Methionyl-tRNA synthetase 1 expression, the possibility as a diagnostic and prognostic factor in papillary thyroid cancer

Methionyl-tRNA synthetase 1 expression, the possibility as a diagnostic and prognostic factor in papillary thyroid cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Methionyl-tRNA synthetase 1 expression, the possibility as a diagnostic and prognostic factor in papillary thyroid cancer Seulkee Park, Jun Sung Lee, Ho Jung Jeong, Hyeok Jun Yun, Seok-Mo Kim, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4703390/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 Dec, 2025 Read the published version in BMC Cancer → Version 1 posted 4 You are reading this latest preprint version Abstract Background Methionyl-tRNA synthetase 1 (MARS1) is a critical enzyme in translation initiation, responsible for catalyzing the transfer of Met to the initiator tRNA. In this study, we aimed to examine whether MARS1 expression is different between normal follicular cells and papillary thyroid carcinoma (PTC) cells in thyroid tissue and whether it can supplement the limitations of general cell staining methods currently performed for diagnosis of PTC. Methods Initially, 103 patients were included to compare MARS1 expression in PTC and normal follicular cells. Next, 100 patients were selected to compare MARS1 expression using immunohistochemical analysis in patients with (n = 50) and without (n = 50) lateral neck metastasis. Results The average MARS1 expression grade of PTC cells was 2.59 and that of normal follicular cells was 1.28. MARS1 expression in the two groups showed significant differences ( p < 0.001). There was a significant difference in the average MARS1 expression grade of PTC cells between the metastasis and non-metastasis groups ( p < 0.05). Additionally, a significant difference was observed in the average MARS1 expression grade between the lymph node of the metastasis group and PTC cells of the non-metastasis group ( p < 0.05). Conclusions Our analyses suggest that MARS1 could be used as a complementary method to the current fine needle aspiration biopsy tissue staining method. Additionally, MARS1 could be a predictor of the prognosis of PTC. Papillary thyroid cancer Methionyl-tRNA synthetase 1 Diagnostic marker Prognostic marker Figures Figure 1 Figure 2 Figure 3 Background Thyroid nodules are generally found on ultrasound scans performed for cervical screening ( 1 ) . Further determination of whether there is a need for observation or additional tests depends on the size and shape of the nodules and whether they classify as hot or cold nodules. Fine needle aspiration biopsy (FNAB) is an important and widely accepted method used in the diagnosis of patients with thyroid nodules ( 2 ) . The results of FNAB are largely divided into 6 categories, according to the Bethesda system for reporting thyroid cytopathology (TBSRTC), of which surgical treatment is generally performed in categories 5 or 6 ( 3 ) . However, in categories 3 and 4, the Bethesda system is ambiguous about whether surgery is required. Category 3 refers to an atypical cell, and generally, surgical treatment is considered when successive FNAB results depict category 3 ( 4 ) . Category 4 refers to follicular neoplasm, and in this case, it is not possible to confirm a possibility of malignancy with FNAB ( 5 ) . The malignancy in category 4 can only be confirmed at the final pathology after surgery. In categories 3 and 4 of TBSRTC, excessive tests or surgical treatments may be performed. This can be considered a limitation of the general FNAB tissue staining method currently being performed ( 6 ) . Methionyl-tRNA synthetase 1 (MARS1) is involved in translation initiation, catalyzing the transfer of Met to the initiator tRNA ( 7 ) . MARS1 links the DNA damage response to global translation control after ultraviolet-induced DNA damage. It is an aminoacyl-tRNA synthetase (ARS), which is a family of housekeeping enzymes that catalyze amino acid ligation to their cognate transfer RNAs (tRNAs) with high precision and, thus, are essential for protein biosynthesis ( 8 ) . ARS enzymes, which consume one molecule of ATP per reaction, activate amino acids to aminoacyl adenylates and deliver them to the acceptor ends of tRNAs. The overexpression of ARS may impact cancer survival and progression; therefore, these enzymes have potential as anticancer therapeutics. The multifunctionality of ARSs and their localization to multiple regions suggest their potential as diagnostic biomarkers for cancer ( 9 ) . Several studies have reported malignancy based on elevated MARS1 expression detected by immunostaining. In this study, we aimed to examine whether MARS1 expression differs between normal follicular cells and papillary thyroid cancer (PTC) cells in the thyroid tissue and verify whether it can supplement the limitations of the currently used general cell staining methods. Methods Study design In this retrospective study, tissues were obtained from patients who underwent surgical treatment for PTC. First, we selected 103 patients diagnosed with PTC from May 8, 2020 to June 8, 2022 to compare MARS1 expression between PTC cells and normal follicular cells obtained from the thyroid tissue of the patients. Second, we selected 100 patients who underwent bilateral thyroidectomy with or without modified radical neck dissection between July 09, 2015 and December 14, 2017, and compared the MARS1 expression in patients with lateral neck metastasis to that in patients without lateral neck metastasis. Of the 100 patients, 50 had lateral neck metastasis and the remaining 50 had no metastasis. For patients with lateral neck metastasis, modified radical neck dissection was performed and lateral neck lymph node was confirmed by permanent pathology. This study was approved by the Institutional Review Board (IRB) of Gangnam Severance Hospital, Yonsei University College of Medicine (IRB protocol: 3-2020-0309). Given the retrospective nature of the study, the requirement for patient approval or informed consent was waived by the IRB. Immunohistochemical staining Immunohistochemical (IHC) staining for MARS1 was performed on paraffin-embedded thyroid tissue blocks cut into 4 µm sections using an automated IHC stainer (BenchMark XT; Ventana Medical Systems, Tucson, AZ, USA) with a primary antibody against human MARS1 (1:300; 0.2 mg/mL; Bicbio Inc., Suwon, South Korea). Interpretation of MARS1 expression MARS1 expression in PTC and normal follicular cells was categorized into four grades (Grade 0, 1, 2, 3) depending on the intensity of the expression. If the MARS1 expression intensity in the thyroid tissue was similar to that in the parathyroid gland or germinal center cells of lymphoid tissue, it was determined as Grade 3. If the MARS1 expression intensity in the thyroid tissue was similar to that in benign thyroid follicles, it was determined as Grade 1. MARS1 expression intensity between Grades 1 and 3 was determined as Grade 2. If MARS1 was not expressed in the sample, it was determined as Grade 0. Figure 1 shows Grades 1, 2, and 3 MARS1 expression in thyroid tissues along with Grade 3 MARS1 expression in metastatic PTC cells in the lymph node. Statistical analysis All statistical analyses were performed using SPSS 27 statistical software. Fisher’s exact or chi-square tests were used to compare categorical variables. Student’s t -test was used to compare continuous variables, which are presented as mean ± standard deviation. Statistical significance was set at p < 0.05. Results MARS1 expression in normal follicular and PTC cells We obtained both normal and cancer tissues from 103 patients, 18 of whom were excluded as IHC evaluation result was insufficient. Table 1 shows the clinical features of the remaining 85 enrolled patients. The number of female patients was 63 (74.1%), and the average age was 44.52 years. The average tumor size was 1.05 cm. Total thyroidectomy was performed for 34 patients, and the remaining 51 patients underwent a partial thyroidectomy. Modified radical neck dissection (MRND) was conducted in 11 patients, two of whom underwent bilateral MRND. The average number of harvested central lymph nodes was 5.33, and the average number of metastatic central lymph nodes was 1.82. Table 1 Clinical features of 85 patients enrolled for determination of MARS1 expression Parameter Values Total number 85 Sex Male 22 Female 63 Surgical extent Total 34 Less than total 51 Lateral neck dissection No 74 Unilateral 9 Bilateral 2 Thyroiditis Yes 29 No 56 Extra-thyroidal lesion Yes 9 No 76 Age (years) 44.52 Size 1.05 (cm) Positive Central LN 1.82 Total Central LN 5.33 LN; Lymph node Figure 2 shows the comparison of MARS1 expression between PTC cells and normal follicular cells in thyroid tissues. Fifty-five patients showed Grade 3 expression in PTC cells. Grade 2 expression was found in 25 patients, and Grade 1 expression in 5 patients. No patient with PTC cells was categorized under Grade 0 MARS1 expression. Fifty-six patients had Grade 1 expression in normal follicular cells. Grade 2 expression was found in 25 patients, and Grade 3 expression in only 1 patient. Three patients showed Grade 0 expression. The average MARS1 expression in PTC cells was 2.59 and that in normal follicular cells was 1.28, with the two groups showing significant differences ( p < 0.001). MARS1 expression with and without lateral neck metastasis We selected 100 patients to compare MARS1 expression between patients with (n = 50) and patients without (n = 50) lateral neck metastasis. Thyroid cancer tissues were obtained from all patients, and lymph node tissues were obtained from patients with lateral neck metastasis. The clinical features of the enrolled patients are shown in Table 2 . Each group comprised 10 male and 40 female patients, and total thyroidectomy was performed for all patients. In the metastasis group, two patients underwent bilateral MRND, while unilateral MRND was performed for the remaining. The average age of each group was 48.78 and 40.62 years, respectively ( p = 0.001). The average tumor size was 1.45 cm for patients who underwent MRND and 1.34 cm for the rest ( p = 0.096). The average number of harvested central lymph nodes was 7.20 and 8.18 ( p = 0.376), while those of harvested metastatic central lymph nodes was 1.38 and 4.14 ( p = 0.000), in patients who did not undergo MRND and those who did, respectively. Table 2 Clinical features of patients divided into LND (-) and LND (+) groups based on whether they underwent lateral neck dissection Parameter LND (-) LND (+) p -value Total number 50 50 Sex Male 10 10 Female 40 40 Surgical extent Total 50 50 Lateral neck dissection Unilateral - 48 Bilateral - 2 Thyroiditis Yes 20 25 No 30 25 Extra-thyroidal lesion Yes - 21 No 50 29 Age 48.78 40.62 0.001 Size 1.34 1.45 0.096 Positive Central LN 1.38 4.14 0.000 Total Central LN 7.20 8.18 0.376 Positive Lateral LN - 4.42 - Total Lateral LN - 28.92 - LND; Lateral neck dissection, LN; Lymph node Figure 3 shows the comparison of MARS1 expression between the lateral neck metastasis group and no metastasis group. In the no metastasis group, 33 patients had Grade 3 expression. Grade 2 expression was found in 17 patients, and none of patients showed Grade 1 expression. In the group with lateral neck metastasis, 49 patients showed Grade 3 expression and only 1 patient showed Grade 2 expression. In the group of patients with lateral neck lymph node, 45 patients showed Grade 3 expression and 5 showed Grade 2 expression. In the group without metastasis, the average MARS1 expression grade was 2.66 ± 0.479, and in patients with metastasis, the average was 2.98 ± 0.141. The average number of lymph nodes in patients with lateral neck metastasis was 2.90 ± 0.303. There was a significant difference in the average MARS1 expression grade in PTC cells between the metastasis and non-metastasis groups ( p < 0.05). There was also a significant difference in the average MARS1 expression grade between the lymph nodes of the metastasis group and PTC cells of the non-metastasis group ( p < 0.05). There was no difference in the average MARS1 expression grade between the lymph nodes and PTC cells of the metastasis group ( p = 0.94). Discussion Elevated MARS1 expression in carcinoma can be used to diagnose malignancy of indeterminate specimens in several cancers. In the biliary stricture, the high sensitivity and accuracy of MARS1 immunofluorescence staining enables the detection of malignancy in patients with biliary strictures ( 10 ) . Furthermore, high MARS1 expression in pancreatic ductal adenocarcinoma could be associated with a poor prognosis ( 11 ) . In non-small-cell lung cancer (NSCLC), MARS1 staining has shown good diagnostic performance for determining lymph node metastasis ( 12 ) . MARS1 is also associated with poor clinical prognosis in NSCLC ( 13 ) . In our study, we found that MARS1 could perform the same role in PTC. The average MARS1 expression was higher in PTC cells than in normal thyroid follicular cells. This could compensate for the vulnerability of conventional FNAB that diagnoses thyroid nodules. When FNAB is carried out for the diagnosis of thyroid nodules, TBSRTC is used to describe the result of FNAB ( 3 ) . In this system, Category 3 (Atypia or undetermined) and Category 4 (Follicular neoplasm) are not considered “confirmed cancer” but have a possibility to be diagnosed as thyroid cancer at the permanent pathology. Therefore, when patients are diagnosed as Category 3 or 4 after FNAB, the surgery option cannot be excluded and, in practice, thyroidectomy is often performed ( 14 ) . If the final pathology does not determine cancer, the surgery performed becomes an unnecessary procedure that was done to rule out the possibility of cancer. Determining MARS1 expression grade has the potential to help avoid this unnecessary process. If the MARS1 expression grade with FNAB is high, surgery would be a reasonable option. If the MARS1 expression grade with FNAB is low or similar to that in normal tissues, the option of surgery could be held off in favor of follow-ups. Another aim of this study was to examine the hypothesis that MARS1 is a possible marker for prognosis in thyroid cancer. Patients with lateral neck metastasis showed a higher average MARS1 expression grade than patients without lateral neck metastasis. Considering that thyroid cancer with lateral neck metastasis is aggressive, the higher MARS1 grade expression could be associated with more aggressive thyroid cancer. Further studies including comparison between groups and the patients’ overall survival are needed to elucidate the relationship between MARS1 expression and prognosis of thyroid cancer. There are several limitations to this study. First, this is a single center retrospective study, and the study population is small. Second, we did not evaluate the actual diagnostic effectiveness of MARS1 in TBSTRC Category 3 and Category 4. Additional studies on Category 3 and Category 4 with MARS1 expression grade would be needed to determine the effectiveness of MARS1 expression as a diagnostic factor. In conclusion, we found that MARS1 expression could be used as a complementary method to the current FNAB tissue staining method for cancer diagnosis. Furthermore, the average MARS1 expression in PTC and normal follicular cells showed significant differences, reinforcing its potential as a diagnostic marker that can also predict prognosis in thyroid cancer cases. Declarations Ethics approval and consent to participate This study was approved by the Institutional Review Board (IRB) of Gangnam Severance Hospital, Yonsei University College of Medicine (IRB protocol: 3-2020-0309). Given the retrospective nature of the study, the requirement for patient approval or informed consent was waived by the IRB. Consent for publication Given the retrospective nature of the study, the requirement for patient approval or informed consent was waived by the IRB. Availability of data and materials The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding The study did not receive any funding. Authors’ contributions Conceptualization: S.M.K, J.H.N.; Data curation: J.S.L, S.K.P.; Formal analysis: J.S.L, S.K.P.; Investigation: J.S.L.; Methodology: S.M.K.; Project administration: S.M.K., J.H.N.; Resources: J.S.L.; Software: S.K.P.; Supervision: S.M.K.; Validation: J.S.L., S.M.K.; Visualization: J.S.L, S.K.P., J.H.N.; Writing – original draft: S.K.P, J.S.L.; Writing – review & editing: H.J.J, H.J.Y, S.M.K, J.H.N, H.J.C, Y.S.L, H.S.C.; Approval of final manuscript: all authors. Acknowledgements We would like to thank Editage (www.editage.com) for English language editing. References Guth S, Theune U, Aberle J, Galach A, Bamberger CM. 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Best Pract Res Clin Endocrinol Metab. 2019;33(4):101292. Kwon NH, Kang T, Lee JY, Kim HH, Kim HR, Hong J, et al. Dual role of methionyl-tRNA synthetase in the regulation of translation and tumor suppressor activity of aminoacyl-tRNA synthetase-interacting multifunctional protein-3. Proc Natl Acad Sci U S A. 2011;108(49):19635–40. Kim S, You S, Hwang D. Aminoacyl-tRNA synthetases and tumorigenesis: more than housekeeping. Nat Rev Cancer. 2011;11(10):708–18. Zhou Z, Sun B, Nie A, Yu D, Bian M. Roles of Aminoacyl-tRNA Synthetases in Cancer. Front Cell Dev Biol. 2020;8:599765. Jang SI, Nahm JH, Kwon NH, Jeong S, Lee TH, Cho JH, et al. Clinical utility of methionyl-tRNA synthetase 1 immunostaining in cytologic brushings of indeterminate biliary strictures: a multicenter prospective study. Gastrointest Endosc. 2021;94(4):733–41. e4. Jang SI, Nahm JH, Lee SY, Cho JH, Do MY, Park JS et al. Prediction of Prognosis in Pancreatic Cancer According to Methionyl-tRNA Synthetase 1 Expression as Determined by Immunohistochemical Staining. Cancers (Basel). 2023;15(22). Lee JM, Kim T, Kim EY, Kim A, Lee DK, Kwon NH, et al. Methionyl-tRNA Synthetase is a Useful Diagnostic Marker for Lymph Node Metastasis in Non-Small Cell Lung Cancer. Yonsei Med J. 2019;60(11):1005–12. Kim EY, Jung JY, Kim A, Kim K, Chang YS. Methionyl-tRNA synthetase overexpression is associated with poor clinical outcomes in non-small cell lung cancer. BMC Cancer. 2017;17(1):467. Francis GL, Waguespack SG, Bauer AJ, Angelos P, Benvenga S, Cerutti JM, et al. Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2015;25(7):716–59. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 03 Dec, 2025 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Revision requested 16 Jul, 2024 Editor assigned by journal 10 Jul, 2024 Submission checks completed at journal 10 Jul, 2024 First submitted to journal 08 Jul, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4703390","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":327651877,"identity":"ade72a18-324b-43a9-b525-e3950a2665da","order_by":0,"name":"Seulkee Park","email":"","orcid":"","institution":"Department of Surgery, Yonsei University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Seulkee","middleName":"","lastName":"Park","suffix":""},{"id":327651878,"identity":"c8b1fb37-1d55-4223-bce1-f8d5f26cf3a2","order_by":1,"name":"Jun Sung Lee","email":"","orcid":"","institution":"Department of Surgery, Thyroid 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Grade 3 expression in metastatic papillary thyroid carcinoma cells in lymph node (c) (Magnification: 400×).\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4703390/v1/04f74f658932b0b4b2847b91.jpg"},{"id":62184460,"identity":"1c085efd-a6b7-477f-a0f6-70f0a6385102","added_by":"auto","created_at":"2024-08-10 11:43:42","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":40939,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMARS1 expression in cells of 85 patients with thyroid cancer\u003c/strong\u003e. MARS1 average expression grades (0, 1, 2, or 3) in papillary thyroid carcinoma (PTC) cells and normal follicular cells of 85 patients with PTC.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4703390/v1/6946a55ba4b774a44e694cfd.jpg"},{"id":62183430,"identity":"1aab6fe7-c436-4a08-a51c-87bd41c12a9a","added_by":"auto","created_at":"2024-08-10 11:35:42","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":80843,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMARS1 expression in lateral neck dissection (LND) group and without LND group. \u003c/strong\u003eComparison of average MARS1 expression grades (0, 1, 2, or 3) between patients with and without lateral neck metastasis.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4703390/v1/4d8f42db381eda6d21492b03.jpg"},{"id":97723779,"identity":"9939251b-f7f3-4fb5-a6f3-959efc206b48","added_by":"auto","created_at":"2025-12-08 16:06:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":898923,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4703390/v1/f2d4c59d-fe72-4e8c-8acd-1da8fbd3ca04.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Methionyl-tRNA synthetase 1 expression, the possibility as a diagnostic and prognostic factor in papillary thyroid cancer","fulltext":[{"header":"Background","content":"\u003cp\u003eThyroid nodules are generally found on ultrasound scans performed for cervical screening \u003csup\u003e(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/sup\u003e. Further determination of whether there is a need for observation or additional tests depends on the size and shape of the nodules and whether they classify as hot or cold nodules. Fine needle aspiration biopsy (FNAB) is an important and widely accepted method used in the diagnosis of patients with thyroid nodules \u003csup\u003e(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe results of FNAB are largely divided into 6 categories, according to the Bethesda system for reporting thyroid cytopathology (TBSRTC), of which surgical treatment is generally performed in categories 5 or 6 \u003csup\u003e(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/sup\u003e. However, in categories 3 and 4, the Bethesda system is ambiguous about whether surgery is required. Category 3 refers to an atypical cell, and generally, surgical treatment is considered when successive FNAB results depict category 3 \u003csup\u003e(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/sup\u003e. Category 4 refers to follicular neoplasm, and in this case, it is not possible to confirm a possibility of malignancy with FNAB \u003csup\u003e(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/sup\u003e. The malignancy in category 4 can only be confirmed at the final pathology after surgery. In categories 3 and 4 of TBSRTC, excessive tests or surgical treatments may be performed. This can be considered a limitation of the general FNAB tissue staining method currently being performed \u003csup\u003e(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMethionyl-tRNA synthetase 1 (MARS1) is involved in translation initiation, catalyzing the transfer of Met to the initiator tRNA \u003csup\u003e(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/sup\u003e. MARS1 links the DNA damage response to global translation control after ultraviolet-induced DNA damage. It is an aminoacyl-tRNA synthetase (ARS), which is a family of housekeeping enzymes that catalyze amino acid ligation to their cognate transfer RNAs (tRNAs) with high precision and, thus, are essential for protein biosynthesis \u003csup\u003e(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/sup\u003e. ARS enzymes, which consume one molecule of ATP per reaction, activate amino acids to aminoacyl adenylates and deliver them to the acceptor ends of tRNAs. The overexpression of ARS may impact cancer survival and progression; therefore, these enzymes have potential as anticancer therapeutics. The multifunctionality of ARSs and their localization to multiple regions suggest their potential as diagnostic biomarkers for cancer \u003csup\u003e(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSeveral studies have reported malignancy based on elevated MARS1 expression detected by immunostaining. In this study, we aimed to examine whether MARS1 expression differs between normal follicular cells and papillary thyroid cancer (PTC) cells in the thyroid tissue and verify whether it can supplement the limitations of the currently used general cell staining methods.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eIn this retrospective study, tissues were obtained from patients who underwent surgical treatment for PTC. First, we selected 103 patients diagnosed with PTC from May 8, 2020 to June 8, 2022 to compare MARS1 expression between PTC cells and normal follicular cells obtained from the thyroid tissue of the patients. Second, we selected 100 patients who underwent bilateral thyroidectomy with or without modified radical neck dissection between July 09, 2015 and December 14, 2017, and compared the MARS1 expression in patients with lateral neck metastasis to that in patients without lateral neck metastasis. Of the 100 patients, 50 had lateral neck metastasis and the remaining 50 had no metastasis. For patients with lateral neck metastasis, modified radical neck dissection was performed and lateral neck lymph node was confirmed by permanent pathology. This study was approved by the Institutional Review Board (IRB) of Gangnam Severance Hospital, Yonsei University College of Medicine (IRB protocol: 3-2020-0309). Given the retrospective nature of the study, the requirement for patient approval or informed consent was waived by the IRB.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eImmunohistochemical staining\u003c/h2\u003e \u003cp\u003eImmunohistochemical (IHC) staining for MARS1 was performed on paraffin-embedded thyroid tissue blocks cut into 4 \u0026micro;m sections using an automated IHC stainer (BenchMark XT; Ventana Medical Systems, Tucson, AZ, USA) with a primary antibody against human MARS1 (1:300; 0.2 mg/mL; Bicbio Inc., Suwon, South Korea).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eInterpretation of MARS1 expression\u003c/h2\u003e \u003cp\u003eMARS1 expression in PTC and normal follicular cells was categorized into four grades (Grade 0, 1, 2, 3) depending on the intensity of the expression. If the MARS1 expression intensity in the thyroid tissue was similar to that in the parathyroid gland or germinal center cells of lymphoid tissue, it was determined as Grade 3. If the MARS1 expression intensity in the thyroid tissue was similar to that in benign thyroid follicles, it was determined as Grade 1. MARS1 expression intensity between Grades 1 and 3 was determined as Grade 2. If MARS1 was not expressed in the sample, it was determined as Grade 0. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows Grades 1, 2, and 3 MARS1 expression in thyroid tissues along with Grade 3 MARS1 expression in metastatic PTC cells in the lymph node.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll statistical analyses were performed using SPSS 27 statistical software. Fisher\u0026rsquo;s exact or chi-square tests were used to compare categorical variables. Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e-test was used to compare continuous variables, which are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. Statistical significance was set at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eMARS1 expression in normal follicular and PTC cells\u003c/h2\u003e \u003cp\u003eWe obtained both normal and cancer tissues from 103 patients, 18 of whom were excluded as IHC evaluation result was insufficient. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the clinical features of the remaining 85 enrolled patients. The number of female patients was 63 (74.1%), and the average age was 44.52 years. The average tumor size was 1.05 cm. Total thyroidectomy was performed for 34 patients, and the remaining 51 patients underwent a partial thyroidectomy. Modified radical neck dissection (MRND) was conducted in 11 patients, two of whom underwent bilateral MRND. The average number of harvested central lymph nodes was 5.33, and the average number of metastatic central lymph nodes was 1.82.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical features of 85 patients enrolled for determination of MARS1 expression\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValues\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal number\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgical extent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLess than total\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLateral neck dissection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnilateral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBilateral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThyroiditis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtra-thyroidal lesion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44.52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSize\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.05 (cm)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive Central LN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal Central LN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eLN; Lymph node\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the comparison of MARS1 expression between PTC cells and normal follicular cells in thyroid tissues. Fifty-five patients showed Grade 3 expression in PTC cells. Grade 2 expression was found in 25 patients, and Grade 1 expression in 5 patients. No patient with PTC cells was categorized under Grade 0 MARS1 expression. Fifty-six patients had Grade 1 expression in normal follicular cells. Grade 2 expression was found in 25 patients, and Grade 3 expression in only 1 patient. Three patients showed Grade 0 expression. The average MARS1 expression in PTC cells was 2.59 and that in normal follicular cells was 1.28, with the two groups showing significant differences (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eMARS1 expression with and without lateral neck metastasis\u003c/h2\u003e \u003cp\u003eWe selected 100 patients to compare MARS1 expression between patients with (n\u0026thinsp;=\u0026thinsp;50) and patients without (n\u0026thinsp;=\u0026thinsp;50) lateral neck metastasis. Thyroid cancer tissues were obtained from all patients, and lymph node tissues were obtained from patients with lateral neck metastasis. The clinical features of the enrolled patients are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Each group comprised 10 male and 40 female patients, and total thyroidectomy was performed for all patients. In the metastasis group, two patients underwent bilateral MRND, while unilateral MRND was performed for the remaining. The average age of each group was 48.78 and 40.62 years, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). The average tumor size was 1.45 cm for patients who underwent MRND and 1.34 cm for the rest (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.096). The average number of harvested central lymph nodes was 7.20 and 8.18 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.376), while those of harvested metastatic central lymph nodes was 1.38 and 4.14 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000), in patients who did not undergo MRND and those who did, respectively.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical features of patients divided into LND (-) and LND (+) groups based on whether they underwent lateral neck dissection\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLND (-)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLND (+)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal number\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgical extent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLateral neck dissection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnilateral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBilateral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThyroiditis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtra-thyroidal lesion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSize\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.096\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive Central LN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal Central LN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.376\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive Lateral LN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal Lateral LN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eLND; Lateral neck dissection, LN; Lymph node\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the comparison of MARS1 expression between the lateral neck metastasis group and no metastasis group. In the no metastasis group, 33 patients had Grade 3 expression. Grade 2 expression was found in 17 patients, and none of patients showed Grade 1 expression. In the group with lateral neck metastasis, 49 patients showed Grade 3 expression and only 1 patient showed Grade 2 expression. In the group of patients with lateral neck lymph node, 45 patients showed Grade 3 expression and 5 showed Grade 2 expression. In the group without metastasis, the average MARS1 expression grade was 2.66\u0026thinsp;\u0026plusmn;\u0026thinsp;0.479, and in patients with metastasis, the average was 2.98\u0026thinsp;\u0026plusmn;\u0026thinsp;0.141. The average number of lymph nodes in patients with lateral neck metastasis was 2.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.303. There was a significant difference in the average MARS1 expression grade in PTC cells between the metastasis and non-metastasis groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). There was also a significant difference in the average MARS1 expression grade between the lymph nodes of the metastasis group and PTC cells of the non-metastasis group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). There was no difference in the average MARS1 expression grade between the lymph nodes and PTC cells of the metastasis group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.94).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eElevated MARS1 expression in carcinoma can be used to diagnose malignancy of indeterminate specimens in several cancers. In the biliary stricture, the high sensitivity and accuracy of MARS1 immunofluorescence staining enables the detection of malignancy in patients with biliary strictures \u003csup\u003e(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/sup\u003e. Furthermore, high MARS1 expression in pancreatic ductal adenocarcinoma could be associated with a poor prognosis \u003csup\u003e(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/sup\u003e. In non-small-cell lung cancer (NSCLC), MARS1 staining has shown good diagnostic performance for determining lymph node metastasis \u003csup\u003e(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/sup\u003e. MARS1 is also associated with poor clinical prognosis in NSCLC \u003csup\u003e(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/sup\u003e. In our study, we found that MARS1 could perform the same role in PTC.\u003c/p\u003e \u003cp\u003eThe average MARS1 expression was higher in PTC cells than in normal thyroid follicular cells. This could compensate for the vulnerability of conventional FNAB that diagnoses thyroid nodules. When FNAB is carried out for the diagnosis of thyroid nodules, TBSRTC is used to describe the result of FNAB \u003csup\u003e(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/sup\u003e. In this system, Category 3 (Atypia or undetermined) and Category 4 (Follicular neoplasm) are not considered \u0026ldquo;confirmed cancer\u0026rdquo; but have a possibility to be diagnosed as thyroid cancer at the permanent pathology. Therefore, when patients are diagnosed as Category 3 or 4 after FNAB, the surgery option cannot be excluded and, in practice, thyroidectomy is often performed \u003csup\u003e(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/sup\u003e. If the final pathology does not determine cancer, the surgery performed becomes an unnecessary procedure that was done to rule out the possibility of cancer. Determining MARS1 expression grade has the potential to help avoid this unnecessary process. If the MARS1 expression grade with FNAB is high, surgery would be a reasonable option. If the MARS1 expression grade with FNAB is low or similar to that in normal tissues, the option of surgery could be held off in favor of follow-ups.\u003c/p\u003e \u003cp\u003eAnother aim of this study was to examine the hypothesis that MARS1 is a possible marker for prognosis in thyroid cancer. Patients with lateral neck metastasis showed a higher average MARS1 expression grade than patients without lateral neck metastasis. Considering that thyroid cancer with lateral neck metastasis is aggressive, the higher MARS1 grade expression could be associated with more aggressive thyroid cancer. Further studies including comparison between groups and the patients\u0026rsquo; overall survival are needed to elucidate the relationship between MARS1 expression and prognosis of thyroid cancer.\u003c/p\u003e \u003cp\u003eThere are several limitations to this study. First, this is a single center retrospective study, and the study population is small. Second, we did not evaluate the actual diagnostic effectiveness of MARS1 in TBSTRC Category 3 and Category 4. Additional studies on Category 3 and Category 4 with MARS1 expression grade would be needed to determine the effectiveness of MARS1 expression as a diagnostic factor.\u003c/p\u003e \u003cp\u003eIn conclusion, we found that MARS1 expression could be used as a complementary method to the current FNAB tissue staining method for cancer diagnosis. Furthermore, the average MARS1 expression in PTC and normal follicular cells showed significant differences, reinforcing its potential as a diagnostic marker that can also predict prognosis in thyroid cancer cases.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board (IRB) of Gangnam Severance Hospital, Yonsei University College of Medicine (IRB protocol: 3-2020-0309). Given the retrospective nature of the study, the requirement for patient approval or informed consent was waived by the IRB.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGiven the retrospective nature of the study, the requirement for patient approval or informed consent was waived by the IRB.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study did not receive any funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: S.M.K,\u0026nbsp;J.H.N.;\u0026nbsp;Data curation: J.S.L,\u0026nbsp;S.K.P.;\u0026nbsp;Formal analysis: J.S.L,\u0026nbsp;S.K.P.;\u0026nbsp; Investigation: J.S.L.; Methodology: S.M.K.; Project administration: S.M.K.,\u0026nbsp;J.H.N.;\u0026nbsp;Resources: J.S.L.; Software:\u0026nbsp;S.K.P.;\u0026nbsp;Supervision: S.M.K.; Validation: J.S.L., S.M.K.; Visualization: J.S.L,\u0026nbsp;S.K.P., J.H.N.;\u0026nbsp;Writing \u0026ndash; original draft:\u0026nbsp;S.K.P, J.S.L.;\u0026nbsp;Writing \u0026ndash; review \u0026amp; editing:\u0026nbsp;H.J.J, H.J.Y, S.M.K,\u0026nbsp;J.H.N, H.J.C, Y.S.L, H.S.C.;\u0026nbsp;Approval of final manuscript: all authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Editage (www.editage.com) for English language editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGuth S, Theune U, Aberle J, Galach A, Bamberger CM. Very high prevalence of thyroid nodules detected by high frequency (13 MHz) ultrasound examination. Eur J Clin Invest. 2009;39(8):699\u0026ndash;706.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrani G, Sponziello M, Pecce V, Ramundo V, Durante C. Contemporary Thyroid Nodule Evaluation and Management. J Clin Endocrinol Metab. 2020;105(9):2869\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWesola M, Jelen M. Bethesda System in the evaluation of thyroid nodules: Review. Adv Clin Exp Med. 2017;26(1):177\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNagarkatti SS, Faquin WC, Lubitz CC, Garcia DM, Barbesino G, Ross DS, et al. Management of thyroid nodules with atypical cytology on fine-needle aspiration biopsy. Ann Surg Oncol. 2013;20(1):60\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStanek-Widera A, Biskup-Fruzynska M, Zembala-Nozynska E, Poltorak S, Snietura M, Lange D. Suspicious for follicular neoplasm or follicular neoplasm? The dilemma of a pathologist and a surgeon. Endokrynol Pol. 2016;67(1):17\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStaubitz JI, Musholt PB, Musholt TJ. The surgical dilemma of primary surgery for follicular thyroid neoplasms. Best Pract Res Clin Endocrinol Metab. 2019;33(4):101292.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKwon NH, Kang T, Lee JY, Kim HH, Kim HR, Hong J, et al. Dual role of methionyl-tRNA synthetase in the regulation of translation and tumor suppressor activity of aminoacyl-tRNA synthetase-interacting multifunctional protein-3. Proc Natl Acad Sci U S A. 2011;108(49):19635\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim S, You S, Hwang D. Aminoacyl-tRNA synthetases and tumorigenesis: more than housekeeping. Nat Rev Cancer. 2011;11(10):708\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou Z, Sun B, Nie A, Yu D, Bian M. Roles of Aminoacyl-tRNA Synthetases in Cancer. Front Cell Dev Biol. 2020;8:599765.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJang SI, Nahm JH, Kwon NH, Jeong S, Lee TH, Cho JH, et al. Clinical utility of methionyl-tRNA synthetase 1 immunostaining in cytologic brushings of indeterminate biliary strictures: a multicenter prospective study. Gastrointest Endosc. 2021;94(4):733\u0026ndash;41. e4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJang SI, Nahm JH, Lee SY, Cho JH, Do MY, Park JS et al. Prediction of Prognosis in Pancreatic Cancer According to Methionyl-tRNA Synthetase 1 Expression as Determined by Immunohistochemical Staining. Cancers (Basel). 2023;15(22).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee JM, Kim T, Kim EY, Kim A, Lee DK, Kwon NH, et al. Methionyl-tRNA Synthetase is a Useful Diagnostic Marker for Lymph Node Metastasis in Non-Small Cell Lung Cancer. Yonsei Med J. 2019;60(11):1005\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim EY, Jung JY, Kim A, Kim K, Chang YS. Methionyl-tRNA synthetase overexpression is associated with poor clinical outcomes in non-small cell lung cancer. BMC Cancer. 2017;17(1):467.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrancis GL, Waguespack SG, Bauer AJ, Angelos P, Benvenga S, Cerutti JM, et al. Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2015;25(7):716\u0026ndash;59.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Papillary thyroid cancer, Methionyl-tRNA synthetase 1, Diagnostic marker, Prognostic marker","lastPublishedDoi":"10.21203/rs.3.rs-4703390/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4703390/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMethionyl-tRNA synthetase 1 (MARS1) is a critical enzyme in translation initiation, responsible for catalyzing the transfer of Met to the initiator tRNA. In this study, we aimed to examine whether MARS1 expression is different between normal follicular cells and papillary thyroid carcinoma (PTC) cells in thyroid tissue and whether it can supplement the limitations of general cell staining methods currently performed for diagnosis of PTC.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eInitially, 103 patients were included to compare MARS1 expression in PTC and normal follicular cells. Next, 100 patients were selected to compare MARS1 expression using immunohistochemical analysis in patients with (n\u0026thinsp;=\u0026thinsp;50) and without (n\u0026thinsp;=\u0026thinsp;50) lateral neck metastasis.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe average MARS1 expression grade of PTC cells was 2.59 and that of normal follicular cells was 1.28. MARS1 expression in the two groups showed significant differences (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). There was a significant difference in the average MARS1 expression grade of PTC cells between the metastasis and non-metastasis groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Additionally, a significant difference was observed in the average MARS1 expression grade between the lymph node of the metastasis group and PTC cells of the non-metastasis group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOur analyses suggest that MARS1 could be used as a complementary method to the current fine needle aspiration biopsy tissue staining method. Additionally, MARS1 could be a predictor of the prognosis of PTC.\u003c/p\u003e","manuscriptTitle":"Methionyl-tRNA synthetase 1 expression, the possibility as a diagnostic and prognostic factor in papillary thyroid cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-10 11:35:37","doi":"10.21203/rs.3.rs-4703390/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-16T11:20:45+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-10T11:35:32+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-10T11:34:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2024-07-08T07:15:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ba59008a-c9f0-4b59-a9ef-f9ad2e372cea","owner":[],"postedDate":"August 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-08T15:59:48+00:00","versionOfRecord":{"articleIdentity":"rs-4703390","link":"https://doi.org/10.1186/s12885-025-15269-4","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2025-12-03 15:57:13","publishedOnDateReadable":"December 3rd, 2025"},"versionCreatedAt":"2024-08-10 11:35:37","video":"","vorDoi":"10.1186/s12885-025-15269-4","vorDoiUrl":"https://doi.org/10.1186/s12885-025-15269-4","workflowStages":[]},"version":"v1","identity":"rs-4703390","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4703390","identity":"rs-4703390","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}