Early versus Late Onset Colorectal Cancer: Pathological Distinctions and Optimal Screening Age Determination in a Decade-Long Study

Early versus Late Onset Colorectal Cancer: Pathological Distinctions and Optimal Screening Age Determination in a Decade-Long Study | 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 Article Early versus Late Onset Colorectal Cancer: Pathological Distinctions and Optimal Screening Age Determination in a Decade-Long Study Jiawei Song, Tenghui Han, Lei Qian, Jun Zhu, Yihuan Qiao, Shuai Liu, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3960581/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Nov, 2024 Read the published version in Scientific Reports → Version 1 posted 12 You are reading this latest preprint version Abstract Background and Aim: The incidence of Early-Onset Colorectal Cancer (EOCRC) is increasing. However, the prognosis of EOCRC compared to Late-Onset Colorectal Cancer (LOCRC), and the ideal age for initial colorectal cancer (CRC) screening are not clear. In this study, we identified the pathological differences between the groups and determined the optimal screening age for CRC patients. Methods: We included 10,172 patients diagnosed with CRC from January 2011 to December 2021 in this study. Survival differences were compared by plotting Kaplan-Meier survival curves and conducting landmark analysis. Additionally, the diagnostic age of CRC patients was analyzed using age cumulative curves. Results : Compared to LOCRC patients, EOCRC patients had a higher proportion of defective mismatch repair (dMMR) and more advanced TNM staging (P < 0.05). The five-year survival of EOCRC patients was significantly better than that of LOCRC patients (P < 0.05). Laparoscopic surgery improved the long-term survival of EOCRC patients. Proficient mismatch repair (pMMR) favored the long-term survival of EOCRC patients. The survival rate of EOCRC patients at TNM stages I and II was higher than that of LOCRC patients at the same stages (P < 0.05). The age cumulative curve showed a substantial increase in the number of CRC patients at 40 years. Conclusion: The long-term prognosis of EOCRC patients is better than that of LOCRC patients, especially among those with pMMR, stages I-II, and who undergo laparoscopic surgery. For high-risk groups, the starting age for CRC screening should be 40 years. Biological sciences/Cancer Health sciences/Gastroenterology early-onset colorectal cancer prognosis screening age surgical modalities microsatellite instability Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. INTRODUCTION 2. Colorectal cancer (CRC) is a global health problem. It is one of three cancer types with the highest incidence and mortality [1]. CRC is generally diagnosed at a later age than other types of cancer, with a median of 68 years for males and 72 years for females, compared to a diagnosis age of 63 years for other cancers [2]. CRC is an age-related disease. In this study, we classified CRC patients as early-onset colorectal cancer (EOCRC) patients if they were diagnosed before turning 50 years old and as late-onset colorectal cancer (LOCRC) patients if they were diagnosed after turning 50 years old. The incidence of LOCRC has decreased in the past two decades, mainly because of changes in risk factors and higher screening rates [3]. However, the incidence of EOCRC has increased significantly [4], which might be partly due to a poor lifestyle (e.g., unhealthy diet, physical inactivity, and obesity) [5–9]. The incidence of EOCRC is expected to increase. Some studies consider that EOCRC patients might face a greater disease burden than LOCRC patients [10–11]. EOCRC patients have a low prevalence of family history (25%) and pathogenic cancer susceptibility genes (16%) [12]. The causes of EOCRC are unclear, and the cancer-related mortality of EOCRC patients may increase in the next decade [13, 14]. Liu et al. found that early-onset patients may have higher overall survival (OS) [15, 16], but Gao et al. found no difference in prognosis between EOCRC and LOCRC patients [17]. However, the effects of different stages, surgical approaches, and subgroups on the OS of EOCRC and LOCRC patients are unclear and need to be determined. The optimal screening age for EOCRC patients is also not known. The American Cancer Society (ACS) recommends screening at the age of 45 years for average-risk populations [18, 19], but some researchers suggest screening at the age of 40 years for minimizing expenses [20]. In this study, we investigated the clinical and pathological differences between EOCRC and LOCRC. We compared and analyzed the OS, clinical features, and pathological characteristics of EOCRC and LOCRC patients to provide deeper insights into the oncological management of young patients. 2. MATERIALS AND METHODS 2.1 General information Between January 2011 and December 2021, 10,172 patients diagnosed with CRC were admitted to Xijing Hospital and treated. Among them, 7,709 patients were regularly followed up, including 1,675 cases of EOCRC and 6,034 cases of LOCRC. Information on clinical variables such as age, gender, albumin, globulin, direct and indirect bilirubin, alkaline phosphatase, γ-glutamyl transferase, alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen 19–9 (CA199), carbohydrate antigen 125 (CA125), fecal occult blood test, hemoglobin (HB), platelet count (PLT), activated partial thromboplastin time (APTT), prothrombin time (PT), mismatch repair (MMR), S-100, CD34, and TNM stage was collected. Peripheral venous blood was collected from the patients at 6:00 a.m. before treatment. Serum levels of tumor biomarkers (CEA, CA199) were measured using a Cobas 8000 analyzer. The inclusion criteria were as follows: 1) pathological diagnosis of CRC, 2) complete follow-up information, and 3) surgical resection of CRC. The exclusion criteria were as follows: 1) multiple primary tumors; 2) known hereditary syndrome; 3) less than one month of follow-up; 4) incomplete visit information, 5) other malignant diseases, 6) colorectal invasion by malignant tumors from other organs, and 7) recurrent CRC. This study was approved by the Medical Ethics Committee of XiJing Hospital (No. KY20232232-F-1) in 2023. The study was approved by the ChiCTR platform (https://www.chictr.org.cn/showproj.html?proj=206034, registration number: ChiCTR2300075253).The study was retrospective, in which oral informed consent was obtained during telephone follow-up with patients. The study protocol was approved by the ethics committee. The study were performed in accordance with the relevant guidelines and regulations. 2.2 Observation indicators and evaluation criteria All CRC patients were followed up until November 2023 after surgery. Follow-up appointments were scheduled every three months in the first year and every six months thereafter. Outpatient reviews were the primary method of follow-up, with telephone consultations performed if required. The study endpoint was OS. The pathological tissues obtained through surgery were stained with hematoxylin and eosin (H&E), and the pathologist made the pathological diagnosis. The clinical and pathological characteristics of the patients were evaluated, and the clinicopathological differences between EOCRC and LOCRC were compared and analyzed. Additionally, survival analysis was conducted to compare the five-year and 10-year survival rates of the two groups. 2.3 Statistical analysis Statistical analyses were conducted using the R software (version 4.2.2). Data distribution was assessed by conducting a normality test, and appropriate descriptive statistics were used for variables that followed a normal/non-normal distribution. Survival curves were generated and compared using the Kaplan-Meier (K-M) method and the log-rank test. Segmented survival curves were plotted using Landmark analysis with a five-year cutoff point. The statistical analyses were conducted and plots were constructed using R-related software packages, including survival, survminer, ggplot2, and ggforce. All differences were considered to be statistically significant at P < 0.05 (two-tailed). 3. RESULTS 3.1 Baseline characteristics of patients During the study period, 10,172 patients were enrolled. Among them, 7,709 patients met the inclusion criteria for a high-quality diagnosis of CRC. The preoperative characteristics of these patients were compared. The demographic and clinical features of the study population are shown in Table 1. The LOCRC group had a slightly higher proportion of males (59.0%) than the EOCRC group (57.8%). The EOCRC patients had a higher prevalence of dMMR (19.0%) than LOCRC patients (9.4%), according to the MMR status. The EOCRC patients had a higher proportion of stage II, III, and IV tumors than LOCRC patients, based on the TNM classification. The key laboratory parameters, including perineural invasion, vascular invasion, alkaline phosphatase, hemoglobin (HB), and platelet count (PLT), differed significantly between the LOCRC and EOCRC groups. These findings suggested that LOCRC and EOCRC patients have different baseline characteristics, which may affect the disease progression and treatment response. 3.2 Comparison of Survival between EOCRC and LOCRC Patients After comparing the survival outcomes of patients with EOCRC and LOCRC, we found no significant difference in the survival rates between these two groups (Fig. 1A) (P > 0.05). For OS analysis, the 12-year follow-up was divided into intervals of five and seven years for landmark analysis. The EOCRC patients showed a significantly higher survival rate than the LOCRC patients after the fifth year (Fig. 1B) (P < 0.05). An examination of the changes in EOCRC patients over the past 12 years showed an increase in their proportion in the yearly diagnosed CRC population (Fig. 1C). A comprehensive analysis of the survival rates of CRC patients showed rates of 94.0%, 84.7%, and 78.4% at one, three, and five years, respectively (Supplementary Fig. 1A). The differences in the survival rates between rectal and colorectal cancer patients were not significant (Supplementary Fig. 1B) (P > 0.05). However, patients with left-sided colon cancer exhibited a more favorable prognosis than those with right-sided colon cancer (Supplementary Fig. 1C) (P < 0.05). 3.3 Impact of surgical modality on survival in patients with EOCRC and LOCRC In this study, we examined the effect of open and laparoscopic surgeries on the survival outcomes of EOCRC and LOCRC patients. The results showed no significant differences in the survival rates between EOCRC and LOCRC patients who underwent either open or laparoscopic surgeries (Fig. 2A and B; P > 0.05). The results of the landmark analysis showed that the long-term survival differences in patients undergoing open surgery were not significant (Fig. 2C; P > 0.05). However, among patients who underwent laparoscopic surgery, EOCRC patients had a significantly higher survival rate than LOCRC patients after five years (Fig. 2D; P < 0.05). Additionally, laparoscopic surgery was associated with significantly greater survival of both EOCRC and LOCRC patients compared to open surgery (Supplementary Fig. 2A and B; P < 0.05). 3.4 Impact of the MMR status on the survival of patients with EOCRC and LOCRC In this study, we analyzed 7,672 patients with CRC who underwent MMR testing, including 6,005 patients with LOCRC and 1,667 patients with EOCRC. K-M survival curves were plotted and landmark analyses were conducted to compare the OS of dMMR patients in EOCRC and LOCRC groups. Our results showed that the difference in the five-year survival rates between the EOCRC and LOCRC groups with either dMMR or pMMR was not significant (Fig. 3A and 3B; P > 0.05). The results of the landmark analysis showed comparable survival rates after five years between the EOCRC and LOCRC groups in dMMR patients (Fig 3C; P > 0.05). Among pMMR patients, the survival rate after five years was significantly higher for the EOCRC group (Fig 3D; P < 0.05). Additionally, the pMMR patients showed a significantly higher survival rate than the dMMR patients in the LOCRC and EOCRC groups (Supplementary Fig. 3A and B; P < 0.05). 3.5 Impact of TNM staging on the survival of patients with EOCRC and LOCRC As EOCRC patients are generally at an advanced TNM stage, they have received much attention from researchers. Therefore, in this study, we compared the overall survival of EOCRC and LOCRC patients at different TNM stages (I-IV) and found that EOCRC patients survived significantly longer than LOCRC patients at TNM stages I and II (Fig. 4A and B; P 0.05). 3.6 Determining the optimal screening age Between 2011 and 2023, our center treated 10,172 CRC patients who were 17–95 years old. These patients were categorized into four age groups: group 1 ( 50 years). As illustrated in Fig. 5A, the distribution was as follows: group 1 included 219 patients (2.15%), group 2 included 662 patients (6.51%), group 3 included 1,810 patients (17.79%), and group 4 included 7,481 patients (73.55%). We also conducted an age-proportional cumulative analysis to assess the age at initial diagnosis. The results showed an inflection point at 40 years, indicating a significant increase in the number of patients above this age (Fig. 5B). 4. DISCUSSION In recent decades, the diagnosis of EOCRC has increased significantly, imposing a greater disease burden on the patients. In contrast, the prevalence and mortality rates of LOCRC have either stabilized or decreased in numerous high-income countries, attracting considerable attention. Comprehensive studies comparing EOCRC and LOCRC patients across various stages, surgical procedures, and subgroups are lacking. The appropriate age for screening and survival outcomes of EOCRC patients are also unclear. In this study, we investigated the clinicopathological distinctions between EOCRC and LOCRC patients, assessed the impact of surgical approaches, MMR status, and TNM staging on survival, and analyzed the diagnosis age to determine the optimal screening age for CRC. We analyzed the clinical characteristics of EOCRC and LOCRC patients. The results suggested that EOCRC patients exhibited a better nutritional status. They also showed a higher ratio of dMMR, along with a greater incidence of perineural and vascular invasion. These observations were similar to the findings of Gabriel et al. [21–23], who reported that EOCRC becomes more aggressive as the tumor stage advances. These changes might be attributed to advanced tumor staging that commonly occurs in EOCRC patients. In this study, the proportion of male patients was slightly higher. This disparity could be linked to variations in the intestinal microbiome, specifically, the presence of lower probiotics and higher oncogenic bacteria in men, which can increase their risk of developing CRC [24]. The incidence of CRC is correlated with androgen levels [25, 26], and mutations in the KRAS oncogene in male patients may increase the expression of the KDM5D gene on the Y-chromosome [27]. Other factors like smoking, alcohol consumption, and dietary habits may also contribute to this gender disparity. These findings highlighted the need to further investigate gender-specific factors related to the development of CRC. We conducted a comparative analysis of rectal and colon cancers and found that the OS rates were similar in both groups. The patients with left-sided CRC exhibited better OS compared to those with right-sided CRC. Although the difference in OS between the early-stage EOCRC and LOCRC patients was not significant, EOCRC patients showed a significantly higher survival rate after five years. This trend occurred probably because EOCRC patients had a higher chance of completing the treatment regimen and receiving more intensive treatment. In the last decade, the number of EOCRC cases increased considerably, imposing a greater disease burden on the younger patient group. The effect of surgical modalities on the survival of EOCRC and LOCRC patients was low. However, by comparing the groups based on surgical approach, we found that patients who underwent laparoscopic surgery showed a significantly higher survival rate than those who underwent open surgery, which matched the findings of other studies [28]. No significant difference was observed in OS between pMMR and dMMR patients in the EOCRC and LOCRC groups, although long-term survival was better for pMMR patients in the EOCRC group than in the LOCRC group. This difference in survival was not found among dMMR patients, probably because their sample size was smaller. The dMMR patients had higher OS than the pMMR patients. Some studies have found a significant prevalence of dMMR in EOCRC patients, with a longer five-year disease-free survival rate in the dMMR group than in the pMMR group [29, 30]. These findings highlighted the need for further research on the effect of the MMR expression status in EOCRC patients. We also found that EOCRC patients generally presented with more advanced TNM stages at diagnosis compared to LOCRC patients. The incidence of advanced disease might be higher because patients with EOCRC are generally diagnosed after the onset of symptoms, resulting in a higher incidence of late detection [31], as shown by O'Sullivan et al. [32]. In contrast, because of regular screening practices, LOCRC patients are diagnosed at earlier stages. For TNM stages I and II, the survival rate of EOCRC patients was considerably higher than that of LOCRC patients. However, in stages III and IV, the differences in the survival rate were not significant. These observations emphasized the need for early screening in younger populations to enhance survival by diagnosing diseases at lower TNM stages. Current medical guidelines suggest that screening for colorectal cancer should begin at age 50; however, this approach overlooks younger at-risk demographics. In this study, we analyzed nearly 12 years of colorectal cancer data, encompassing 10,172 cases. The incidence rate of colorectal cancer in individuals under 30 years was relatively low at 1.93% but increased sharply after the age of 40, and reached 15.93% in the 40–50-year-old age group. Correspondingly, the age-proportional cumulative curve showed a significant increase in the number of patients who were 40 years old, marking a critical inflection point. Zaborowski et al. emphasized the need for earlier screening and risk assessment for CRC, particularly for individuals at high risk [33, 34]. Studies have shown that the prevalence of young-onset adenoma is around 9%, and the prevalence increases with age. The risk for metachronous advanced neoplasia after diagnosis is around 6% [35], with a majority being disseminated cases of EOCRC. The U.S. Multi-Society Task Force (MSTF) on CRC recommends screening all relatives (≥40 years old) of CRC patients diagnosed before 60 years [36]. The 2023 CSCO guidelines suggested regular CRC screening from 50 years of age for those at average risk. Only about 20% of individuals diagnosed with CRC before 50 years carry a cancer-related genetic mutation [37]. After implementing standardized screening guidelines in the United States in 2000, the incidence and mortality of CRC decreased. This decrease is particularly noticeable among those who are 65 years old and older and undergo regular screening. In contrast, an approximate annual increase of 2% was found in the incidence of proximal, distal colon, and rectal cancers in individuals under 50. This increase was most pronounced in the 20–29-year-old age group [38]. A recent large-scale screening study in China involving nearly 100,000 residents suggested initiating screening for CRC at over 40 years of age [39]. Considering that some individuals may have additional risk factors, initiating CRC screening at 50 years may lead to more advanced disease stages and poorer prognosis. Because of the prevalent sedentary lifestyle and unhealthy diet, earlier screening for specific populations is advisable. We recommend that CRC screening should start at age 40 in the Chinese population, particularly for groups with a higher incidence of the disease or other risk factors. Lowering the screening age can reduce the tumor burden on EOCRC patients, which can decrease the incidence and mortality rates. This study provided insights into the differences between EOCRC and LOCRC patients. However, it had certain limitations. First, as it was a retrospective cohort study, the partial lack of baseline patient information may have affected the precision of our interpretations. Second, as this was a single-center study, our findings may not fully represent other populations and cannot be used to analyze CRC incidence trends among patients over 40, based on demographic data. Additionally, the analysis of EOCRC patient subgroups was limited due to incomplete MMR testing and a relatively small sample size. Despite these limitations, our study provided important insights into the clinical characteristics of EOCRC patients and their differences from LOCRC patients, corroborated by other relevant studies. Our findings highlighted the importance of early screening of EOCRC patients to lower their TNM stage and improve survival outcomes. 5. CONCLUSION The long-term survival rate of EOCRC patients was higher than that of LOCRC patients, especially for those with pMMR, TNM stages I-II, and who underwent laparoscopic surgery. Due to the substantial increase in CRC cases starting at age 40, we recommend starting CRC screening for high-risk groups in China at and above this age. This approach can decrease CRC-related mortality and enhance the prognosis for younger patients, thus facilitating early diagnosis and treatment. Declarations Acknowledgments: We are thankful to Air Force Military Medical University first affiliation Xijing digestive hospital (Shaanxi, China) for supporting this research. Funding This work was supported by the National Natural Science Foundation of China [82172781]. Author contribution: JL , XC and PY designed the study. JS , TH and LQ contributed to the conception of the study and completed the manuscript together. JZ, YQ and SL contributed significantly to statistical analysis and manuscript preparation. All authors contributed to the article and approved the submitted version. Data availability: Datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Conflicts of interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest References Sung H, Ferlay J, Siegel RL et al. 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Supplementary Files table.docx SupplementaryFigures.pdf Cite Share Download PDF Status: Published Journal Publication published 09 Nov, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 18 Sep, 2024 Reviews received at journal 16 Sep, 2024 Reviewers agreed at journal 01 Sep, 2024 Reviews received at journal 22 May, 2024 Reviewers agreed at journal 22 May, 2024 Reviews received at journal 05 Apr, 2024 Reviewers agreed at journal 04 Apr, 2024 Reviewers invited by journal 05 Mar, 2024 Editor assigned by journal 04 Mar, 2024 Editor invited by journal 28 Feb, 2024 Submission checks completed at journal 28 Feb, 2024 First submitted to journal 16 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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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-3960581","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":275443394,"identity":"161bef84-f97d-4ecd-a0c6-9ba5e7645c98","order_by":0,"name":"Jiawei Song","email":"","orcid":"","institution":"Xijing Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jiawei","middleName":"","lastName":"Song","suffix":""},{"id":275443395,"identity":"d00f15b0-9f96-4cb7-b18f-19dc0d183318","order_by":1,"name":"Tenghui Han","email":"","orcid":"","institution":"Airborne Army Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tenghui","middleName":"","lastName":"Han","suffix":""},{"id":275443396,"identity":"877339b4-fc0b-48f8-8c44-11bb101d9ccb","order_by":2,"name":"Lei Qian","email":"","orcid":"","institution":"Xijing Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lei","middleName":"","lastName":"Qian","suffix":""},{"id":275443397,"identity":"9f7bfe60-310a-438c-a449-00745f7bb7d0","order_by":3,"name":"Jun Zhu","email":"","orcid":"","institution":"Xijing Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Zhu","suffix":""},{"id":275443398,"identity":"ebc8e51c-7ef4-4769-b5c3-37af8890ee45","order_by":4,"name":"Yihuan Qiao","email":"","orcid":"","institution":"Xijing Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yihuan","middleName":"","lastName":"Qiao","suffix":""},{"id":275443399,"identity":"928b9651-8095-4808-9da0-05c26e6d6e83","order_by":5,"name":"Shuai Liu","email":"","orcid":"","institution":"Xijing Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shuai","middleName":"","lastName":"Liu","suffix":""},{"id":275443400,"identity":"58374926-c52a-4810-afb8-31f9f89129bd","order_by":6,"name":"Pengfei Yu","email":"","orcid":"","institution":"Xijing Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Pengfei","middleName":"","lastName":"Yu","suffix":""},{"id":275443401,"identity":"703b7307-e16c-4b90-b94e-bfd32215abaf","order_by":7,"name":"Xiaoping Chen","email":"","orcid":"","institution":"The Southern Theater Air Force Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaoping","middleName":"","lastName":"Chen","suffix":""},{"id":275443402,"identity":"3cc24600-2a42-4229-8814-7979dc3f51ad","order_by":8,"name":"Jipeng Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA90lEQVRIiWNgGAWjYBACxmYwZcHDxt7/weADkEGsFgkePp4DBoUzgAxiLZNgkJNIMPjMA2QQBMztvAcfF/ySkGGTSEjcbFMjIWNwI/cAw4+KbXgcxpdsPLNPgoeN58Fh45xjEjwGN/ISGHvO3MajhcdMmrcHqIU9sc04hw2kJceAmbENrxbz32AtDMnsvy3+EafFjJnnB1ALRxqDMWMbUVr4kqV5G0B+OcNg2Av0lOSZNwYH8fnFsP/swc88f2zs5dt7GAx+fLOx5zueY/jgRwUeLQ3AuGNsQxJROMDAcACneiCQZwBF9x9kkQZ86kfBKBgFo2AkAgBxzUzRWrZZTgAAAABJRU5ErkJggg==","orcid":"","institution":"Xijing Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jipeng","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2024-02-16 07:15:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3960581/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3960581/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-76951-4","type":"published","date":"2024-11-09T15:56:59+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":51972852,"identity":"0d59f147-a59d-4386-83e7-267701e8255e","added_by":"auto","created_at":"2024-03-04 18:58:31","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":82197,"visible":true,"origin":"","legend":"\u003cp\u003eTrend in the proportion of EOCRC patients in CRC patients (A). Kaplan–Meier estimates of survival probability in the EOCRC and LOCRC (B); Landmark analysis distinguishes OS of EOCRC and LOCRC after 5 years of follow-up (C);\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3960581/v1/678e6e7b0437020ce6c781af.jpg"},{"id":51974209,"identity":"6d123382-e539-47e8-94ac-44c383b1db2f","added_by":"auto","created_at":"2024-03-04 19:06:31","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":104619,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier estimates of survival probabilities for EOCRC and LOCRC are shown in open surgery (A) and laparoscopic surgery (B). Landmark analysis shows survival of EOCRC and LOCRC after 5 years during Open surgery (C) and laparoscopic surgery (D).\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3960581/v1/19b595ac1cad73ee697f7f90.jpg"},{"id":51972858,"identity":"73e267dd-6faa-4fa3-8ab2-f4604bc90a84","added_by":"auto","created_at":"2024-03-04 18:58:31","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":92684,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier estimates of survival probabilities for EOCRC and LOCRC are shown in dMMR (A) and pMMR (B). Landmark analysis showed survival rates for EOCRC and LOCRC after 5 years in dMMR (C) and pMMR (D).\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3960581/v1/8a2b1045ce10157616f582f4.jpg"},{"id":51974617,"identity":"ac573279-7925-4ccb-a1e6-2d9dff3b5800","added_by":"auto","created_at":"2024-03-04 19:14:31","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":91348,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier estimates of the survival probability of EOCRC and LOCRC are shown in TNM stage I (A), stage II (B), stage III (C), and stage IV (D)\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3960581/v1/cb30f2cb28996e2f0b0e46ab.jpg"},{"id":51972854,"identity":"975c1d88-1198-46bb-b45c-2aa157a5167a","added_by":"auto","created_at":"2024-03-04 18:58:31","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":70403,"visible":true,"origin":"","legend":"\u003cp\u003eThe pie chart shows the percentage of patients with CRC by age group (A); The cumulative age proportion curve shows the age of the inflection point when the number of patients with CRC increases dramatically (B); Group1 is for CRC patients under 30 years old; Group2 is for CRC patients aged 30 to 40; Group3 is for CRC patients aged 40 to 50; and Group4 is for CRC patients over 50.\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3960581/v1/1f791b1f05cb0570cb3e9752.jpg"},{"id":68749785,"identity":"61fa02f5-6074-4178-929a-c4b420ecda9e","added_by":"auto","created_at":"2024-11-11 16:04:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":873417,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3960581/v1/ada98bbf-5d0d-40c3-a172-0bfff14d654a.pdf"},{"id":51972856,"identity":"1d03f043-7842-4d9e-802b-40e906f26a5f","added_by":"auto","created_at":"2024-03-04 18:58:31","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":4012576,"visible":true,"origin":"","legend":"","description":"","filename":"table.docx","url":"https://assets-eu.researchsquare.com/files/rs-3960581/v1/e3ab630cba54a12f8da515c7.docx"},{"id":51974210,"identity":"2d48401b-adf9-4bea-813b-a73a806e83c1","added_by":"auto","created_at":"2024-03-04 19:06:31","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":3609520,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3960581/v1/926b40c8cd3f6a9ec8a777f2.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Early versus Late Onset Colorectal Cancer: Pathological Distinctions and Optimal Screening Age Determination in a Decade-Long Study","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003e2. Colorectal cancer (CRC) is a global health problem. It is one of three cancer types with the highest incidence and mortality [1]. CRC is generally diagnosed at a later age than other types of cancer, with a median of 68 years for males and 72 years for females, compared to a diagnosis age of 63 years for other cancers [2]. CRC is an age-related disease. In this study, we classified CRC patients as early-onset colorectal cancer (EOCRC) patients if they were diagnosed before turning 50 years old and as late-onset colorectal cancer (LOCRC) patients if they were diagnosed after turning 50 years old. The incidence of LOCRC has decreased in the past two decades, mainly because of changes in risk factors and higher screening rates [3]. However, the incidence of EOCRC has increased significantly [4], which might be partly due to a poor lifestyle (e.g., unhealthy diet, physical inactivity, and obesity) [5\u0026ndash;9].\u003c/p\u003e\n\u003cp\u003eThe incidence of EOCRC is expected to increase. Some studies consider that EOCRC patients might face a greater disease burden than LOCRC patients [10\u0026ndash;11]. EOCRC patients have a low prevalence of family history (25%) and pathogenic cancer susceptibility genes (16%) [12]. The causes of EOCRC are unclear, and the cancer-related mortality of EOCRC patients may increase in the next decade [13, 14]. Liu et al. found that early-onset patients may have higher overall survival (OS) [15, 16], but Gao et al. found no difference in prognosis between EOCRC and LOCRC patients [17]. However, the effects of different stages, surgical approaches, and subgroups on the OS of EOCRC and LOCRC patients are unclear and need to be determined. The optimal screening age for EOCRC patients is also not known. The American Cancer Society (ACS) recommends screening at the age of 45 years for average-risk populations [18, 19], but some researchers suggest screening at the age of 40 years for minimizing expenses [20].\u003c/p\u003e\n\u003cp\u003eIn this study, we investigated the clinical and pathological differences between EOCRC and LOCRC. We compared and analyzed the OS, clinical features, and pathological characteristics of EOCRC and LOCRC patients to provide deeper insights into the oncological management of young patients.\u003c/p\u003e"},{"header":"2. MATERIALS AND METHODS ","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003e2.1 General information\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBetween January 2011 and December 2021, 10,172 patients diagnosed with CRC were admitted to Xijing Hospital and treated. Among them, 7,709 patients were regularly followed up, including 1,675 cases of EOCRC and 6,034 cases of LOCRC. Information on clinical variables such as age, gender, albumin, globulin, direct and indirect bilirubin, alkaline phosphatase, \u0026gamma;-glutamyl transferase, alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen 19\u0026ndash;9 (CA199), carbohydrate antigen 125 (CA125), fecal occult blood test, hemoglobin (HB), platelet count (PLT), activated partial thromboplastin time (APTT), prothrombin time (PT), mismatch repair (MMR), S-100, CD34, and TNM stage was collected. Peripheral venous blood was collected from the patients at 6:00 a.m. before treatment. Serum levels of tumor biomarkers (CEA, CA199) were measured using a Cobas 8000 analyzer. The inclusion criteria were as follows: 1) pathological diagnosis of CRC, 2) complete follow-up information, and 3) surgical resection of CRC. The exclusion criteria were as follows: 1) multiple primary tumors; 2) known hereditary syndrome; 3) less than one month of follow-up; 4) incomplete visit information, 5) other malignant diseases, 6) colorectal invasion by malignant tumors from other organs, and 7) recurrent CRC.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Medical Ethics Committee of XiJing Hospital (No. KY20232232-F-1) in 2023. The study was approved by the ChiCTR platform (https://www.chictr.org.cn/showproj.html?proj=206034, registration number:\u0026nbsp;ChiCTR2300075253).The study was retrospective, in which oral informed consent was obtained during telephone follow-up with patients. The study protocol was approved by the ethics committee. The study were performed in accordance with the relevant guidelines and regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e2.2 Observation indicators and evaluation criteria\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll CRC patients were followed up until November 2023 after surgery. Follow-up appointments were scheduled every three months in the first year and every six months thereafter. Outpatient reviews were the primary method of follow-up, with telephone consultations performed if required. The study endpoint was OS. The pathological tissues obtained through surgery were stained with hematoxylin and eosin (H\u0026amp;E), and the pathologist made the pathological diagnosis. The clinical and pathological characteristics of the patients were evaluated, and the clinicopathological differences between EOCRC and LOCRC were compared and analyzed. Additionally, survival analysis was conducted to compare the five-year and 10-year survival rates of the two groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e2.3 Statistical analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analyses were conducted using the R software (version 4.2.2). Data distribution was assessed by conducting a normality test, and appropriate descriptive statistics were used for variables that followed a normal/non-normal distribution. Survival curves were generated and compared using the Kaplan-Meier (K-M) method and the log-rank test. Segmented survival curves were plotted using Landmark analysis with a five-year cutoff point. The statistical analyses were conducted and plots were constructed using R-related software packages, including survival, survminer, ggplot2, and ggforce. All differences were considered to be statistically significant at P \u0026lt; 0.05 (two-tailed).\u003c/p\u003e"},{"header":"3. RESULTS","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003e3.1 Baseline characteristics of patients\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the study period, 10,172 patients were enrolled. Among them, 7,709 patients met the inclusion criteria for a high-quality diagnosis of CRC. The preoperative characteristics of these patients were compared. The demographic and clinical features of the study population are shown in Table 1. The LOCRC group had a slightly higher proportion of males (59.0%) than the EOCRC group (57.8%). The EOCRC patients had a higher prevalence of dMMR (19.0%) than LOCRC patients (9.4%), according to the MMR status. The EOCRC patients had a higher proportion of stage II, III, and IV tumors than LOCRC patients, based on the TNM classification. The key laboratory parameters, including perineural invasion, vascular invasion, alkaline phosphatase, hemoglobin (HB), and platelet count (PLT), differed significantly between the LOCRC and EOCRC groups. These findings suggested that LOCRC and EOCRC patients have different baseline characteristics, which may affect the disease progression and treatment response.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e3.2 Comparison of Survival between EOCRC and LOCRC Patients\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter comparing the survival outcomes of patients with EOCRC and LOCRC, we found no significant difference in the survival rates between these two groups (Fig. 1A) (P \u0026gt; 0.05). For OS analysis, the 12-year follow-up was divided into intervals of five and seven years for landmark analysis. The EOCRC patients showed a significantly higher survival rate than the LOCRC patients after the fifth year (Fig. 1B) (P \u0026lt; 0.05). An examination of the changes in EOCRC patients over the past 12 years showed an increase in their proportion in the yearly diagnosed CRC population (Fig. 1C). A comprehensive analysis of the survival rates of CRC patients showed rates of 94.0%, 84.7%, and 78.4% at one, three, and five years, respectively (Supplementary Fig. 1A). The differences in the survival rates between rectal and colorectal cancer patients were not significant (Supplementary Fig. 1B) (P \u0026gt; 0.05). However, patients with left-sided colon cancer exhibited a more favorable prognosis than those with right-sided colon cancer (Supplementary Fig. 1C) (P \u0026lt; 0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e3.3 Impact of surgical modality on survival in patients with EOCRC and LOCRC\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study, we examined the effect of open and laparoscopic surgeries on the survival outcomes of EOCRC and LOCRC patients. The results showed no significant differences in the survival rates between EOCRC and LOCRC patients who underwent either open or laparoscopic surgeries (Fig. 2A and B; P \u0026gt; 0.05). The results of the landmark analysis showed that the long-term survival differences in patients undergoing open surgery were not significant (Fig. 2C; P \u0026gt; 0.05). However, among patients who underwent laparoscopic surgery, EOCRC patients had a significantly higher survival rate than LOCRC patients after five years (Fig. 2D; P \u0026lt; 0.05). Additionally, laparoscopic surgery was associated with significantly greater survival of both EOCRC and LOCRC patients compared to open surgery (Supplementary Fig. 2A and B; P \u0026lt; 0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e3.4 Impact of the MMR status on the survival of patients with EOCRC and LOCRC\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study, we analyzed 7,672 patients with CRC who underwent MMR testing, including 6,005 patients with LOCRC and 1,667 patients with EOCRC. K-M survival curves were plotted and landmark analyses were conducted to compare the OS of dMMR patients in EOCRC and LOCRC groups. Our results showed that the difference in the five-year survival rates between the EOCRC and LOCRC groups with either dMMR or pMMR was not significant (Fig. 3A and 3B; P \u0026gt; 0.05). The results of the landmark analysis showed comparable survival rates after five years between the EOCRC and LOCRC groups in dMMR patients (Fig 3C; P \u0026gt; 0.05). Among pMMR patients, the survival rate after five years was significantly higher for the EOCRC group (Fig 3D; P \u0026lt; 0.05). Additionally, the pMMR patients showed a significantly higher survival rate than the dMMR patients in the LOCRC and EOCRC groups (Supplementary Fig. 3A and B; P \u0026lt; 0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e3.5 Impact of TNM staging on the survival of patients with EOCRC and LOCRC\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs EOCRC patients are generally at an advanced TNM stage, they have received much attention from researchers. Therefore, in this study, we compared the overall survival of EOCRC and LOCRC patients at different TNM stages (I-IV) and found that EOCRC patients survived significantly longer than LOCRC patients at TNM stages I and II (Fig. 4A and B; P \u0026lt; 0.05). However, the difference in survival between the groups at TNM stages III and IV was not significant (Fig. 4C and D; P \u0026gt; 0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e3.6 Determining the optimal screening age\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBetween 2011 and 2023, our center treated 10,172 CRC patients who were 17\u0026ndash;95 years old. These patients were categorized into four age groups: group 1 (\u0026lt; 30 years), group 2 (30\u0026ndash;40 years), group 3 (40\u0026ndash;50 years), and group 4 (\u0026gt; 50 years). As illustrated in Fig. 5A, the distribution was as follows: group 1 included 219 patients (2.15%), group 2 included 662 patients (6.51%), group 3 included 1,810 patients (17.79%), and group 4 included 7,481 patients (73.55%). We also conducted an age-proportional cumulative analysis to assess the age at initial diagnosis. The results showed an inflection point at 40 years, indicating a significant increase in the number of patients above this age (Fig. 5B).\u003c/p\u003e"},{"header":"4. DISCUSSION","content":"\u003cp\u003eIn recent decades, the diagnosis of EOCRC has increased significantly, imposing a greater disease burden on the patients. In contrast, the prevalence and mortality rates of LOCRC have either stabilized or decreased in numerous high-income countries, attracting considerable attention. Comprehensive studies comparing EOCRC and LOCRC patients across various stages, surgical procedures, and subgroups are lacking. The appropriate age for screening and survival outcomes of EOCRC patients are also unclear. In this study, we investigated the clinicopathological distinctions between EOCRC and LOCRC patients, assessed the impact of surgical approaches, MMR status, and TNM staging on survival, and analyzed the diagnosis age to determine the optimal screening age for CRC.\u003c/p\u003e\n\u003cp\u003eWe analyzed the clinical characteristics of EOCRC and LOCRC patients. The results suggested that EOCRC patients exhibited a better nutritional status. They also showed a higher ratio of dMMR, along with a greater incidence of perineural and vascular invasion. These observations were similar to the findings of Gabriel et al. [21\u0026ndash;23], who reported that EOCRC becomes more aggressive as the tumor stage advances. These changes might be attributed to advanced tumor staging that commonly occurs in EOCRC patients. In this study, the proportion of male patients was slightly higher. This disparity could be linked to variations in the intestinal microbiome, specifically, the presence of lower probiotics and higher oncogenic bacteria in men, which can increase their risk of developing CRC [24]. The incidence of CRC is correlated with androgen levels [25, 26], and mutations in the KRAS oncogene in male patients may increase the expression of the KDM5D gene on the Y-chromosome [27]. Other factors like smoking, alcohol consumption, and dietary habits may also contribute to this gender disparity. These findings highlighted the need to further investigate gender-specific factors related to the development of CRC.\u003c/p\u003e\n\u003cp\u003eWe conducted a comparative analysis of rectal and colon cancers and found that the OS rates were similar in both groups. The patients with left-sided CRC exhibited better OS compared to those with right-sided CRC. Although the difference in OS between the early-stage EOCRC and LOCRC patients was not significant, EOCRC patients showed a significantly higher survival rate after five years. This trend occurred probably because EOCRC patients had a higher chance of completing the treatment regimen and receiving more intensive treatment. In the last decade, the number of EOCRC cases increased considerably, imposing a greater disease burden on the younger patient group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe effect of surgical modalities on the survival of EOCRC and LOCRC patients was low. However, by comparing the groups based on surgical approach, we found that patients who underwent laparoscopic surgery showed a significantly higher survival rate than those who underwent open surgery, which matched the findings of other studies [28]. No significant difference was observed in OS between pMMR and dMMR patients in the EOCRC and LOCRC groups, although long-term survival was better for pMMR patients in the EOCRC group than in the LOCRC group. This difference in survival was not found among dMMR patients, probably because their sample size was smaller. The dMMR patients had higher OS than the pMMR patients. Some studies have found a significant prevalence of dMMR in EOCRC patients, with a longer five-year disease-free survival rate in the dMMR group than in the pMMR group [29, 30]. These findings highlighted the need for further research on the effect of the MMR expression status in EOCRC patients.\u003c/p\u003e\n\u003cp\u003eWe also found that EOCRC patients generally presented with more advanced TNM stages at diagnosis compared to LOCRC patients. The incidence of advanced disease might be higher because patients with EOCRC are generally diagnosed after the onset of symptoms, resulting in a higher incidence of late detection [31], as shown by O\u0026apos;Sullivan et al. [32]. In contrast, because of regular screening practices, LOCRC patients are diagnosed at earlier stages. For TNM stages I and II, the survival rate of EOCRC patients was considerably higher than that of LOCRC patients. However, in stages III and IV, the differences in the survival rate were not significant. These observations emphasized the need for early screening in younger populations to enhance survival by diagnosing diseases at lower TNM stages. Current medical guidelines suggest that screening for colorectal cancer should begin at age 50; however, this approach overlooks younger at-risk demographics. In this study, we analyzed nearly 12 years of colorectal cancer data, encompassing 10,172 cases. The incidence rate of colorectal cancer in individuals under 30 years was relatively low at 1.93% but increased sharply after the age of 40, and reached 15.93% in the 40\u0026ndash;50-year-old age group. Correspondingly, the age-proportional cumulative curve showed a significant increase in the number of patients who were 40 years old, marking a critical inflection point.\u003c/p\u003e\n\u003cp\u003eZaborowski et al. emphasized the need for earlier screening and risk assessment for CRC, particularly for individuals at high risk [33, 34]. Studies have shown that the prevalence of young-onset adenoma is around 9%, and the prevalence increases with age. The risk for metachronous advanced neoplasia after diagnosis is around 6% [35], with a majority being disseminated cases of EOCRC. The U.S. Multi-Society Task Force (MSTF) on CRC recommends screening all relatives (\u0026ge;40 years old) of CRC patients diagnosed before 60 years [36]. The 2023 CSCO guidelines suggested regular CRC screening from 50 years of age for those at average risk. Only about 20% of individuals diagnosed with CRC before 50 years carry a cancer-related genetic mutation [37]. After implementing standardized screening guidelines in the United States in 2000, the incidence and mortality of CRC decreased. This decrease is particularly noticeable among those who are 65 years old and older and undergo regular screening. In contrast, an approximate annual increase of 2% was found in the incidence of proximal, distal colon, and rectal cancers in individuals under 50. This increase was most pronounced in the 20\u0026ndash;29-year-old age group [38]. A recent large-scale screening study in China involving nearly 100,000 residents suggested initiating screening for CRC at over 40 years of age [39].\u003c/p\u003e\n\u003cp\u003eConsidering that some individuals may have additional risk factors, initiating CRC screening at 50 years may lead to more advanced disease stages and poorer prognosis. Because of the prevalent sedentary lifestyle and unhealthy diet, earlier screening for specific populations is advisable. We recommend that CRC screening should start at age 40 in the Chinese population, particularly for groups with a higher incidence of the disease or other risk factors. Lowering the screening age can reduce the tumor burden on EOCRC patients, which can decrease the incidence and mortality rates.\u003c/p\u003e\n\u003cp\u003eThis study provided insights into the differences between EOCRC and LOCRC patients. However, it had certain limitations. First, as it was a retrospective cohort study, the partial lack of baseline patient information may have affected the precision of our interpretations. Second, as this was a single-center study, our findings may not fully represent other populations and cannot be used to analyze CRC incidence trends among patients over 40, based on demographic data. Additionally, the analysis of EOCRC patient subgroups was limited due to incomplete MMR testing and a relatively small sample size. Despite these limitations, our study provided important insights into the clinical characteristics of EOCRC patients and their differences from LOCRC patients, corroborated by other relevant studies. Our findings highlighted the importance of early screening of EOCRC patients to lower their TNM stage and improve survival outcomes.\u003c/p\u003e"},{"header":"5. CONCLUSION","content":"\u003cp\u003eThe long-term survival rate of EOCRC patients was higher than that of LOCRC patients, especially for those with pMMR, TNM stages I-II, and who underwent laparoscopic surgery. Due to the substantial increase in CRC cases starting at age 40, we recommend starting CRC screening for high-risk groups in China at and above this age. This approach can decrease CRC-related mortality and enhance the prognosis for younger patients, thus facilitating early diagnosis and treatment.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are thankful to Air Force Military Medical University first affiliation Xijing digestive hospital (Shaanxi, China) for supporting this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China [82172781].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contribution:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJL , XC and PY designed the study. JS , TH and LQ contributed to the conception of the study and completed the manuscript together. JZ, YQ and SL contributed significantly to statistical analysis and manuscript preparation. All authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDatasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSung H, Ferlay J, Siegel RL et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021; 71: 209-249.\u003c/li\u003e\n\u003cli\u003eTrivedi PD, Mohapatra A, Morris MK et al. 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Cancer Med 2019; 8: 2496-2502.\u003cstrong\u003e\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"early-onset colorectal cancer, prognosis, screening age, surgical modalities, microsatellite instability","lastPublishedDoi":"10.21203/rs.3.rs-3960581/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3960581/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground and Aim: \u003c/strong\u003eThe incidence of Early-Onset Colorectal Cancer (EOCRC) is increasing. However, the prognosis of EOCRC compared to Late-Onset Colorectal Cancer (LOCRC), and the ideal age for initial colorectal cancer (CRC) screening are not clear. In this study, we identified the pathological differences between the groups and determined the optimal screening age for CRC patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We included 10,172 patients diagnosed with CRC from January 2011 to December 2021 in this study. Survival differences were compared by plotting Kaplan-Meier survival curves and conducting landmark analysis. Additionally, the diagnostic age of CRC patients was analyzed using age cumulative curves.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: Compared to LOCRC patients, EOCRC patients had a higher proportion of defective mismatch repair (dMMR) and more advanced TNM staging (P \u0026lt; 0.05). The five-year survival of EOCRC patients was significantly better than that of LOCRC patients (P \u0026lt; 0.05). Laparoscopic surgery improved the long-term survival of EOCRC patients. Proficient mismatch repair (pMMR) favored the long-term survival of EOCRC patients. The survival rate of EOCRC patients at TNM stages I and II was higher than that of LOCRC patients at the same stages (P \u0026lt; 0.05). The age cumulative curve showed a substantial increase in the number of CRC patients at 40 years.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eThe long-term prognosis of EOCRC patients is better than that of LOCRC patients, especially among those with pMMR, stages I-II, and who undergo laparoscopic surgery. For high-risk groups, the starting age for CRC screening should be 40 years.\u003c/p\u003e","manuscriptTitle":"Early versus Late Onset Colorectal Cancer: Pathological Distinctions and Optimal Screening Age Determination in a Decade-Long Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-04 18:58:26","doi":"10.21203/rs.3.rs-3960581/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-09-18T04:53:18+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-16T22:14:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"326347301879956686012462007823331430423","date":"2024-09-01T22:21:57+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-22T14:32:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"147799420258099490971543336094769903630","date":"2024-05-22T13:37:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-05T14:02:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"7ed60ea1-2d72-40c9-8caf-a08db45dbe03","date":"2024-04-04T22:18:36+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-05T06:35:55+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-04T06:29:39+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-02-28T17:22:19+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-02-28T15:52:45+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-02-16T07:14:01+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c194ee0c-ddbe-4cf2-807e-a08aadf2e550","owner":[],"postedDate":"March 4th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":29036765,"name":"Biological sciences/Cancer"},{"id":29036766,"name":"Health sciences/Gastroenterology"}],"tags":[],"updatedAt":"2024-11-11T15:58:59+00:00","versionOfRecord":{"articleIdentity":"rs-3960581","link":"https://doi.org/10.1038/s41598-024-76951-4","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-11-09 15:56:59","publishedOnDateReadable":"November 9th, 2024"},"versionCreatedAt":"2024-03-04 18:58:26","video":"","vorDoi":"10.1038/s41598-024-76951-4","vorDoiUrl":"https://doi.org/10.1038/s41598-024-76951-4","workflowStages":[]},"version":"v1","identity":"rs-3960581","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3960581","identity":"rs-3960581","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}