cases are critically analyzed to elucidate commonalities and potential triggers for the development of this autoimmune disorder, highlighting the vital role of autoimmune mechanisms in inducing GD. We also discuss the molecular mechanisms underlying vaccine-induced autoimmunity, including antigen presentation, bystander activation, molecular mimicry, and the induction of inflammatory factors following vaccination. Understanding these mechanisms in COVID-19 vaccine-induced GD could enhance patient care and guide vaccination policies.

Abstract Context Diffuse sclerosing papillary thyroid cancer (DSPTC) is rare, with limited data on its molecular genetics. Objective We studied the molecular genetics of a cohort of DSPTC. Methods DNA was isolated from paraffin blocks of 22 patients with DSPTC (15 females, 7 males, median age 18 years, range 8-81). We performed polymerase chain reaction–based Sanger sequencing and a next-generation sequencing (NGS) gene panel to characterize the genomic landscape of these tumors. We classified genetic alterations to definitely or probably pathogenic. Definitely pathogenic are genetic alterations that are well known to be associated with PTC (e.g., BRAFV600E). Probably pathogenic are other alterations in genes that were reported in The Cancer Genome Atlas or the poorly differentiated and anaplastic thyroid cancer datasets. Results Three tumors were tested only by Sanger sequencing and were negative for BRAFV600E, HRAS, KRAS, NRAS, TERT promoter, PTEN, and PIK3CA mutations. The other 19 tumors tested by NGS showed definitely pathogenic alterations in 10 patients (52.6%): 2/19 (10.5%) BRAFV600E, 5/19 (26.3%) CCDC6-RET (RET/PTC1), 1/19 (5.3%) NCOA4-RET (RET/PTC3), 1/19 (5.3%) STRN-ALK fusion, and 2/19 (10.6%) TP53 mutations. Probably pathogenic alterations occurred in 13/19 tumors (68.4%) and included variants in POLE (31.6%), CDKN2A (26%), NF1 (21%), BRCA2 (15.8%), SETD2 (5.3%), ATM (5.3%), FLT3 (5.3%), and ROS1 (5.3%). In 1 patient, the gene panel showed no alterations. No mutations were found in the RAS, PTEN, PIK3CA, or TERT promoter in all patients. There was no clear genotype/phenotype correlation. Conclusion In DSPTC, fusion genes are common, BRAFV600E is rare, and other usual point mutations are absent. Pathogenic and likely pathogenic variants in POLE, NF1, CDKN2A, BRCA2, TP53, SETD2, ATM, FLT3, and ROS1 occur in about two-thirds of DTPTC.

Lung metastases are common in pediatric thyroid cancer (TC). We present an analysis of a series of lung metastases in pediatric TC. Data from 20 patients (16 females, 4 males; median age, 14.5 years; range 10 to 18 years) were analyzed. The tumors included differentiated TC in 19 patients and poorly differentiated TC in 1 patient. Lung metastasis presented with three distinct radiological patterns: lung uptake on diagnostic radioactive iodine whole body scan (DxWBS) only in 3 patients (15%); lung uptake on DxWBS and CT scan as micrometastases (≤1 cm) in 16 patients (80%); and lung uptake on DxWBS and CT scan as macrometastases (>1 cm) in 1 patient (5%). Iodine-131 therapies were administered to all patients (median, three; range one to eight) with a median cumulative administered activity of 317.5 mCi (range, 109 to 682 mCi). None of the patients achieved a complete response but the biochemical response was substantial. During a median follow-up period of 8.2 years (range, 0.75 to 16.3 years), 1 patient (5%) died, 1 patient (5%) had a biochemically incomplete response, 2 patients (10%) had an indeterminate response, 1 patient (5%) had progressive structural disease, and 14 patients (70%) had stable structural disease. Mutational testing of 10 of 20 tumors revealed only two PIK3CA mutations in a single tumor. Lung metastases are common in pediatric TC and present most frequently with bilateral radioiodine-avid micrometastases. Known single point mutations in adult TC are rare in pediatric TC. The biochemical response to iodine-131 can be substantial but resolution of structural abnormalities is rare.

Giant prolactinomas are defined as pituitary adenomas (PAs) ≥ 4 cm with plasma prolactin level > 1000 ng/ml with no other co-secretory component. The reasons for development of giant prolactinomas are not clear but genetics play an important pathogenic mechanism in some PAs. In this report, we describe a middle-aged woman who incidentally was found to have an infiltrative giant prolactinoma involving the sellar, supra- and parasellar regions and occupying most of the middle fossae of the skull extending all the way to the occipital and upper cervical regions. Anteriorly, it extends to the sphenoid and parasellar sinuses, nasopharynx and nasal cavities. It was initially thought to be a nasopharyngeal cancer but biopsy from a protruding component from the right nostril showed that it was a prolactinoma. Prolactin level after several dilutions was extremely high at 277,500 ng/ml (normal range 3.4–24.1 ng/ml). Surprisingly, her pituitary function evaluation showed only mild central hypothyroidism [(FT4 11.4 pmol/l (normal range 12–22) and TSH 1.9 mU/l (normal range 0.27–4.2)] and hypogonadotropic hypogonadism (E2 47 pmol/l, LH 1.9 u/l, FSH 5.9 u/l). Cosyntropin stimulation test was normal suggesting normal pituitary adrenal axis but insulin-induced hypoglycaemia test was not performed. In retrospect, the patient reported chronic nasal congestion and snoring, headaches on/off and deterioration in her hearing and visual acuity over the last few years. She ascribed these symptoms to sinusitis and advancing age, respectively. Whole exome sequencing revealed a novel variant in CDH23 (NM_022124.6:c.2621C > A, p.Ala874Asp), a gene that has been previously reported to be associated with PAs. The patient was treated with small doses of cabergoline (0.5 mg twice weekly) and reported remarkable improvement in her symptoms. Radiological evaluation confirmed the significant response of this giant prolactinoma to cabergoline.

Long non-coding RNAs (lncRNAs) play an important role in the regulation of key cellular processes in early development and cancer. LncRNA Oip5-as1 facilitates stem cell self-renewal in mouse by sponging mmu-miR-7 and modulating NANOG level, yet its role in cancer is less understood. We analyzed OIP5-AS1 expression in oral tumors and in TCGA datasets. We observed overexpression of OIP5-AS1 in oral tumors ( P  < 0.001) and in tumors of epithelial origin from TCGA. OIP5-AS1 expression was strongly associated with undifferentiated tumors ( P  = 0.0038). In silico analysis showed miR-7 binding site is conserved in mouse and human OIP5-AS1 . However, human NANOG 3′-UTR lost the binding site for hsa-miR-7a-3. Therefore, we screened for other miRNAs that can be sponged by OIP5-AS1 and identified six potential miRNAs and their downstream target genes. Expression analysis showed downregulation of miRNAs and upregulation of downstream target genes, particularly in undifferentiated tumors with high-level of OIP5-AS1 suggesting OIP5-AS1 could post-transcriptionally modulate the downstream target genes. Further, systematic epigenomic analysis of OIP5-AS1 promoter revealed binding motifs for MYC, NANOG and KLF4 suggesting that OIP5-AS1 could be transactivated by stemness-associated transcription factors in cancer. OIP5-AS1 overexpression in undifferentiated oral tumors may be suggestive of enhanced cancer stemness, and consequently, poor clinical outcome.

Background BRAF is the most frequently mutated gene in differentiated thyroid cancer (DTC). Previous studies on DTC have well documented high rates of the BRAF V600E mutation in patients of mixed ages. Previous studies either included a mix of pediatric and adult patients or pediatric patients only. However, the prevalence of hotspot and non-hotspot BRAF mutations and its significance in pure adult DTCs is not yet well determined. In this study we determine the frequency of this classical BRAF mutation and other rare BRAF mutations in pure adult DTCs. Methods A total of 204 adult DTC samples (Age >18 years) were analyzed for mutations in exon 15 of the BRAF gene by performing polymerase chain reaction (PCR) amplification of tumor genomic DNAs and direct sequencing of amplicons using Sanger sequencing. Obtained results were correlated to clinical and pathological characteristics of DTCs. Statistical analyses were performed using SPSS (The Statistical Package for Social Sciences) version 20 software. Results Overall, BRAF mutations were identified in 48.5 % (99/204) of adult DTCs. Three rare non-hotspot mutations (T599I, T599dup and K601E) were detected in four tumor samples (2 %). One (K601E) of these non-hotspot mutations occurred in conventional papillary thyroid cancer (CPTC) and other three (T599I, T599dup and K601E) were found in follicular variant PTC. We found significant association between BRAF V600E mutation and age ( P  < 0.0001), extrathyroidal invasion ( P  = 0.017), lymph node metastasis ( P  = 0.038) and TNM stage III/IV ( P  = 0.001). Conclusions Our study is the first to report BRAF mutations in a pure adult sample of DTCs of Saudi Arabian ethnicity. Our results show a high rate and a strong prognostic role of the classical BRAF V600E mutation and also suggest a common occurrence of non-hot spot mutations in adult DTC from this highly inbred population.

Abstract Context Multiple tumors in the same patient suggest a genetic predisposition. Here, we report a patient who presented with several unusual types of malignant and benign tumors, presumably due to a pathogenic germline PMS1 mutation. Case A 69-year-old woman presented with a 2-year history of abdominal pain and diarrhea. A computed tomography scan of the abdomen revealed a gastrointestinal neuroendocrine tumor (GiNET) with liver metastases and a nonfunctional benign adrenal adenoma. Bilateral large lung nodules were thought to be also metastases from the GiNET but turned out to be differentiated thyroid cancer metastases, which later progressed to anaplastic thyroid cancer (ATC) and led to the patient's demise. A right sphenoid wing meningioma causing partial hypopituitarism was diagnosed during her evaluation. A mammogram and a breast ultrasound revealed a 0.3-cm left breast nodule. Due to the multiplicity of her tumors, whole exome sequencing was performed. This revealed a previously described PMS1 deletion mutation causing a frameshift and truncation (NM_000534c.1258delC, p.His420Ilefs*22) but no other pathogenic variant in other cancer genes. DNA isolated from the ATC tumor tissue showed loss of heterozygosity of the same mutation, highly suggestive of its pathogenic role in thyroid cancer and presumably other tumors. Conclusion This case reports several tumors including thyroid cancer, GiNET, adrenal adenoma, meningioma, and breast nodule, likely due to the PMS1 mutation found in this patient.