Evaluation of cereblon expression in gastrointestinal tract tumors

Evaluation of cereblon expression in gastrointestinal tract tumors | 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 Evaluation of cereblon expression in gastrointestinal tract tumors Mustafa Degirmenci This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4283954/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: This retrospective study has aimed to determine the possible prognostic significance of cereblon (CRBN) expression in gastrointestinal tract tumors. Methods: In this study, cases of gastrointestinal tract tumors including neuroendocrine tumors (n:38), gastric adenocarcinomas (n:152) and colorectal carcinomas (n:87) diagnosed in the Pathology Laboratory of Tepecik Training and Research Hospital between 2008 and 2018 were evaluated. We investigated the presence of CRBN protein expression in tumor tissues using IHC staining. The relationship between CRBN expression and various prognostic factors was analyzed. Results: Most of the cases were male (n=179, 64.6%). The mean age of the patients was 60.5± 13.1 years. Overall survival in malignant cases was 30.5±21.8 months, with the shortest survival of 24.7 months in gastric carcinomas. CRBN expression was detected in 92 (33.2%) cases. CRBN positivity rates were highest in neuroendocrine carcinomas (55.6%) and lowest in gastric carcinomas (22.4%). The presence of CRBN expression was statistically significantly different among tumor types (p<0.001). When each group was evaluated separately, a statistically significant relationship was detected between CRBN expression and survival only in gastric carcinomas (p= 0.036). However, contrary to expectations, survival was shorter in patients with CRBN- positive tumors. Conclusion : In cancer treatment, it is very important to identify new targeted treatment options, especially for aggressive tumor types. Since some currently used immunomodulatory drugs target CRBN protein, the use of immunomodulatory drugs may be considered in addition to current therapies in the treatment of solid tumors expressing high levels of CRBN. Cancer Biology Oncology Cereblon CRBN colorectal carcinomas gastric carcinomas neuroendocrine tumors Figures Figure 1 Figure 2 Figure 3 Introduction Cereblon (CRBN) is a component of the E3 ubiquitin ligase complex. CRBN also acts as a substrate receptor for Cullin-RING ligase 4 (CRL4). This complex regulates ion transport, protein degradation, cell proliferation, metabolism and apoptosis at the cellular level [ 1 ]. In the ubiquitin and proteasome system (UPS), CRBN plays a role in the degradation or activation of proteins involved in cell survival. CRBN was first identified as a protein involved in learning and memorization functions in the brain. It was later found to play a role in important biological functions in other tissues. Neuronal diseases, malignancies, autoimmune and metabolic diseases may develop in cases of CRBN protein degradation. Although CRBN has been investigated more frequently in neoplastic diseases including hematologic malignancies such as myeloma and leukemia, the importance of CRBN expression levels in diagnosis and prognosis has not been clearly established even in hematologic cancers [ 2 ]. However, data suggesting its contribution to treatment and successful results of immunomodulatory therapies targeting the cerebrum in hematologic malignancies have increased the hope that similar results can be obtained in other cancer types. Immunomodulatory drugs such as thalidomide derivatives have been found to inhibit the function of the ubiquitin-proteasome system (UPS), which mediates DNA repair, replication and transcription by binding to CRBN [ 3 ]. Thalidomide derivatives show antiproliferative effects in multiple myeloma cells by affecting the UPS system and induce cytokine production from T cells. In clinical studies on hematologic malignancies, thalidomide and its derivatives have been shown to contribute favorably to treatment and survival [ 4 , 5 ]. Recently, new CRBN binding compounds have been developed and named "cereblon modulators". Among cereblon modulators, CC-122 (avadomide) and CC-220 (iberdomide) were added to standard therapies in early phase studies performed in cases with myeloma and lymphoma and used as monotherapy in resistant cases with achievement of promising effective results [ 6 , 7 ]. Among solid tumors, colorectal cancers, gastric cancers and neuroendocrine tumors are the leading malignancies among gastrointestinal system cancers. HER2 overexpression, MSI, CEA, CEA, RAS, BRAF mutation tests have been used for diagnosis and treatment planning. In advanced stages, biological agents are added to systemic chemotherapy treatment according to the presence of these markers. In recent years, successful results of immunotherapy agents (anti-PD1 and anti-PDL1) in the management of tumors with MSI-H have made a significant progress in disease control. However, in a significant number of cases with advanced disease and even in some early stage cancer patients, cure is not achieved and progression occurs with the development of resistance at certain stages of systemic therapies. New markers are needed to guide the diagnosis, prognosis and treatment planning of gastrointestinal tract cancers. The lack of these markers is one of the factors contributing to the slow progress in the fight against cancer today. The aim of this study was to determine the possible prognostic significance of CRBN in a group of gastrointestinal tract tumors including gastric cancer, colorectal carcinomas and gastrointestinal neuroendocrine tumors (NETs), so as to investigate its relationship with clinicopathological parameters and to evaluate its potential as a target molecule for therapy. Materials and Methods In this study, we immunohistochemically investigated the tissue expression of CRBN protein in tissue samples obtained from a total of 277 patients including those with grade 1 (n:20), and grades 2, and 3 (n:18) gastrointestinal neuroendocrine tumors (NETs), gastric adenocarcinomas (n:152), and colorectal carcinomas (n:87) diagnosed in Pathology Laboratory of Izmir Tepecik Training and Research Hospital between 2008–2018. Retrospective analysis of patient files was performed. This study was approved by the Ethics Committee of Izmir Democracy University (2020/10 − 01). Blocks containing viable tumor tissue samples were selected from the slides reevaluated by hematoxylin-eosin (H&E) staining for further immunohistochemical analysis (IHC). Microarray blocks were also prepared in cases with gastric carcinomas. Paraffin blocks selected for immunohistochemical analyses were sectioned at 3–5 micron thickness, and placed on lysinized slides. IHC analyses were performed manually using the streptavidin-biotin peroxidase method (Invitrogen, Camarillo, CA, USA). Prepared slides were kept at 60°C overnight, deparaffinized in xylene and rehydrated with distilled water by gradually reducing its alcohol concentrations. All slides were subjected to microwave treatment (heat-induced epitope recovery in 10 mm/L citrate buffer at pH 6.0 for 20 min, followed by cooling at room temperature for 20 min) and blocked for endogenous peroxidase and biotin. A polyclonal antibody against CRBN (Invitrogen, PA5-38037, 1/200 dilution) was used. CRBN expression was assessed in all tissue samples according to mapping and addressing procedures. Tissue samples in which CRBN expression could not be evaluated or shed tissue samples were not included in analyses. Pathologists unaware of the clinical characteristics of the patients, graded the staining patterns by examining the slides. Brown granular or diffuse cytoplasmic and/or nuclear staining for CRBN in tumor cells was considered positive. Some tumor cells also showed strong nuclear CRBN expression (Fig. 1). Since the tumor areas observed in the microarray blocks were quite small and the surrounding stroma was usually not observed, only the expression in tumor cells was recorded and the expression in inflammatory cells was not taken into consideration. The relationship between immunohistochemically detected CRBN expression levels and various prognostic factors was analyzed. Statistical analysis Statistical analysis was performed using SPSS 25.0 statistical package. Chi-square test was used to compare qualitative, and Mann-Whitney U test to compare nonparametric data. The nonparametric Kruskal-Wallis test was used to compare measurements in more than two groups. Kaplan-Meier survival analysis was used to compare the difference in survival rates between the groups. p ≤ 0.05 was accepted as the level of statistical significance. Results Most of the cases were male (n = 179, 64.6%). The mean age of the patients was 60.5 ± 13.1 years. Overall survival in malignant cases was 30.5 ± 21.8 months, with the shortest survival of 24.7 months in gastric carcinomas. CRBN expression was detected in 92 (33.2%) cases. CRBN-expressing neoplasms included colorectal carcinomas in 40, gastric carcinomas in 34, and NETs in 18 (grade 1, n:9, and grade 2–3, n:9) cases. When evaluated within each group, the highest and lowest CRBN positivity rates were detected in cases with neuroendocrine carcinomas (55.6%) and gastric carcinomas (22.4%), respectively. The presence of CRBN expression varied statistically significantly among tumor types (p < 0.001) (Fig. 2). Mann-Whitney U test showed no statistically significant correlation between CRBN expression and survival (p = 0.587). Kaplan-Meier survival analysis did no reveal any significant correlation between survival time and CRBN expression (p = 0.642) (Fig. 3). However, when CRBN expression was evaluated according to individual tumor groups, survival time was statistically significantly shorter in CRBN positive cases with gastric carcinomas (p = 0.036). In NETs, CRBN positivity was higher in larger tumors (p = 0.015). CRBN positivity was also statistically associated with tumor type (p = 0.01) and tumor localization (p = 0.03). General findings are given in Tables 1–3. Discussion Immunomodulatory drugs including thalidomide, lenalidomide, and pomalidomide are being used in the treatment of multiple myeloma, myelodysplastic syndrome, chronic lymphocytic lymphoma, and diffuse large β-cell lymphoma. Thalidomide affects cell proliferation and apoptosis by targeting intracellular CRBN expression levels. Studies comparing CRBN expression levels and explaining its importance, especially in solid organ tumors, are extremely limited in number. It has been shown that in myeloma cell lines, cell viability decreases and apoptosis increases with silencing of CRBN [ 8 ]. In some of the clinical studies any statistically significant results could not be obtained in correlative analyses performed between CRBN levels, response to treatments with IMIDs and survival in hematologic malignancies, while a positive correlation was revealed in some other studies. In addition, it has been suggested that lower cereblon levels are associated with resistance to treatment with IMIDs and decreased survival rates [ 9 , 10 ]. In a single-center study by Kahraman et al., CRBN levels in bone marrow biopsy specimens of 96 patients diagnosed with multiple myeloma were retrospectively examined using immunohistochemical methods and cytoplasmic and/or nuclear staining was observed in bone marrow biopsy specimens of all myeloma patients. Strong nuclear staining was observed in 24% of cases, but no significant relationship was found between CRBN levels, treatment response and survival [ 11 ]. In some studies conducted in solid cancers, especially in lung, kidney and skin cancers, lower CRBN expression levels were detected compared to normal tissues. Low levels of CRBN expression had been associated with high grade and advanced stage of the disease, decreased response to treatment comparatively and lower survival rates [ 12 ]. However, in our study, although CRBN expression was not associated with survival in all cases, a statistically significant correlation was found between these two parameters in cases with gastric carcinomas. However, contrary to most studies in the literature, significantly shorter survival was observed in patients with tumors that did not express CRBN. In our study, CRBN expression was found to be at markedly different intensities according to tumor types. The most aggressive gastric carcinoma group had the lowest CRBN expression levels. Similar to the study of Hyo Jae Shin et al., the lower level of CRBN expression in gastric cancer in our study may be due to the fact that this cancer type has a worse prognosis when compared to colorectal carcinomas and NETs. The different levels of CRBN expression in our study suggest that immunomodulatory therapies targeting CRBN may be useful in the treatment of CRBN-expressing solid GIS tumors. Overexpression of proteins in various signaling pathways is recognized as the root cause of initiation and development of carcinogenesis [ 13 ]. Unfortunately, most of these drugs do not target enzymatic activities and mechanism of inhibition of these activities with small molecule inhibitors has not been explicitly clarified. While conventional small molecule inhibitors usually inhibit the enzymatic activity of the targeted protein, proteolysis targeting chimeras (PROTAC) affect not only the enzymatic activity of the protein but also its non-enzymatic activity by cleaving the entire protein [ 14 ]. PROTAC utilizes a cellular ubiquitin-dependent proteolysis system for efficient degradation of a protein of interest. PROTAC consists of a target protein ligand and an E3 ligase ligand, thus enabling degradation of the target protein due to the proximity induced by ubiquitin ligases. Although numerous PROTACs have been developed to date using previously reported protein ligands for degradation, E3 ligase ligands have been mostly limited to CRBN or VHL ligands. However, the main advantage of PROTACs is their ability to induce protein degradation efficiently even at low concentrations [ 15 ]. However, PROTACs provide more effective and more durable inactivation of signal transduction and growth inhibition without having to worry about rebinding in the kinase group. A comparison between PROTACs and small molecule inhibitors (SMIs) and monoclonal antibodies (mAbs) reveals that PROTACs can target cytoskeletal proteins and disrupt "unstable" targets, while SMIs cannot target cytoskeletal proteins and disrupt unstable targets. PROTACs are orally bioavailable, whereas mAbs are not orally bioavailable and can only target membrane proteins [ 16 ]. While traditional small molecule inhibitors act by blocking protein function, PROTACs function by degrading proteins by means of proteasomes. Emphasis has been placed on the development of new technologies to overcome acquired drug resistance. PROTAC technology targets the androgen receptor for enzalutamide-resistant prostate cancer but the estrogen receptor for drug-resistant breast cancer [ 17 , 18 ]. In the light of current studies, PROTACs may provide a new treatment option for aggressive tumors expressing CRBNs which are closely related to the UPS system. Thanks to the successful results obtained with drugs targeting cerebron in the treatment of hematologic malignancies, new studies on immunomodulatory drugs have accelerated the research on heterobifunctional molecules called PROTACs for the degradation of the targeted protein. Although the importance of the cereblon and the ubiquitin proteasome protein degradation system in the prognosis and treatment of hematologic malignancies has been determined, studies in solid cancers are at the preclinical stage. Therefore, new treatment approaches need to be developed with studies targeting this system. Agents developed with PROTAC technology will increase the likelihood of achieving successful results in gastrointestinal tumors refractory to chemotherapeutic drugs such as irinotecan, oxaliplatin and 5-FU and combinations of biological agents (anti- VEGF or anti -EGFR antibodies). In the evolution of targeted therapy, CRBN is a molecule on the agenda, especially in the treatment of hematologic neoplasms. Information and research on solid tumors are extremely limited in the literature. In cancer treatment, it is very important to identify new targeted treatment modalities, especially for aggressive cancer types. Since some immunomodulatory drugs currently used target CRBN protein, the use of these drugs may be considered in the treatment of solid tumors expressing high levels of CRBN. Studies have revealed the presence of an association between CRBN expression and survival in multiple myeloma patients treated with IMiDs [ 19 ]. Therefore, CRBN has been identified as a primary target of IMiD immunomodulatory compounds used for MM patients. Detection of CRBN levels in tumor tissue samples has gained importance. Therefore, researchers have started to investigate the most accurate detection method for CRBN levels in tumor tissue. Some publications have reported that higher CRBN protein or gene expression levels are associated with more favorable clinical outcomes in treated MM patients [ 10 ]. However, the results are questionable as there is no correlation between CRBN mRNA and protein levels. Since, on the other hand immunostaining is not very specific in revealing the expression pattern of CRBN, immunohistochemically it is very difficult to determine CRBN protein levels, the immunostaining method to be used and the cells to be evaluated. In most studies in the literature, CRBN expression has been measured at the m-RNA expression level. These studies have been generally conducted on patients diagnosed with multiple myeloma. In bone marrow biopsy material of patients with multiple myeloma, myeloma cells often show both cytoplasmic and nuclear CRBN positivity. In some myeloma cells, only cytoplasmic staining is observed. The localization of intracellular CRBN varies considerably. It has been reported that it is mostly found in the juxtanuclear region and in the cytoplasm. However, it is known that nuclear localization may also occur. Since studies are generally related with total CRBN level and its expression [11;13] the clinical significance of different intracellular localizations of CRBN has not been specified yet. In our study, we evaluated both cytoplasmic and nuclear staining with CRBN as CRBN positivity. We focused only on the staining status in tumor cells. However, some studies have reported that the staining status of immune cells around the tumor and even their ratio to each other have clinical importance. Since there is no guiding method on how to make the evaluation, we only looked for, and evaluated CRBN expression in our study. Most studies have reported that immunohistochemical evaluation of CRBN should be performed not only on the tumor cells but also on the immune cells in the microenvironment. In our study, since gastric carcinomas were evaluated by tissue microarray technology and NETs were evaluated on very limited material, only tumor cells were taken into consideration, and immune cells or normal mucosa around the tumor were not assessed. Any systematic study has not investigated the expression and functions of CRBN in solid organ tumors so far. The first study on this subject was conducted by Shin et al. The authors found that CRBN mRNA expression was decreased in some cancer types, including lung adenocarcinoma, renal clear cell carcinoma and cutaneous malignant melanoma, compared to normal cells. This study was planned as a multiomics study and analyses were performed only at the m-RNA level in specific cancer types. Therefore, the reflection of relevant information obtained on immunohistochemical analyses in routine pathology is limited in scope [ 12 ]. In a very recent study, CRBN levels for 33 different cancer types have been evaluated in both cancer, and normal tissue samples using various bioinformatic methods. Expression and activity of CRBN in tumor cells were at a lower level compared to tumor-free cells. Since we only evaluated tumor tissue samples in our study, we could not comment on tumor-free normal tissues [ 20 ]. While the exact mechanisms and effects of CRBN in carcinogenesis are still under investigation, the available evidence suggests that CRBN and its related pathways may be potential targets for therapeutic interventions in cancer treatment. Further research is needed to better understand the specific roles of CRBN in different cancer types and how it could be utilized for improved diagnostic and therapeutic strategies. It is crucial to understand that cancer is a complex and multifaceted disease and that the cereblon is just one of many factors involved in the process of carcinogenesis. Ongoing research aims to deepen our understanding of the molecular mechanisms underlying cancer development and identify novel therapeutic targets to improve patient outcomes. Although our study is the first to compare immunohistochemical CRBN staining in various gastrointestinal tumors, some limitations still exist. First of all, the main limitation of the study is that all analyses were performed on small tumor tissue samples, especially in cases with gastric carcinomas and NETs. Therefore, the status of CRBN expression in normal tissue samples is unknown. The exact physiological mechanisms of CRBN in cancerogenesis are unclear. It is also unclear by which method CRN levels in cancer tissue samples will be measured and how deviations from the normal tissue levels will be evaluated. Further studies on the feasibility of targeting CRBN in GIS cancer treatment protocols will shed light on this issue. Conclusion In cancer treatment, it is very important to identify new targeted treatment options, especially for aggressive tumor types. Since some currently used immunomodulatory drugs target CRBN protein, the use of immunomodulatory drugs may be considered in addition to current therapies in the treatment of solid tumors expressing high levels of CRBN. Declarations Funding The authors did not receive support from any organization for the submitted work. Conflict of interest The authors have no relevant financial or non-financial interests to disclose. Ethical approval All clinical samples were conducted by the Declaration of Helsinki and approved by the Ethics Committee of Izmir Democracy University (2020/10-01). Consent to participate Informed consent was obtained from all individual participants included in the study. Author contributions All authors contributed to the study conception and design. MD: visualization, data curation and writing. GD: investigation, data curation. DSK: investigation and validation. AGP: investigation. DA: validation. MEE: validation. UV: supervision. All authors read and approved the final manuscript. Data availability The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request. References Kazantsev A, Krasavin M. Ligands for cereblon: 2017–2021 patent overview. Expert Opinion on Therapeutic Patents 32(2):171-190, 2022. Kim HK , Ko TH, Nyamaa B, et al.: Cereblon in health and disease. Pflügers Archiv-European Journal of Physiology 2016; 468: 1299-1309. Ito T, Ando H, Suzuki T, et al.;Identification of a primary target of thalidomide teratogenicity. Science 2010;327:1345-1350. Broyl A, Kuiper R, van Duin M, et al. : High cereblon expression is associated with better survival in patients with newly diagnosed multiple myeloma treated with thalidomide maintenance. Blood. The Journal of the American Society of Hematology 2013;121;4: 624-627. 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Clinical Lymphoma Myeloma and Leukemia 2016;16;11: 610-615. Li Y, Dou Y, Leprevost F, et al.; Proteogenomic data and resources for pan-cancer analysis. Cancer cell 2023;41;8: 1397-1406. Tables Table 1 Association between quantitative findings of cases with different tumor types according to the CRBN expression. CRBN Tumor groups Absent Present P Gastric carcinoma Mean ±SD Mean ±SD Age (year) 63.4±12.4 63.7±8.8 0.353 Tumor diameter (cm) 5.5±3.1 6.0±3.2 0.198 Survival (months) 26.3±21.7 19.2±17.6 0.036 Colorectal carcinoma Mean ±SD Mean ±SD Age (year) 59.3±10.4 60.0±11.1 0.514 Tumor diameter (cm) 4.9±1.9 5.7±2.0 0.109 Survival (months) 39.1±18.3 43.3±19.3 0.173 NET Mean ±SD Mean ±SD Age (year) 46.3±17.6 56.2±18.1 0.105 Tumor diameter (cm) 1.3±1.1 2.1±1.3 0.015 Survival (months) 25.5±22.0 16.5±9.8 0.990 Table 2 Association between qualitative findings of patients according to the CRBN expression. CRBN EXPRESSION Absent N/% Present N/ % P Tumor groups Gastric carcinoma Colorectal carcinoma NET grade 1 NET grades 2 and 3 118/ 63.8 47/ 25.4 12/ 6.5 8/ 4.3 34/ 37.0 40/ 43.5 8/ 8.7 10/ 10.9 <0.001 Gender Male Female 117/ 63.2 68/ 36.8 62/ 67.4 30/ 32.6 0.496 Age group ≥61 years <61 years 95/ 51.4 90/ 48.6 53/ 57.6 39/ 42.4 0.325 Tumor location Stomach Small bowel Appendix Right colon Left colon 128/ 69.2 3/ 1.6 6/ 3.2 15/ 8.1 33/ 17.8 43/ 46.7 3/ 3.3 6/ 6.5 16/ 17.4 24/ 26.1 0.003 Survival status Deceased Survived 78/ 42.2 107/ 57.8 36/ 39.1 56/ 60.9 0.629 Lymph node metastases Absent Present 71/ 38.4 114/ 61.6 36/ 39.1 56/ 60.9 0.904 Location of distant metastases Absent Liver Lung Periton Ovary 151/ 81.6 20/ 10.8 9/ 4.9 3/ 1.6 2/ 1.1 78/ 84.8 13/ 14.1 1/ 1.1 - - 0.264 Tumor grade Grade 1 Grade 2 Grade 3 15/ 8.1 112/ 60.5 58/ 31.4 9/ 9.8 60/ 65.2 23/ 25.0 0.532 Tumor stage Early Late 72/ 38.9 113/ 61.1 38/ 41.3 54/ 58.7 0.702 Table 3 Association between clinicopathological parameters and tumor types Tumor groups Gastric cancer N/ % Colorectal cancer N/ % NET grade 1 N/ % NET grade 2,3 N/ % p Gender Male Female 49/32.2 103/67.8 58/66.7 29/33.3 9/45 11/55 9/50 9/50 0.118 Age group ≥61 years <61 years 93/61.2 59/38.8 42/48.3 45/51.7 5/25 15/75 8/44.4 10/55.6 0.009 Tumor location Stomach Small bowel Appendix Right colon Left colon 152/100 - - - - - - - 31/35.6 56/64.4 7/35 4/20 9/45 - - 12/66.7 2/11.1 3/16.7 - 1/5.6 <0.001 Survival status Deceased Survived 78/51.3 74/48.7 34/39.1 53/60.9 - 20/100 5/27.8 13/72.7 <0.001 Lymph node metastases Absent Present 33/21.7 119/78.3 43/49.4 44/50.6 1/5 19/95 12/66.7 6/33.3 0.003 Location of distant metastases Absent Liver Lung Periton Ovary 121/79.6 14/9.2 7/4.2 4/2.6 2/1.3 72/82.8 15/17.2 - - - 20/100 - - - - 12/66.7 4/22.2 2/11.1 - - 0.800 Tumor grade Grade 1 Grade 2 Grade I3 - 81/53.3 71/46.7 4/4.6 79/90.8 4/4.6 20/100 - - - 12/66.7 6/33.3 <0.001 Tumor stage Early Late 34/22.4 118/77.6 44/50.6 43/49.4 20/100 - 12/66.7 6/33.3 <0.001 CRBN Negative Positive 118/77.6 34/22.4 47/54 40/46 12/60 8/40 8/44.4 10/55.6 <0.001 Additional Declarations The authors declare no competing interests. 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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-4283954","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":292501438,"identity":"76ca1a95-dd99-4951-b648-4d73d2b951df","order_by":0,"name":"Mustafa Degirmenci","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8UlEQVRIie3QoQrCQBzH8RsLK0OrvoUPIL6IZYdg2olgmaAyiyvCqkH0FbRc/o+DXTkRm2BwYDVos+l/ImjZhk3wvozjF+4TboTodL8YPD/MxJF46TD9L4ij0mEUk3d0kp4FpCSDnei79U45sHZAF8NmOUBy83gmqSrVjTa83asIuwuUSzYThm9M1SGT1PauE425oCvTdpDEzEdiGpMccjyn5P4i85gtC8neAiSAxAKg/oCtikhVuQRJi86EjT85BrZGEuW9pSTl6TrmDRqG8nS5DEZssRVRcvOyCSF27XOI54Sc+5iVfI5R/mWdTqf7yx4BXmxnmHQ5ewAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-6988-9205","institution":"Health Science University Faculty of Medicine, Medical Oncology Department, Izmir, Turkey","correspondingAuthor":true,"prefix":"","firstName":"Mustafa","middleName":"","lastName":"Degirmenci","suffix":""}],"badges":[],"createdAt":"2024-04-17 20:47:42","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-4283954/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4283954/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":55002163,"identity":"48d1afcc-8614-4726-b856-0e43b5dc674e","added_by":"auto","created_at":"2024-04-19 18:39:15","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":373666,"visible":true,"origin":"","legend":"\u003cp\u003eA colon carcinoma with strong cytoplasmic and nuclear CRBN expression (DABx 200).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4283954/v1/4c6f4715a7dabe77d9d9855e.png"},{"id":55002164,"identity":"f7bd8191-2dbb-40e8-9b8e-96dd9dfd9097","added_by":"auto","created_at":"2024-04-19 18:39:15","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":32837,"visible":true,"origin":"","legend":"\u003cp\u003eChange in CRBN expression according to tumor groups (p\u0026lt; 0.001).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4283954/v1/c50f4f7793ba9a505e8c3876.png"},{"id":55002162,"identity":"865f18f0-6726-4368-8e9a-c4ac4e2ab76f","added_by":"auto","created_at":"2024-04-19 18:39:15","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":50652,"visible":true,"origin":"","legend":"\u003cp\u003eNo survival difference according to the presence of CRBN (Log Rank, p= 0,642).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4283954/v1/d2639b1e6ee6026df637ef49.png"},{"id":55004719,"identity":"14b6d853-1db0-4552-a4c2-edda371f4413","added_by":"auto","created_at":"2024-04-19 18:47:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":982943,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4283954/v1/d806d30e-b69e-4025-b29b-636191e639e9.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eEvaluation of cereblon expression in gastrointestinal tract tumors\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCereblon (CRBN) is a component of the E3 ubiquitin ligase complex. CRBN also acts as a substrate receptor for Cullin-RING ligase 4 (CRL4). This complex regulates ion transport, protein degradation, cell proliferation, metabolism and apoptosis at the cellular level [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In the ubiquitin and proteasome system (UPS), CRBN plays a role in the degradation or activation of proteins involved in cell survival. CRBN was first identified as a protein involved in learning and memorization functions in the brain. It was later found to play a role in important biological functions in other tissues. Neuronal diseases, malignancies, autoimmune and metabolic diseases may develop in cases of CRBN protein degradation. Although CRBN has been investigated more frequently in neoplastic diseases including hematologic malignancies such as myeloma and leukemia, the importance of CRBN expression levels in diagnosis and prognosis has not been clearly established even in hematologic cancers [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, data suggesting its contribution to treatment and successful results of immunomodulatory therapies targeting the cerebrum in hematologic malignancies have increased the hope that similar results can be obtained in other cancer types. Immunomodulatory drugs such as thalidomide derivatives have been found to inhibit the function of the ubiquitin-proteasome system (UPS), which mediates DNA repair, replication and transcription by binding to CRBN [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Thalidomide derivatives show antiproliferative effects in multiple myeloma cells by affecting the UPS system and induce cytokine production from T cells. In clinical studies on hematologic malignancies, thalidomide and its derivatives have been shown to contribute favorably to treatment and survival [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Recently, new CRBN binding compounds have been developed and named \"cereblon modulators\". Among cereblon modulators, CC-122 (avadomide) and CC-220 (iberdomide) were added to standard therapies in early phase studies performed in cases with myeloma and lymphoma and used as monotherapy in resistant cases with achievement of promising effective results [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAmong solid tumors, colorectal cancers, gastric cancers and neuroendocrine tumors are the leading malignancies among gastrointestinal system cancers. HER2 overexpression, MSI, CEA, CEA, RAS, BRAF mutation tests have been used for diagnosis and treatment planning. In advanced stages, biological agents are added to systemic chemotherapy treatment according to the presence of these markers. In recent years, successful results of immunotherapy agents (anti-PD1 and anti-PDL1) in the management of tumors with MSI-H have made a significant progress in disease control. However, in a significant number of cases with advanced disease and even in some early stage cancer patients, cure is not achieved and progression occurs with the development of resistance at certain stages of systemic therapies. New markers are needed to guide the diagnosis, prognosis and treatment planning of gastrointestinal tract cancers. The lack of these markers is one of the factors contributing to the slow progress in the fight against cancer today.\u003c/p\u003e \u003cp\u003eThe aim of this study was to determine the possible prognostic significance of CRBN in a group of gastrointestinal tract tumors including gastric cancer, colorectal carcinomas and gastrointestinal neuroendocrine tumors (NETs), so as to investigate its relationship with clinicopathological parameters and to evaluate its potential as a target molecule for therapy.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e In this study, we immunohistochemically investigated the tissue expression of CRBN protein in tissue samples obtained from a total of 277 patients including those with grade 1 (n:20), and grades 2, and 3 (n:18) gastrointestinal neuroendocrine tumors (NETs), gastric adenocarcinomas (n:152), and colorectal carcinomas (n:87) diagnosed in Pathology Laboratory of Izmir Tepecik Training and Research Hospital between 2008\u0026ndash;2018. Retrospective analysis of patient files was performed. This study was approved by the Ethics Committee of Izmir Democracy University (2020/10\u0026thinsp;\u0026minus;\u0026thinsp;01). Blocks containing viable tumor tissue samples were selected from the slides reevaluated by hematoxylin-eosin (H\u0026amp;E) staining for further immunohistochemical analysis (IHC). Microarray blocks were also prepared in cases with gastric carcinomas. Paraffin blocks selected for immunohistochemical analyses were sectioned at 3\u0026ndash;5 micron thickness, and placed on lysinized slides. IHC analyses were performed manually using the streptavidin-biotin peroxidase method (Invitrogen, Camarillo, CA, USA). Prepared slides were kept at 60\u0026deg;C overnight, deparaffinized in xylene and rehydrated with distilled water by gradually reducing its alcohol concentrations. All slides were subjected to microwave treatment (heat-induced epitope recovery in 10 mm/L citrate buffer at pH 6.0 for 20 min, followed by cooling at room temperature for 20 min) and blocked for endogenous peroxidase and biotin. A polyclonal antibody against CRBN (Invitrogen, PA5-38037, 1/200 dilution) was used. CRBN expression was assessed in all tissue samples according to mapping and addressing procedures. Tissue samples in which CRBN expression could not be evaluated or shed tissue samples were not included in analyses. Pathologists unaware of the clinical characteristics of the patients, graded the staining patterns by examining the slides. Brown granular or diffuse cytoplasmic and/or nuclear staining for CRBN in tumor cells was considered positive. Some tumor cells also showed strong nuclear CRBN expression (Fig.\u0026nbsp;1). Since the tumor areas observed in the microarray blocks were quite small and the surrounding stroma was usually not observed, only the expression in tumor cells was recorded and the expression in inflammatory cells was not taken into consideration.\u003c/p\u003e \u003cp\u003eThe relationship between immunohistochemically detected CRBN expression levels and various prognostic factors was analyzed.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed using SPSS 25.0 statistical package. Chi-square test was used to compare qualitative, and Mann-Whitney U test to compare nonparametric data. The nonparametric Kruskal-Wallis test was used to compare measurements in more than two groups. Kaplan-Meier survival analysis was used to compare the difference in survival rates between the groups. p\u0026thinsp;\u0026le;\u0026thinsp;0.05 was accepted as the level of statistical significance.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eMost of the cases were male (n\u0026thinsp;=\u0026thinsp;179, 64.6%). The mean age of the patients was 60.5\u0026thinsp;\u0026plusmn;\u0026thinsp;13.1 years. Overall survival in malignant cases was 30.5\u0026thinsp;\u0026plusmn;\u0026thinsp;21.8 months, with the shortest survival of 24.7 months in gastric carcinomas. CRBN expression was detected in 92 (33.2%) cases. CRBN-expressing neoplasms included colorectal carcinomas in 40, gastric carcinomas in 34, and NETs in 18 (grade 1, n:9, and grade 2\u0026ndash;3, n:9) cases. When evaluated within each group, the highest and lowest CRBN positivity rates were detected in cases with neuroendocrine carcinomas (55.6%) and gastric carcinomas (22.4%), respectively. The presence of CRBN expression varied statistically significantly among tumor types (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;2). Mann-Whitney U test showed no statistically significant correlation between CRBN expression and survival (p\u0026thinsp;=\u0026thinsp;0.587). Kaplan-Meier survival analysis did no reveal any significant correlation between survival time and CRBN expression (p\u0026thinsp;=\u0026thinsp;0.642) (Fig.\u0026nbsp;3). However, when CRBN expression was evaluated according to individual tumor groups, survival time was statistically significantly shorter in CRBN positive cases with gastric carcinomas (p\u0026thinsp;=\u0026thinsp;0.036). In NETs, CRBN positivity was higher in larger tumors (p\u0026thinsp;=\u0026thinsp;0.015). CRBN positivity was also statistically associated with tumor type (p\u0026thinsp;=\u0026thinsp;0.01) and tumor localization (p\u0026thinsp;=\u0026thinsp;0.03). General findings are given in Tables\u0026nbsp;1\u0026ndash;3.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eImmunomodulatory drugs including thalidomide, lenalidomide, and pomalidomide are being used in the treatment of multiple myeloma, myelodysplastic syndrome, chronic lymphocytic lymphoma, and diffuse large β-cell lymphoma. Thalidomide affects cell proliferation and apoptosis by targeting intracellular CRBN expression levels. Studies comparing CRBN expression levels and explaining its importance, especially in solid organ tumors, are extremely limited in number. It has been shown that in myeloma cell lines, cell viability decreases and apoptosis increases with silencing of CRBN [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In some of the clinical studies any statistically significant results could not be obtained in correlative analyses performed between CRBN levels, response to treatments with IMIDs and survival in hematologic malignancies, while a positive correlation was revealed in some other studies. In addition, it has been suggested that lower cereblon levels are associated with resistance to treatment with IMIDs and decreased survival rates [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn a single-center study by Kahraman et al., CRBN levels in bone marrow biopsy specimens of 96 patients diagnosed with multiple myeloma were retrospectively examined using immunohistochemical methods and cytoplasmic and/or nuclear staining was observed in bone marrow biopsy specimens of all myeloma patients. Strong nuclear staining was observed in 24% of cases, but no significant relationship was found between CRBN levels, treatment response and survival [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In some studies conducted in solid cancers, especially in lung, kidney and skin cancers, lower CRBN expression levels were detected compared to normal tissues. Low levels of CRBN expression had been associated with high grade and advanced stage of the disease, decreased response to treatment comparatively and lower survival rates [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, in our study, although CRBN expression was not associated with survival in all cases, a statistically significant correlation was found between these two parameters in cases with gastric carcinomas. However, contrary to most studies in the literature, significantly shorter survival was observed in patients with tumors that did not express CRBN.\u003c/p\u003e \u003cp\u003eIn our study, CRBN expression was found to be at markedly different intensities according to tumor types. The most aggressive gastric carcinoma group had the lowest CRBN expression levels. Similar to the study of Hyo Jae Shin et al., the lower level of CRBN expression in gastric cancer in our study may be due to the fact that this cancer type has a worse prognosis when compared to colorectal carcinomas and NETs. The different levels of CRBN expression in our study suggest that immunomodulatory therapies targeting CRBN may be useful in the treatment of CRBN-expressing solid GIS tumors.\u003c/p\u003e \u003cp\u003eOverexpression of proteins in various signaling pathways is recognized as the root cause of initiation and development of carcinogenesis [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Unfortunately, most of these drugs do not target enzymatic activities and mechanism of inhibition of these activities with small molecule inhibitors has not been explicitly clarified. While conventional small molecule inhibitors usually inhibit the enzymatic activity of the targeted protein, proteolysis targeting chimeras (PROTAC) affect not only the enzymatic activity of the protein but also its non-enzymatic activity by cleaving the entire protein [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. PROTAC utilizes a cellular ubiquitin-dependent proteolysis system for efficient degradation of a protein of interest. PROTAC consists of a target protein ligand and an E3 ligase ligand, thus enabling degradation of the target protein due to the proximity induced by ubiquitin ligases. Although numerous PROTACs have been developed to date using previously reported protein ligands for degradation, E3 ligase ligands have been mostly limited to CRBN or VHL ligands. However, the main advantage of PROTACs is their ability to induce protein degradation efficiently even at low concentrations [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, PROTACs provide more effective and more durable inactivation of signal transduction and growth inhibition without having to worry about rebinding in the kinase group. A comparison between PROTACs and small molecule inhibitors (SMIs) and monoclonal antibodies (mAbs) reveals that PROTACs can target cytoskeletal proteins and disrupt \"unstable\" targets, while SMIs cannot target cytoskeletal proteins and disrupt unstable targets. PROTACs are orally bioavailable, whereas mAbs are not orally bioavailable and can only target membrane proteins [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. While traditional small molecule inhibitors act by blocking protein function, PROTACs function by degrading proteins by means of proteasomes. Emphasis has been placed on the development of new technologies to overcome acquired drug resistance. PROTAC technology targets the androgen receptor for enzalutamide-resistant prostate cancer but the estrogen receptor for drug-resistant breast cancer [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In the light of current studies, PROTACs may provide a new treatment option for aggressive tumors expressing CRBNs which are closely related to the UPS system.\u003c/p\u003e \u003cp\u003eThanks to the successful results obtained with drugs targeting cerebron in the treatment of hematologic malignancies, new studies on immunomodulatory drugs have accelerated the research on heterobifunctional molecules called PROTACs for the degradation of the targeted protein. Although the importance of the cereblon and the ubiquitin proteasome protein degradation system in the prognosis and treatment of hematologic malignancies has been determined, studies in solid cancers are at the preclinical stage. Therefore, new treatment approaches need to be developed with studies targeting this system. Agents developed with PROTAC technology will increase the likelihood of achieving successful results in gastrointestinal tumors refractory to chemotherapeutic drugs such as irinotecan, oxaliplatin and 5-FU and combinations of biological agents (anti- VEGF or anti -EGFR antibodies). In the evolution of targeted therapy, CRBN is a molecule on the agenda, especially in the treatment of hematologic neoplasms. Information and research on solid tumors are extremely limited in the literature. In cancer treatment, it is very important to identify new targeted treatment modalities, especially for aggressive cancer types. Since some immunomodulatory drugs currently used target CRBN protein, the use of these drugs may be considered in the treatment of solid tumors expressing high levels of CRBN.\u003c/p\u003e \u003cp\u003eStudies have revealed the presence of an association between CRBN expression and survival in multiple myeloma patients treated with IMiDs [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Therefore, CRBN has been identified as a primary target of IMiD immunomodulatory compounds used for MM patients. Detection of CRBN levels in tumor tissue samples has gained importance. Therefore, researchers have started to investigate the most accurate detection method for CRBN levels in tumor tissue. Some publications have reported that higher CRBN protein or gene expression levels are associated with more favorable clinical outcomes in treated MM patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, the results are questionable as there is no correlation between CRBN mRNA and protein levels. Since, on the other hand immunostaining is not very specific in revealing the expression pattern of CRBN, immunohistochemically it is very difficult to determine CRBN protein levels, the immunostaining method to be used and the cells to be evaluated.\u003c/p\u003e \u003cp\u003eIn most studies in the literature, CRBN expression has been measured at the m-RNA expression level. These studies have been generally conducted on patients diagnosed with multiple myeloma. In bone marrow biopsy material of patients with multiple myeloma, myeloma cells often show both cytoplasmic and nuclear CRBN positivity. In some myeloma cells, only cytoplasmic staining is observed. The localization of intracellular CRBN varies considerably. It has been reported that it is mostly found in the juxtanuclear region and in the cytoplasm. However, it is known that nuclear localization may also occur. Since studies are generally related with total CRBN level and its expression [11;13] the clinical significance of different intracellular localizations of CRBN has not been specified yet. In our study, we evaluated both cytoplasmic and nuclear staining with CRBN as CRBN positivity. We focused only on the staining status in tumor cells. However, some studies have reported that the staining status of immune cells around the tumor and even their ratio to each other have clinical importance. Since there is no guiding method on how to make the evaluation, we only looked for, and evaluated CRBN expression in our study. Most studies have reported that immunohistochemical evaluation of CRBN should be performed not only on the tumor cells but also on the immune cells in the microenvironment.\u003c/p\u003e \u003cp\u003eIn our study, since gastric carcinomas were evaluated by tissue microarray technology and NETs were evaluated on very limited material, only tumor cells were taken into consideration, and immune cells or normal mucosa around the tumor were not assessed. Any systematic study has not investigated the expression and functions of CRBN in solid organ tumors so far. The first study on this subject was conducted by Shin et al. The authors found that CRBN mRNA expression was decreased in some cancer types, including lung adenocarcinoma, renal clear cell carcinoma and cutaneous malignant melanoma, compared to normal cells. This study was planned as a multiomics study and analyses were performed only at the m-RNA level in specific cancer types. Therefore, the reflection of relevant information obtained on immunohistochemical analyses in routine pathology is limited in scope [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn a very recent study, CRBN levels for 33 different cancer types have been evaluated in both cancer, and normal tissue samples using various bioinformatic methods. Expression and activity of CRBN in tumor cells were at a lower level compared to tumor-free cells. Since we only evaluated tumor tissue samples in our study, we could not comment on tumor-free normal tissues [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. While the exact mechanisms and effects of CRBN in carcinogenesis are still under investigation, the available evidence suggests that CRBN and its related pathways may be potential targets for therapeutic interventions in cancer treatment. Further research is needed to better understand the specific roles of CRBN in different cancer types and how it could be utilized for improved diagnostic and therapeutic strategies. It is crucial to understand that cancer is a complex and multifaceted disease and that the cereblon is just one of many factors involved in the process of carcinogenesis. Ongoing research aims to deepen our understanding of the molecular mechanisms underlying cancer development and identify novel therapeutic targets to improve patient outcomes.\u003c/p\u003e \u003cp\u003eAlthough our study is the first to compare immunohistochemical CRBN staining in various gastrointestinal tumors, some limitations still exist. First of all, the main limitation of the study is that all analyses were performed on small tumor tissue samples, especially in cases with gastric carcinomas and NETs. Therefore, the status of CRBN expression in normal tissue samples is unknown. The exact physiological mechanisms of CRBN in cancerogenesis are unclear. It is also unclear by which method CRN levels in cancer tissue samples will be measured and how deviations from the normal tissue levels will be evaluated. Further studies on the feasibility of targeting CRBN in GIS cancer treatment protocols will shed light on this issue.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn cancer treatment, it is very important to identify new targeted treatment options, especially for aggressive tumor types. Since some currently used immunomodulatory drugs target CRBN protein, the use of immunomodulatory drugs may be considered in addition to current therapies in the treatment of solid tumors expressing high levels of CRBN.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors did not receive support from any organization for the submitted work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll clinical samples were conducted by the Declaration of Helsinki and approved by the Ethics Committee of Izmir Democracy University (2020/10-01).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eInformed consent was obtained from all individual participants included in the study.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAll authors contributed to the study conception and design.\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eMD: visualization, data curation and writing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGD: investigation, data curation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDSK: investigation and validation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAGP: investigation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDA: validation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMEE: validation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUV: supervision.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAll authors read and approved the final manuscript.\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKazantsev A, Krasavin M. Ligands for cereblon: 2017\u0026ndash;2021 patent overview. Expert Opinion on Therapeutic Patents 32(2):171-190, 2022.\u003c/li\u003e\n\u003cli\u003eKim HK , Ko TH, Nyamaa B, et al.: Cereblon in health and disease. \u003cem\u003ePfl\u0026uuml;gers Archiv-European Journal of Physiology\u003c/em\u003e 2016; 468: 1299-1309.\u003c/li\u003e\n\u003cli\u003eIto T, Ando H, Suzuki T, et al.;Identification of a primary target of thalidomide teratogenicity. \u003cem\u003eScience\u003c/em\u003e 2010;327:1345-1350.\u003c/li\u003e\n\u003cli\u003eBroyl A, Kuiper R, van Duin M, et al. : High cereblon expression is associated with better survival in patients with newly diagnosed multiple myeloma treated with thalidomide maintenance. \u003cem\u003eBlood. The Journal of the American Society of Hematology \u003c/em\u003e2013;121;4: 624-627.\u003c/li\u003e\n\u003cli\u003e Rajkumar SV, Blood E, Vesole D, et al. : Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. \u003cem\u003eJournal of clinical oncology\u003c/em\u003e 2006;24;3: 431-436.\u003c/li\u003e\n\u003cli\u003eLonial S, Popat R, Hulin C, et al.: Iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma (CC-220-MM-001): a multicentre, multicohort, open-label, phase 1/2 trial. \u003cem\u003eThe Lancet Haematology \u003c/em\u003e2022;9;11: e822-e832.\u003c/li\u003e\n\u003cli\u003eZhu YX, Braggio E, Shi CX, et al.: Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. \u003cem\u003eBlood, The Journal of the American Society of Hematology\u003c/em\u003e 2011;118;18: 4771-4779.\u003c/li\u003e\n\u003cli\u003eSchuster SR, Kortuem KM, Zhu YX, et al.:The clinical significance of cereblon expression in multiple myeloma. \u003cem\u003eLeukemia research \u003c/em\u003e2014; 38;1: 23-28.\u003c/li\u003e\n\u003cli\u003eHeintel D, Rocci A, Ludwig H, et al.: High expression of cereblon (CRBN) is associated with improved clinical response in patients with multiple myeloma treated with lenalidomide and dexamethasone. \u003cem\u003eBritish journal of haematology \u003c/em\u003e2013;161;5: 695-700.\u003c/li\u003e\n\u003cli\u003eKahraman DS, Diniz G, Ceylan C, et al.: Evaluation of the Prognostic Significance of Cereblon Protein Expression in Multiple Myeloma. \u003cem\u003eClinical Laboratory\u003c/em\u003e 2022;1;68-69.\u003c/li\u003e\n\u003cli\u003eShin HJ, Lee KJ, Gil M.:Multiomic Analysis of Cereblon Expression and Its Prognostic Value in Kidney Renal Clear Cell Carcinoma, Lung Adenocarcinoma, and Skin Cutaneous Melanoma. \u003cem\u003eJournal of 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the variants by an orally bioavailable Proteolysis Targeting Chimeras compound in castration resistant prostate cancer. \u003cem\u003eEBioMedicine\u003c/em\u003e 2023;90.\u003c/li\u003e\n\u003cli\u003eZhang X, Zhang Z, Xue X, et al.: PROTAC Degrader of Estrogen Receptor Targeting DNA-Binding Domain in Breast Cancer.\u003cem\u003eACS Pharmacology \u0026amp; Translational Science\u003c/em\u003e 2022;11: 1109-1118.\u003c/li\u003e\n\u003cli\u003eKriegsmann K, Baertsch MA, Awwad, et al.: Cereblon-binding proteins expression levels correlate with hyperdiploidy in newly diagnosed multiple myeloma patients. \u003cem\u003eBlood cancer journal\u003c/em\u003e 2019;9;2: 13.\u003c/li\u003e\n\u003cli\u003eBila J, Sretenovic A, Jelicic J, et al.: Prognostic significance of cereblon expression in patients with multiple myeloma. \u003cem\u003eClinical Lymphoma Myeloma and Leukemia\u003c/em\u003e 2016;16;11: 610-615.\u003c/li\u003e\n\u003cli\u003eLi Y, Dou Y, Leprevost F, et al.; Proteogenomic data and resources for pan-cancer analysis. \u003cem\u003eCancer cell\u003c/em\u003e 2023;41;8: 1397-1406.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1\u0026nbsp;\u003c/strong\u003eAssociation between quantitative findings of cases with different tumor types according to the CRBN expression.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"425\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.64705882352941%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"62.35294117647059%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCRBN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.64705882352941%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor groups\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.352941176470587%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbsent\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.470588235294116%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePresent\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.529411764705882%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.64705882352941%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGastric carcinoma\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.352941176470587%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean \u0026plusmn;SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.470588235294116%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean \u0026plusmn;SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.529411764705882%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.64705882352941%\" valign=\"top\"\u003e\n \u003cp\u003eAge (year)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.352941176470587%\" valign=\"top\"\u003e\n \u003cp\u003e63.4\u0026plusmn;12.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.470588235294116%\" valign=\"top\"\u003e\n \u003cp\u003e63.7\u0026plusmn;8.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.529411764705882%\" valign=\"top\"\u003e\n \u003cp\u003e0.353\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.64705882352941%\" valign=\"top\"\u003e\n \u003cp\u003eTumor diameter (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.352941176470587%\" valign=\"top\"\u003e\n \u003cp\u003e5.5\u0026plusmn;3.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.470588235294116%\" valign=\"top\"\u003e\n \u003cp\u003e6.0\u0026plusmn;3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.529411764705882%\" valign=\"top\"\u003e\n \u003cp\u003e0.198\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.64705882352941%\" valign=\"top\"\u003e\n \u003cp\u003eSurvival (months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.352941176470587%\" valign=\"top\"\u003e\n \u003cp\u003e26.3\u0026plusmn;21.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.470588235294116%\" valign=\"top\"\u003e\n \u003cp\u003e19.2\u0026plusmn;17.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.529411764705882%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.036\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.64705882352941%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eColorectal carcinoma\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.352941176470587%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean \u0026plusmn;SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.470588235294116%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean \u0026plusmn;SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.529411764705882%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.64705882352941%\" valign=\"top\"\u003e\n \u003cp\u003eAge (year)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.352941176470587%\" valign=\"top\"\u003e\n \u003cp\u003e59.3\u0026plusmn;10.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.470588235294116%\" valign=\"top\"\u003e\n \u003cp\u003e60.0\u0026plusmn;11.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.529411764705882%\" valign=\"top\"\u003e\n \u003cp\u003e0.514\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.64705882352941%\" valign=\"top\"\u003e\n \u003cp\u003eTumor diameter (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.352941176470587%\" valign=\"top\"\u003e\n \u003cp\u003e4.9\u0026plusmn;1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.470588235294116%\" valign=\"top\"\u003e\n \u003cp\u003e5.7\u0026plusmn;2.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.529411764705882%\" valign=\"top\"\u003e\n \u003cp\u003e0.109\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.64705882352941%\" valign=\"top\"\u003e\n \u003cp\u003eSurvival (months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.352941176470587%\" valign=\"top\"\u003e\n \u003cp\u003e39.1\u0026plusmn;18.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.470588235294116%\" valign=\"top\"\u003e\n \u003cp\u003e43.3\u0026plusmn;19.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.529411764705882%\" valign=\"top\"\u003e\n \u003cp\u003e0.173\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.64705882352941%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNET\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.352941176470587%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean \u0026plusmn;SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.470588235294116%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean \u0026plusmn;SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.529411764705882%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.64705882352941%\" valign=\"top\"\u003e\n \u003cp\u003eAge (year)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.352941176470587%\" valign=\"top\"\u003e\n \u003cp\u003e46.3\u0026plusmn;17.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.470588235294116%\" valign=\"top\"\u003e\n \u003cp\u003e56.2\u0026plusmn;18.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.529411764705882%\" valign=\"top\"\u003e\n \u003cp\u003e0.105\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.64705882352941%\" valign=\"top\"\u003e\n \u003cp\u003eTumor diameter (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.352941176470587%\" valign=\"top\"\u003e\n \u003cp\u003e1.3\u0026plusmn;1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.470588235294116%\" valign=\"top\"\u003e\n \u003cp\u003e2.1\u0026plusmn;1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.529411764705882%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.015\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.64705882352941%\" valign=\"top\"\u003e\n \u003cp\u003eSurvival (months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.352941176470587%\" valign=\"top\"\u003e\n \u003cp\u003e25.5\u0026plusmn;22.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.470588235294116%\" valign=\"top\"\u003e\n \u003cp\u003e16.5\u0026plusmn;9.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.529411764705882%\" valign=\"top\"\u003e\n \u003cp\u003e0.990\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eTable 2\u003c/strong\u003e Association between qualitative findings of patients according to the CRBN expression.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"576\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"47.56944444444444%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCRBN EXPRESSION\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.354166666666668%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbsent \u0026nbsp;N/%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.618055555555557%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePresent N/ %\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.055555555555557%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor groups\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGastric carcinoma\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eColorectal carcinoma\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNET grade 1\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNET grades 2 and 3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.354166666666668%\" valign=\"top\"\u003e\n \u003cp\u003e118/ 63.8\u003c/p\u003e\n \u003cp\u003e47/ 25.4\u003c/p\u003e\n \u003cp\u003e12/ 6.5\u003c/p\u003e\n \u003cp\u003e8/ 4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.618055555555557%\" valign=\"top\"\u003e\n \u003cp\u003e34/ 37.0\u003c/p\u003e\n \u003cp\u003e40/ 43.5\u003c/p\u003e\n \u003cp\u003e8/ 8.7\u003c/p\u003e\n \u003cp\u003e10/ 10.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.055555555555557%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eFemale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.354166666666668%\" valign=\"top\"\u003e\n \u003cp\u003e117/ 63.2\u003c/p\u003e\n \u003cp\u003e68/ 36.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.618055555555557%\" valign=\"top\"\u003e\n \u003cp\u003e62/ 67.4\u003c/p\u003e\n \u003cp\u003e30/ 32.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e0.496\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.055555555555557%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026ge;61 years\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;61 years \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.354166666666668%\" valign=\"top\"\u003e\n \u003cp\u003e95/ 51.4\u003c/p\u003e\n \u003cp\u003e90/ 48.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.618055555555557%\" valign=\"top\"\u003e\n \u003cp\u003e53/ 57.6\u003c/p\u003e\n \u003cp\u003e39/ 42.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e0.325\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.055555555555557%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor location\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStomach\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eSmall bowel\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAppendix\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eRight colon\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eLeft colon\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.354166666666668%\" valign=\"top\"\u003e\n \u003cp\u003e128/ 69.2\u003c/p\u003e\n \u003cp\u003e3/ 1.6\u003c/p\u003e\n \u003cp\u003e6/ 3.2\u003c/p\u003e\n \u003cp\u003e15/ 8.1\u003c/p\u003e\n \u003cp\u003e33/ 17.8\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.618055555555557%\" valign=\"top\"\u003e\n \u003cp\u003e43/ 46.7\u003c/p\u003e\n \u003cp\u003e3/ 3.3\u003c/p\u003e\n \u003cp\u003e6/ 6.5\u003c/p\u003e\n \u003cp\u003e16/ 17.4\u003c/p\u003e\n \u003cp\u003e24/ 26.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.003\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.055555555555557%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSurvival status\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDeceased\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eSurvived\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.354166666666668%\" valign=\"top\"\u003e\n \u003cp\u003e78/ 42.2\u003c/p\u003e\n \u003cp\u003e107/ 57.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.618055555555557%\" valign=\"top\"\u003e\n \u003cp\u003e36/ 39.1\u003c/p\u003e\n \u003cp\u003e56/ 60.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e0.629\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.055555555555557%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLymph node metastases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbsent\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePresent\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.354166666666668%\" valign=\"top\"\u003e\n \u003cp\u003e71/ 38.4\u003c/p\u003e\n \u003cp\u003e114/ 61.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.618055555555557%\" valign=\"top\"\u003e\n \u003cp\u003e36/ 39.1\u003c/p\u003e\n \u003cp\u003e56/ 60.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e0.904\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.055555555555557%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLocation of distant metastases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbsent\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eLiver\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eLung\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePeriton\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eOvary\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.354166666666668%\" valign=\"top\"\u003e\n \u003cp\u003e151/ 81.6\u003c/p\u003e\n \u003cp\u003e20/ 10.8\u003c/p\u003e\n \u003cp\u003e9/ 4.9\u003c/p\u003e\n \u003cp\u003e3/ 1.6\u003c/p\u003e\n \u003cp\u003e2/ 1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.618055555555557%\" valign=\"top\"\u003e\n \u003cp\u003e78/ 84.8\u003c/p\u003e\n \u003cp\u003e13/ 14.1\u003c/p\u003e\n \u003cp\u003e1/ 1.1\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e0.264\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.055555555555557%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor \u0026nbsp;grade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 1\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 2\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.354166666666668%\" valign=\"top\"\u003e\n \u003cp\u003e15/ 8.1\u003c/p\u003e\n \u003cp\u003e112/ 60.5\u003c/p\u003e\n \u003cp\u003e58/ 31.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.618055555555557%\" valign=\"top\"\u003e\n \u003cp\u003e9/ 9.8\u003c/p\u003e\n \u003cp\u003e60/ 65.2\u003c/p\u003e\n \u003cp\u003e23/ 25.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e0.532\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.055555555555557%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.51388888888889%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEarly\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eLate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.354166666666668%\" valign=\"top\"\u003e\n \u003cp\u003e72/ 38.9\u003c/p\u003e\n \u003cp\u003e113/ 61.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.618055555555557%\" valign=\"top\"\u003e\n \u003cp\u003e38/ 41.3\u003c/p\u003e\n \u003cp\u003e54/ 58.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e0.702\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u0026nbsp;\u003c/strong\u003eAssociation between clinicopathological parameters and tumor types\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"529\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.84905660377358%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor groups\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.39622641509434%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGastric cancer\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN/ %\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.41509433962264%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eColorectal cancer\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN/ %\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.132075471698114%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNET grade 1\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN/ %\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.88679245283019%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNET grade 2,3\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN/ %\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.320754716981131%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.735849056603772%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.11320754716981%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eFemale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.39622641509434%\" valign=\"top\"\u003e\n \u003cp\u003e49/32.2\u003c/p\u003e\n \u003cp\u003e103/67.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.41509433962264%\" valign=\"top\"\u003e\n \u003cp\u003e58/66.7\u003c/p\u003e\n \u003cp\u003e29/33.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.132075471698114%\" valign=\"top\"\u003e\n \u003cp\u003e9/45\u003c/p\u003e\n \u003cp\u003e11/55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.88679245283019%\" valign=\"top\"\u003e\n \u003cp\u003e9/50\u003c/p\u003e\n \u003cp\u003e9/50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.320754716981131%\" valign=\"top\"\u003e\n \u003cp\u003e0.118\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.735849056603772%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.11320754716981%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026ge;61 years\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;61 years \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.39622641509434%\" valign=\"top\"\u003e\n \u003cp\u003e93/61.2\u003c/p\u003e\n \u003cp\u003e59/38.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.41509433962264%\" valign=\"top\"\u003e\n \u003cp\u003e42/48.3\u003c/p\u003e\n \u003cp\u003e45/51.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.132075471698114%\" valign=\"top\"\u003e\n \u003cp\u003e5/25\u003c/p\u003e\n \u003cp\u003e15/75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.88679245283019%\" valign=\"top\"\u003e\n \u003cp\u003e8/44.4\u003c/p\u003e\n \u003cp\u003e10/55.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.320754716981131%\" valign=\"top\"\u003e\n 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width=\"16.41509433962264%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e31/35.6\u003c/p\u003e\n \u003cp\u003e56/64.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.132075471698114%\" valign=\"top\"\u003e\n \u003cp\u003e7/35\u003c/p\u003e\n \u003cp\u003e4/20\u003c/p\u003e\n \u003cp\u003e9/45\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.88679245283019%\" valign=\"top\"\u003e\n \u003cp\u003e12/66.7\u003c/p\u003e\n \u003cp\u003e2/11.1\u003c/p\u003e\n \u003cp\u003e3/16.7\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e1/5.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.320754716981131%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.735849056603772%\" valign=\"top\"\u003e\n 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\u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.735849056603772%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLymph node metastases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.11320754716981%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbsent\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePresent\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.39622641509434%\" valign=\"top\"\u003e\n \u003cp\u003e33/21.7\u003c/p\u003e\n \u003cp\u003e119/78.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.41509433962264%\" valign=\"top\"\u003e\n \u003cp\u003e43/49.4\u003c/p\u003e\n \u003cp\u003e44/50.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.132075471698114%\" valign=\"top\"\u003e\n \u003cp\u003e1/5\u003c/p\u003e\n \u003cp\u003e19/95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.88679245283019%\" valign=\"top\"\u003e\n \u003cp\u003e12/66.7\u003c/p\u003e\n \u003cp\u003e6/33.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.320754716981131%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.003\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.735849056603772%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLocation of distant metastases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.11320754716981%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbsent\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eLiver\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eLung\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePeriton\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eOvary\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.39622641509434%\" valign=\"top\"\u003e\n \u003cp\u003e121/79.6\u003c/p\u003e\n \u003cp\u003e14/9.2\u003c/p\u003e\n \u003cp\u003e7/4.2\u003c/p\u003e\n \u003cp\u003e4/2.6\u003c/p\u003e\n \u003cp\u003e2/1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.41509433962264%\" valign=\"top\"\u003e\n \u003cp\u003e72/82.8\u003c/p\u003e\n \u003cp\u003e15/17.2\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.132075471698114%\" valign=\"top\"\u003e\n \u003cp\u003e20/100\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.88679245283019%\" valign=\"top\"\u003e\n \u003cp\u003e12/66.7\u003c/p\u003e\n \u003cp\u003e4/22.2\u003c/p\u003e\n \u003cp\u003e2/11.1\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.320754716981131%\" valign=\"top\"\u003e\n \u003cp\u003e0.800\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.735849056603772%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor grade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.11320754716981%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 1\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 2\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eGrade I3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.39622641509434%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e81/53.3\u003c/p\u003e\n \u003cp\u003e71/46.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.41509433962264%\" valign=\"top\"\u003e\n \u003cp\u003e4/4.6\u003c/p\u003e\n \u003cp\u003e79/90.8\u003c/p\u003e\n \u003cp\u003e4/4.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.132075471698114%\" valign=\"top\"\u003e\n \u003cp\u003e20/100\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.88679245283019%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e12/66.7\u003c/p\u003e\n \u003cp\u003e6/33.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.320754716981131%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.735849056603772%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.11320754716981%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEarly\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eLate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.39622641509434%\" valign=\"top\"\u003e\n \u003cp\u003e34/22.4\u003c/p\u003e\n \u003cp\u003e118/77.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.41509433962264%\" valign=\"top\"\u003e\n \u003cp\u003e44/50.6\u003c/p\u003e\n \u003cp\u003e43/49.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.132075471698114%\" valign=\"top\"\u003e\n \u003cp\u003e20/100\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.88679245283019%\" valign=\"top\"\u003e\n \u003cp\u003e12/66.7\u003c/p\u003e\n \u003cp\u003e6/33.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.320754716981131%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.735849056603772%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCRBN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.11320754716981%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNegative Positive\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.39622641509434%\" valign=\"top\"\u003e\n \u003cp\u003e118/77.6\u003c/p\u003e\n \u003cp\u003e34/22.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.41509433962264%\" valign=\"top\"\u003e\n \u003cp\u003e47/54\u003c/p\u003e\n \u003cp\u003e40/46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.132075471698114%\" valign=\"top\"\u003e\n \u003cp\u003e12/60\u003c/p\u003e\n \u003cp\u003e8/40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.88679245283019%\" valign=\"top\"\u003e\n \u003cp\u003e8/44.4\u003c/p\u003e\n \u003cp\u003e10/55.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.320754716981131%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Sağlık Bilimleri Üniversitesi","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Cereblon, CRBN, colorectal carcinomas, gastric carcinomas, neuroendocrine tumors","lastPublishedDoi":"10.21203/rs.3.rs-4283954/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4283954/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eThis retrospective study has aimed to determine the possible prognostic significance of cereblon (CRBN) expression in gastrointestinal tract tumors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eIn this study, cases of gastrointestinal tract tumors including neuroendocrine tumors (n:38), gastric adenocarcinomas (n:152) and colorectal carcinomas (n:87) diagnosed in the Pathology Laboratory of Tepecik Training and Research Hospital between 2008 and 2018 were evaluated. We investigated the presence of CRBN protein expression in tumor tissues using IHC staining. The relationship between CRBN expression and various prognostic factors was analyzed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eMost of the cases were male (n=179, 64.6%). The mean age of the patients was 60.5± 13.1 years. Overall survival in malignant cases was 30.5±21.8 months, with the shortest survival of 24.7 months in gastric carcinomas. CRBN expression was detected in 92 (33.2%) cases. CRBN positivity rates were highest in neuroendocrine carcinomas (55.6%) and lowest in gastric carcinomas (22.4%). The presence of CRBN expression was statistically significantly different among tumor types (p\u0026lt;0.001). When each group was evaluated separately, a statistically significant relationship was detected between CRBN expression and survival only in gastric carcinomas (p= 0.036). However, contrary to expectations, survival was shorter in patients with CRBN- positive tumors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: In cancer treatment, it is very important to identify new targeted treatment options, especially for aggressive tumor types. Since some currently used immunomodulatory drugs target CRBN protein, the use of immunomodulatory drugs may be considered in addition to current therapies in the treatment of solid tumors expressing high levels of CRBN.\u003c/p\u003e","manuscriptTitle":"Evaluation of cereblon expression in gastrointestinal tract tumors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-19 18:39:10","doi":"10.21203/rs.3.rs-4283954/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4d5ef97a-f8c4-47e4-b4e9-bd7c38fed189","owner":[],"postedDate":"April 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":30817959,"name":"Cancer Biology"},{"id":30817960,"name":"Oncology"}],"tags":[],"updatedAt":"2024-04-19T18:39:10+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-19 18:39:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4283954","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4283954","identity":"rs-4283954","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}