5-Fluorouracil (5-FU) resistance in colorectal cancer (CRC) involves oxidative stress mechanisms, but the role of epitranscriptomic regulation remains unclear. This study investigates how oxidative post-translational modifications of the N6-methyladenosine (m6A) methyltransferase METTL16 contribute to 5-FU resistance. Parental (HCT8, HCT15) and 5-FU-resistant CRC cells were compared using redox proteomics, m6A-seq, RNA-seq, and functional assays. METTL16 S-glutathionylation was assessed via streptavidin pulldown and mass spectrometry. IGF2BP3’s role was validated through knockdown/overexpression, patient-derived organoids (PDOs), and xenograft models. Clinical relevance was evaluated in 112 CRC patient tissues and data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Drug synergy was tested using isoliquiritigenin (ISO) combined with 5-FU. Resistant cells exhibited elevated global protein S-glutathionylation and reduced m6A RNA methylation. METTL16 underwent site-specific S-glutathionylation at Cys548, leading to its degradation and subsequent m6A loss. Integrative omics identified IGF2BP3 as a key METTL16 target: reduced m6A on IGF2BP3 mRNA enhanced its nuclear export, splicing, and overexpression. IGF2BP3 knockdown sensitized resistant cells to 5-FU in vitro and in vivo, while overexpression conferred resistance. Mechanistically, IGF2BP3 destabilized CFTR mRNA (an ABC transporter), reducing 5-FU uptake. Clinically, high IGF2BP3 correlated with poor survival and 5-FU resistance in CRC patients. Targeting IGF2BP3 with ISO synergized with 5-FU, overcoming resistance in cells and xenografts. Oxidative stress-induced METTL16 S-glutathionylation drives 5-FU resistance by reducing m6A modification, enabling IGF2BP3 overexpression and CFTR suppression. IGF2BP3 is a biomarker of clinical resistance, and its targeting with ISO represents a promising combinatorial strategy to restore 5-FU efficacy in CRC.

Early diagnosis of sub-centimeter lung metastases is critical for timely decision-making and improved prognosis in patients with colorectal cancer. The diagnostic evaluation of indeterminate sub-centimeter lung nodules in colorectal cancer patients remains a crucial challenge. We aim to develop and validate a deep learning model for differentiating sub-centimeter lung metastases noninvasively. Our retrospective study included 1335 colorectal cancer patients with pretreated sub-centimeter lung metastases from 3 centers and 1335 benign lung nodules from one center. The primary cohort comprised 1194 patients, who were randomly assigned (8:2) to training and internal validation cohorts. Two external validation cohorts (EVC) consisted of 101 (EVC1) and 40 (EVC2) patients. The deep learning framework employed a fully automated VNet-based segmentation model for non-contrast computed tomography (CT) scans, integrated with a ResNet18 classifier for discriminating whether sub-centimeter lung nodules are benign or metastatic. Moreover, stepwise validation of subgroups was performed according to the maximum diameter of the nodules (10, 9, 8, 7, 6, 5, ≤ 4 mm). The automatic segmentation model achieved a dice coefficient of 0.825. In primary cohort, the accuracy by radiologists was 0.705. The AUC in deep learning model showed 0.953 (95

The Homeobox (HOX) gene family is capable of binding to specific deoxyribonucleic acid (DNA) sequences, thereby modulating gene expression through activation or repression, which subsequently influences cellular behaviors including proliferation, adhesion, differentiation, and metastasis. Nevertheless, the role of Homeobox D10 (HOXD10) in the prognosis and progression of hepatocellular carcinoma (HCC) remains to be elucidated. The expression of HOXD10 in HCC was subsequently validated through Western blot and immunohistochemistry analysis. The functional role of HOXD10 in HCC was evaluated using a combination of high- and low-expression experiments, incorporating both in vitro and in vivo methodologies. Furthermore, The Cancer Genome Atlas (TCGA) database was employed to investigate the functional networks related to HOXD10. The research specifically investigated the relationship between HOXD10 expression and cancer stem cells (CSCs), emphasizing the role of N6-methyladenosine (m6A) methylation and the PI3K/AKT/mTOR signaling pathway in hepatocellular carcinoma (HCC). The marked upregulation of HOXD10 expression in HCC suggests its potential impact on adverse prognostic outcomes. Furthermore, HOXD10 expression exhibited a significant association with the T stage, vascular invasion, and histological grade of HCC. Elevated HOXD10 expression was found to significantly enhance HCC cell proliferation, invasion, and migration. Notably, there was a significant correlation between HOXD10 expression and the activation of m6A methylation, as well as the PI3K/AKT/mTOR signaling pathway. The results of this study corroborate the hypothesis that HOXD10 serves as a novel biomarker for tumor progression in HCC. Furthermore, HOXD10 has the capacity to activate the PI3K/AKT/mTOR signaling pathway through the regulation of m6A RNA methylation levels, thereby facilitating the self-renewal of hepatic cancer stem cells (HCSCs).

Studies have demonstrated that the nervous system plays an important role in cancer progression. Nevertheless, the effect of mesenchymal stem cells (MSCs) on cancer has yielded conflicting results. In this study, we discovered that cancer-derived MSCs (CA-MSCs) not only exhibit the properties of neural stem cells (NSCs) but also express a significant amount of neural-related products. These products include neurotrophic factors, neuropeptides, synapse-related products, and axon guidance factors. These identified products exhibit similar or different expression status among human NSCs, cancer and fat-derived MSCs. CA-MSCs expressed more BDNF, GDNF, and NGF than NSCs. Based on these neural-related products expressed by CA-MSCs, expression-prognostic analysis was conducted. It revealed that the expression of MDK and MANF was higher in cancer, and the expression of BDNF, NPTX1, and NGF increased as the tumor stage advanced. For ten neuropeptides, their expression levels were lower in cancer. Thirty synapse-related products displayed their respective expression status between cancer and normal tissues. SYPL1, SYBP2/3, and STX4 had a significant impact on tumor prognosis. Higher levels of syntaxin-4, neugrin, and other axogenesis products were associated with a worse prognosis in cancer. Moreover, immunohistochemistry revealed that NSC-like CA-MSCs were abundant in cancer and exhibited a clear growth-promoting effect on cancer. Briefly, CA-MSCs, which are densely distributed in cancer and have the characteristics of NSCs, express a large number of nerve-related products. These products may have significant effects on tumor progression and prognosis.

This study aimed to analyze trends in colorectal cancer (CRC) burden attributable to lifestyle factors in China (1990–2021), focusing on shifts of lifestyle, and to project future trajectories to inform public health strategies. Data from the Global Burden of Disease Study 2021 were utilized to assess deaths, disability-adjusted life years (DALYs), and age-standardized rates (ASRs) for CRC linked to nine lifestyle factors (including: diet low in whole grains, diet low in milk, diet low in fiber, diet low in calcium, diet high in red meat, diet high in processed meat, smoking, high alcohol use, and high BMI). Statistical analyses included estimated annual percentage change (EAPC), Joinpoint regression, age-period-cohort modeling, and Autoregressive Integrated Moving Average (ARIMA) projections (2022–2050). Between 1990 and 2021, the burden of CRC attributable to most dietary factors declined, with significant reductions in low fiber (DALYs EAPC: -3.77) and low calcium intake (DALYs EAPC: -3.18). In contrast, processed meat intake showed an increase (DALYs EAPC: 1.64). Alcohol-related CRC burden rose slightly (DALYs EAPC: 0.35), while high BMI showed a marked increase (DALYs EAPC: 2.31). ARIMA projections suggest continued declines in dietary risk-related CRC burden. In contrast, the burden attributable to high body-mass index (BMI) is projected to rise substantially through 2050. While improved dietary habits have reduced CRC burden in China, rising obesity pose growing threats. Public health policies must prioritize interventions targeting processed meat intake, and weight management to curb future CRC incidence and mortality.

Abstract Objectives To evaluate the prognostic impact of CT-derived body composition metrics and clinical factors, and to develop a prognostic model in patients with stage II rectal cancer. Materials and methods This retrospective study analyzed consecutive stage II rectal cancer patients who underwent radical surgery. The predictive value of body composition metrics and clinical factors was evaluated. A Cox proportional hazards model-derived nomogram, based on independent risk factors identified through univariate and multivariate analyses, was established and validated to predict overall survival (OS). Results Among 975 patients (median age 63 years, IQR 55–70 years; 644 [66.1%] males), 183 deaths were recorded during a median follow-up period of 53 months (IQR 33–83 months). Low skeletal muscle density (SMD) (OR = 0.43; 95% CI: 0.20, 0.91), age ≥ 65 years, and CA125 positive (p < 0.05) were risk factors for severe postoperative complications. High visceral-to-subcutaneous adipose ratio (VSR) (OR = 1.33; 95% CI: 1.02, 1.73), body mass index (BMI) > 24.9, and T4 stage (p < 0.05) were risk factors for prolonged hospitalization. After univariate and multivariate analyses, the nomogram based on age, gross type, perineural invasion, lymphovascular invasion, inflammatory burden index, subcutaneous fat area (SFA), and SMD (p < 0.05) exhibited area under the curve values of 0.77/0.62, 0.77/0.62, and 0.75/0.67 at 1-year, 3-year, and 5-year OS in training/validation sets, respectively. Conclusions In predicting the prognosis of stage II rectal cancer patients, VSR, SFA, and SMD were superior to other body composition metrics. The nomogram integrating body composition metrics and clinical factors showed superior predictive performance for OS compared to a single risk factor alone. Critical relevance statement CT-derived body composition metrics can predict the prognosis of rectal cancer patients by reflecting the nutritional and metabolic status. Key Points Body composition metrics’ prognostic utility in stage II rectal cancer is clear. Body composition metrics are associated with clinical outcomes in stage II rectal cancer. Body composition is a predictive biomarker for stage II rectal cancer. Graphical Abstract

The controversy surrounding the continuation of postoperative adjuvant chemotherapy (AC) for locally advanced rectal cancer patients who underwent neoadjuvant therapy (NAT) still existed. The study aimed to identify the individuals that would benefit from AC from those with stage ypII/III rectal cancer. Data for this retrospective study were obtained from the Surveillance, Epidemiology, and End Results (SEER) database and the local database. Subgroup differentiation of the beneficiary population by classification and regression tree analysis. The primary endpoint was overall survival (OS). 15,671 patients were included from the SEER database and 508 patients from local database. The proportions receiving AC were 41.9

Global ageing will further exacerbate the cancer burden, and the intersection of cancer and ageing represents an emerging and significant global public health challenge. Based on the Global Burden of Disease 2021 (GBD 2021) data, we utilized the estimated annual percentage change and Joinpoint regression model to examine the temporal trends in the global cancer burden among elderly population from 1990 to 2021. Pearson's rank correlation analysis was conducted to assess the relationship between disease burden and the socio-demographic index (SDI). Furthermore, an autoregressive integrated moving average (ARIMA) model was employed to forecast future trends (from 2022 to 2050). From 1990 to 2021, the incidence rate of cancer among the elderly population exhibited a continuous upward trend, with the steepest annual increase in high-SDI regions (AAPC = 1.03 (0.83–1.23)). During the same period, overall mortality rate experienced a decline, falling by -0.47 per year (95

Lymph node ratio (LNR) and log odds of positive lymph nodes (LOODS) are considered to be potentially more rigorous metastatic lymph node stratification patterns than AJCC N stage due to the integration of the number of examined lymph nodes. Based on the data of colorectal cancer obtained from the Surveillance, Epidemiology, and End Result (SEER) database, comparison of the stratification performance between different prognostic models was validated by statistical methods, includingchi-square test, Cox regression analysis, Kaplan-Meier survival analysis, and Time-dependent Area Under Curve. A prognostic outcome-oriented statistical method based on Log-rank test was performed to determine the cutoff value of LNR. External validation cohort obtained from Zhejiang Cancer Hospital was used to validate the model performance and cutoff value. In the SEER database cohort, the optimal cutoff value for adequate or inadequate lymph node clearance was 14. In performance comparisons, LNR performance was superior to lymph node count alone and similar to LODDS. The optimal cutoff values for LNR were analyzed to be 0.11 (P < 0.001), 0.39 (P < 0.001) and 0.68 (P < 0.001), respectively. The stratification performance of modified N stage phased with the above cutoff value outperforms AJCC N stage. Kaplan-Meier survival analysis of the differences in patient distribution between the two staging systems also demonstrated the excellence of the LNR system. Above results were verified in the external verification cohort. The modified N stage based on LNR has better stratification performance than the AJCC N stage.

Lung metastasectomy has been considered the cornerstone of treatment of resectable colorectal cancer pulmonary oligometastases (CRCPOM). However, the role of chemotherapy in the neoadjuvant setting remains unclear. This study aimed to determine whether neoadjuvant therapy (NAT) could further improve survival outcomes of patients with resectable CRCPOM. We included all 253 consecutive patients at our center between 2010 and 2022. Propensity score matching (PSM) was performed to balance the baseline characteristics. The efficacy of NAT was evaluated using the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Disease-free survival (DFS) was the primary endpoint, which was estimated by the Kaplan–Meier method. Multivariate analyses were conducted using Cox proportional hazards regression to identify independent predictors. The cumulative 5- and 10-year DFS rates following lung metastasectomy were 48.3

BACKGROUND:Our objective was to evaluate the prognostic value of immune infiltration within the intratumoral and peritumoral tissues and to establish a novel histopathology-related immunoscore associated with postoperative colorectal cancer prognosis. METHODS:In the tissue microarrays, a total of 104 patients with colorectal cancer were enrolled and randomly assigned to the derivation cohort (n = 61) or the validation cohort (n = 43). Eighteen prognostic immune biomarkers in both intratumoral and peritumoral tissues were examined by the multiplexed immunohistochemistry method, with quantification performed through digital pathology. The histopathology-related immunoscore score was constructed using least absolute shrinkage and selection operator Cox analysis by selected immune features. On the basis of the Cox regression analysis, 3 predictive models were established. Harrell C-statistics were used to assess the performance of those models. RESULTS:The area under the curve was 0.743 (confidence interval, 0.457-1.000) in the derivation cohort and 0.739 (confidence interval, 0.538-0.940) in the validation cohort. Subsequently, the groups were classified on the basis of the optimal cutoff value, with the high-risk group exhibiting a poorer prognosis. Furthermore, 3 predictive clinical models were constructed, incorporating the significant risk factors and histopathology-related immunoscore score. The first model incorporating both histopathology-related immunoscore score and statistically significant factors identified through univariate analysis demonstrated superior predictive capability for survival across all 3 models, with an area under the curve of 0.852 and C-index of 0.837. CONCLUSION:The histopathology-related immunoscore score offers a novel means of estimating of survival in patients with colorectal cancer. These findings indicated that the immunoscore and the clinical factors might serve as complementary tools to TNM staging to improve the accuracy of patient survival prediction.

Circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) provides a powerful approach to predict recurrence in colorectal cancer (CRC) and potentially improve survival outcomes for individuals diagnosed with CRC. Currently, there are two primary technical approaches for the detection of MRD using ctDNA: the tumor-informed assays and the tumor-agnostic assays. Multiple studies have demonstrated the role of MRD detection in CRC patients after radical therapy, including early relapse monitoring, molecular profiling, and treatment response prediction. Numerous interventional clinical trials based on ctDNA are underway to explore the value of MRD in optimizing adjuvant treatment decisions for patients with CRC. Once validated, ctDNA-MRD has the potential to impact current clinical treatment decisions. In this review, we summarize current techniques for detecting MRD based on ctDNA and review the data that have been collected to date on MRD detection in CRC patients who received curative-intent therapy. We also discuss prospective research of ctDNA MRD detection in this patient population and provide guidelines for the current and future use of MRD in clinical practice.

Colorectal cancer (CRC) is the most common gastrointestinal malignancy worldwide, with increasing morbidity and mortality. Heat shock transcription factor 1 (HSF1), as an important transcription factor regulating the expression of heat shock proteins, has been proven to play a crucial role in the development of various tumors. Yet the potential mechanism and clinical significance of HSF1 in CRC remain unclear and require further exploration. We used TCGA database to understand the clinical significance of HSF1 in CRC. Then, we verified the expression of HSF1 in CRC tissues by immunohistochemistry and analyzed its clinical significance. By constructing stable knockdown and overexpressed of HSF1 in cell lines to investigate the potential mechanisms of HSF1 to regulate CRC cell proliferation, migration, and invasion in vivo and in vitro. Next, differential genes expressed by HSF1 in CRC were analyzed by bioinformatics technology, and their correlation and interaction were verified by PCR, WB, and CHIP experiments. We confirmed that HSF1 is highly expressed in CRC and its upregulation is associated with poor prognosis of malignant events in CRC. Functionally, HSF1 can enhance the proliferation, invasion, and migration of CRC cell lines. In vivo experiments have shown that knockdown of HSF1 can inhibit tumor growth. In terms of molecular mechanism, we found that HSF1 can directly bind to the transcription factor binding site of CLDN3 and activate its transcription. Our research demonstrates the clinical significance and carcinogenic effect of HSF1. The functional mechanisms of HSF1 and its targets may serve as diagnostic and therapeutic targets for CRC.

Background The prognostic value of tumor deposits (TDs) in stage III colorectal cancer (CRC) patients is poorly described based on the current tumor node metastasis (TNM) stage system. Materials and methods Based on the data from the Surveillance, Epidemiology, and End Result (SEER) database between 2010 to 2020 and local hospital between 2006 to 2022, the clinicopathological features of stage III CRC patients with TDs were screened by Chi-square test. Kaplan-Meier curves were performed to describe the significant difference in overall survival (OS) among the different groups, and log-rank tests were used to compare the cumulative survival distributions. Result Patients with TDs exhibited more aggressive tumors, characterized by advanced T staging (T3&T4), N staging (N2), perineural invasion, and more advanced TNM stage. The presence of TDs was identified as a negative prognostic factor in stage III CRC patients, with the co-existence of TDs and lymph node metastasis associated the poorest prognosis. A pairwise comparison revealed no statistically significant difference between TD+N1a/b and N1c groups, while the OS of TD-LN+ (TD- N1a/b) patients was the most favorable within the N1 stage. Notably, patients with a single lymph node positive had a significantly better OS than those with a single TD positive. Conclusion The presence of tumor deposits was a negative prognostic factor in stage III colorectal cancer patients, and the significance of tumor deposits was underestimated in the current TNM staging system.

BackgroundThe survival paradox (ie, the prognosis of the population at earlier tumor stages is worse than that of the population at later stages) has been observed in colorectal cancer based on the American Joint Committee on Cancer Tumor-Nodes-Metastases staging system. We aimed to clarify the reason for the survival paradox and its impact on patient treatment.MethodsWe conducted a retrospective study analyzing eligible patients with colorectal cancer from the Surveillance, Epidemiology, and End Results database and Zhejiang Cancer Hospital between 2010 and 2019. Adjusting for confounders using propensity score matching allowed confirmation of the effect of staging on the survival paradox.ResultsBased on the Surveillance, Epidemiology, and End Results database, the subgroups with survival paradox might be IIB/C versus IIIA, IIA versus IIIA, and T4N0 (IIB/C) versus T3N1 (IIIB). After propensity score matching, stage IIB/C still had a worse prognosis than stage IIIA (5-year overall survival: 69.3% vs 78.5%, P < .001). Interestingly, the proportion of stage IIIA people receiving chemotherapy was higher than that of stage IIB/C (P < .001), and logistic regression models showed that staging was the reason for deciding whether a patient receives chemotherapy or not. These phenomena between stage IIB/C and IIIA were verified in the local database.ConclusionThese results suggested that the survival paradox was mainly due to underestimation of stage T4 weights or overestimation of stage N1 weights, and the low proportion of chemotherapy in patients with T4N0M0 colorectal cancer (proven to be more malignant than stage IIIA) might be related to the assignment to earlier stages, resulting in a lack of attention and poor compliance to chemotherapy in these patients.

Supplementary Table S1: Primer sequence of gene used for qPCR in mouse. Supplementary Table S2: Primer sequence of gene used for qPCR in human. Supplementary Table S3: List of antibodies used for immunohistochemical staining.

Supplementary figure legends

Objective: To investigate the impact of relative locations of multiple foci and microsatellite status of sporadic, synchronous, multiple, primary, colorectal carcinomas on clinicopathological features and prognosis. Methods: The clinicopathologic and prognostic data of 278 patients with sporadic, synchronous, multiple, primary, colorectal carcinomas who had been admitted to the Department of Colorectal Surgery at Zhejiang Cancer Hospital from January 2008 to July 2022 were retrospectively collected. The patients were categorized into three groups based on the relative locations of their multiple cancer foci: (1) a right-sided group that comprised patients with multiple cancer foci in the cecum, ascending colon, hepatic flexure of the colon, and transverse colon; (2) a left-sided group that comprised patients with multiple cancer foci in the splenic flexure of the colon, descending colon, sigmoid colon, and rectum; and (3) a left- and right-sided group that comprised patients with multiple cancer foci in the right half of the colon and left half of the colon/rectum. Additionally, the patients were further divided into two groups based on microsatellite status: a high microsatellite instability (MSI-H) and a low MSI/stable MSI (MSI/L&MSS) group. We compared differences in clinical characteristics and prognostic indicators between these groups. The χ2 test was utilized to compare selected clinical characteristics, whereas Kaplan-Meier survival analyses and log-rank tests were performed to compare their effects on prognosis. Result: Among 278 patients with SSCRC, 256 (92.1%) presented with two cancer foci and 22 (7.9%) with more than two foci. Additionally, 255 patients (91.7%) had adenocarcinomas, whereas the remaining 23 (8.3%) had mucinous adenocarcinomas. Lymph node metastases were identified in 136 patients (48.9%); the cancer foci had infiltrated beyond the muscular layer in 238 (85.6%); and 147 patients (52.9%) were diagnosed with TNM Stage III-IV disease. There were 155 patients (55.8%) in the left-sided group, 55 (19.8%) in the right-sided group, and 68 (24.5%) in the left- and right-sided group. Immunohistochemical examination of all four mismatch repair proteins were performed in 199 cases, revealing that 166 of these patients had MSI/L&MSS and 33 MSI-H disease. In the left-sided, left- and right-sided, and right-sided groups, the proportion of women was 16.8% (26/155), 26.5% (18/68), and 49.1% (27/55), respectively; these differences are statistically significant (χ2=22.335, P<0.001). The proportions of patients with more than three cancer foci were 5.2% (8/155), 16.2% (11/68), and 5.5% (3/55), respectively; these differences are statistically significant (χ2=8.438, P=0.015). The proportions of mucinous adenocarcinomas were 4.5% (7/155), 8.8% (6/68), and 18.2% (10/55), respectively; these differences are statistically significant (χ2=10.026, P=0.007). The proportions of patients with lymph node metastases were 55.5% (86/155), 48.5% (33/68), and 30.9% (17/55); these differences are statistically significant (χ2=9.817, P=0.007). The proportions of patients with Stage T3 & T4 disease in each group according to location were 81.3% (126/155), 88.2% (60/68), and 94.5% (52/55), respectively; these differences are statistically significant (χ2=6.293,P=0.043). The proportions of TNM Stage III-IV tumors were 59.4% (92/155), 54.4% (37/68), and 32.7% (18/55), respectively; these differences are statistically significant (χ2=11.637, P=0.003). Age, size of cancer foci, presence of distant metastasis, adenoma, nerve invasion, and vascular invasion did not differ significantly between the three groups (all P>0.05). Compared with those with MSI-H, patients with MSI/L&MSS disease were more likely to be aged >65 years and male (50.6% [84/166] vs. 15.2% [5/33], χ2=13.994,P<0.001; 80.7% [134/166] vs. 54.5% [18/33], χ2=10.457,P=0.001), more likely to be in the left-sided group (63.3% [105/166] vs. 24.2% [8/33], χ2=18.232, P<0.001), had a higher proportion of cancer foci of diameter <4 cm (54.8% [91/166] vs. 33.3% [11/33], χ2=5.086,P=0.024), and a lower proportion of mucinous adenocarcinomas (4.2% [7/166] vs. 27.3% [9/33], χ2=19.791,P<0.001), more likely to develop distant metastases (22.3% [37/166] vs. 6.1% [2/33], χ2=4.601,P=0.032), more likely to have lymph node metastases (57.2% [95/166) vs. 24.2% [8/33], χ2=11.996,P<0.001) and nerve invasion (28.9% [48/166] vs. 6.1% [2/33], χ2=7.643, P=0.006), had a higher proportion of TNM Stage III-IV disease (60.2% [100/166] vs. 24.2% [8/33], χ2=14.374, P<0.001), and a smaller proportion of family history of tumors (28.9% [48/166] vs. 60.6% [20/33], χ2=12.228, P<0.001). All the above-listed differences are statistically significant (all P<0.05). The differences in number of cancer foci, depth of infiltration, presence or absence of adenomas, and vascular invasion were not statistically significant (all P>0.05). In the 33 patients with MSI-H status and mismatch repair protein loss, the highest frequency of deletion was found in PMS-2 (66.7%, 22/33), followed by MLH-1 (57.6%, 19/33), whereas the proportions of MSH-2 (33.3%, 11/33) and MSH-6 (24.2%, 8/33) deletions were relatively low. There were statistically significant differences in the 3-year overall survival rates among the groups according to relative locations of cancer foci. The 3-year overall survival rates were 96.8%, 79.6%, and 88.5% in the right-sided, left- and right-sided, and left-sided groups, respectively (P=0.021). As to microsatellite status, the 3-year overall survival rate of patients with MSI-H disease was 93.8%, which is significantly better than the 78.4% for those with MSI/L & MSS (P=0.026). Conclusions: Among sporadic, synchronous, multiple, primary, colorectal carcinomas, those with right-sided disease had the deepest local infiltration, whereas those with left-sided disease had the greatest number of lymph node metastases, most advanced clinical TNM stage, lowest percentage of MSI-H disease, and the poorest prognosis.

BackgroundPhosphoinositide 3-kinases (PI3Ks) are lipid enzymes that regulate a wide range of intracellular functions. In contrast to Class I and Class III PI3K, which have more detailed descriptions, Class II PI3K has only recently become the focus of functional research. PIK3C2A is a classical member of the PI3Ks class II. However, the role of PIK3C2A in cancer prognosis and progression remains unknown. MethodsThe expression pattern and prognostic significance of PIK3C2A in human malignancies were investigated using multiple datasets and scRNA-seq data. The PIK3C2A expression in renal clear cell carcinoma (KIRC) was then validated utilizing Western blot. The functional role of PIK3C2A in KIRC was assessed using combined function loss experiments with in vitro experiments. Furthermore, the correlation of PIK3C2A expression with tumor immunity was investigated in KIRC. The TCGA database was employed to investigate PIK3C2A functional networks. ResultsSignificant decrease in PIK3C2A expression in KIRC, demonstrated that it potentially influences the prognosis of diverse tumors, particularly KIRC. In addition, PIK3C2A was significantly correlated with the T stage, M stage, pathologic stage, and histologic grade of KIRC. Nomogram models were constructed and used to predict patient survival based on the results of multivariate Cox regression analysis. PIK3C2A knockdown resulted in significantly increased KIRC cell proliferation. Of note, PIK3C2A expression demonstrated a significant correlation with the infiltrating levels of primary immune cells in KIRC. ConclusionThese findings support the hypothesis that PIK3C2A is a novel biomarker for tumor progression and indicates dynamic shifts in immune infiltration in KIRC. Furthermore, aberrant PIK3C2A expression can influence the biological activity of cancer cells.