Microsatellite Instability Tumors Research Articles

The potential of ESCO2 as a prognostic and immunotherapeutic marker of pan-cancer and its role in anti-PD1 treatment of bladder cancer

Background Establishment of sister chromatid cohesion N-acetyltransferase 2 (ESCO2), a member of the EFO2 family, is implicated in the pathogenesis and progression of various cancers. However, there has been limited comprehensive pan-cancer analysis conducted on ESCO2 thus far. Methods Publicly available databases, such as the UCSC Xena database, were utilized to examine differential expression patterns across various cancer types. In addition, variations in expression levels were investigated across distinct clinical stages. Univariate Cox regression and Kaplan-Meier survival analyses were conducted to evaluate the impact on overall survival (OS), disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI) at a pan-cancer level. The correlation between ESCO2 expression and immune cell infiltration was examined to gain insight into the tumor microenvironment in different cancers. The results of the bioinformatic analysis were validated using immunotherapy clinical trials and pathological specimens. CCK-8 and transwell assay experiments were performed to investigate the biological function of ESCO2. Results ESCO2 expression was found to be up-regulated in most cancers, with a correlation to TNM stages. Prognostic analysis indicated that overexpression of ESCO2 was associated with poor prognosis in various cancers. Furthermore, the correlation between ESCO2 expression and immune cell infiltration suggested its potential as a predictor for immunotherapy efficacy. Notably, ESCO2 expression showed positive associations with immunoinhibitor, immnostimulator, MHC molecule, chemokine receptor, tumor mutation burden (TMB) and microsatellite instability (MSI) levels in bladder cancer (BLCA). The validation cohort for immunotherapy corroborated these findings and substantiated that ESCO2 could function as an autonomous prognostic biomarker and a promising target for cancer treatment via immunotherapy. In addition, in vitro experiments confirmed the role of ESCO2 in influcing the proliferation, invasion and migration of BLCA cells. Conclusion ESCO2 participates in regulating the immune infiltration and affecting the prognosis of patients in many cancers, especially in BLCA. ESCO2 may serve as a prognostic and immunotherapy biomarker in future treatment of human cancer.

The Prognostic Value and Immunotherapeutic Characteristics of GFPT2 in Pan-cancer

Purpose: The purpose of this study is to investigate the underlying relationship of diagnosis and therapy between glutamine-fructose-6-phosphate transaminase 2 (GFPT2) and various cancers. Methods: The Cancer Genome Atlas (TCGA) database was utilized to get gene expression RNAseq and clinical data for 33 tumors. The immunotherapeutic cohorts, including GSE35640, GSE78220, GSE67501, GSE181815, and IMvigor210, were derived from the Gene Expression Omnibus database (GEO) and a previously released article. Differential expression analysis of GFPT2 was performed using several clinical factors, and prognostic analysis was performed using Cox proportional hazard regression. In addition, the Cell type Identification By Estimating Relative Subsets Of RNA transcripts (CIBERSORT) and the Estimation of STromal and Immune cells in MAlignant Tumor tissues utilizing Expression data (ESTIMATE) algorithms were used to investigate the connection between GFPT2 and the tumor microenvironment. This approach additionally incorporated dynamic immunological indicators, such as tumor mutational burden (TMB) and microsatellite instability (MSI). In addition, a correlation between GFPT2 expression and the effectiveness of anticancer drugs was plotted for discussion. Results: GFPT2 expression significantly differed in 11 out of 33 cancers. Although the distinct correlation between GFPT2 expression and clinical parameters had no wide distribution in pan-cancer, it demonstrated the potential prognostic validity of gene expression. GFPT2 demonstrated a strong correlation with immune infiltration, immune modulators, and immunerelated biomarkers. Furthermore, a variance analysis demonstrated a significant relationship between GFPT2 and the efficacy of immunotherapy. In addition, GFPT2 was associated with increased sensitivity of drugs such as Olaparib and Lenvatinib and decreased sensitivity of drugs such as Nilotinib. Conclusion: Collectively, GFPT2 is potentially useful as a biomarker for prognostic prediction and immune infiltration in a variety of malignancies ,and could lead to exciting new approaches to personalized oncotherapy.

Abstract B058: Nous-209 off-the-shelf vaccine targets neoantigens mutations well represented both in primary and metachronous incident CRCs from Lynch syndrome patients

Abstract Lynch Syndrome (LS) is the most common hereditary cancer syndrome, caused by germline mutations in one of the four DNA mismatch repair (MMR) genes. LS patients have a high risk to develop microsatellite instable (MSI) colorectal cancers. Tumors developed by LS carriers display high levels of microsatellite instability, which leads to the accumulation of large numbers of mutations, among which frameshift insertion/deletions (indels) within microsatellite (MS) loci are very common and shared among different tumors. When indels occur in coding genes they give rise to frameshift peptides (FSPs) with a very high potential to act as safe and potent neoantigens for a vaccine. NOUS-209 is a genetic vaccine encoding 209 neoantigens, shared across sporadic and hereditary MSI tumors, developed for interception and treatment of MSI tumors. Phase 1b trial evaluating NOUS-209 monotherapy in healthy LS carriers showed the induction of a potent and broad immune response. Here, we characterize indels encoding FSPs in a cohort of 50 incident MSI CRC from LS patients detected during routine screening (38 primary tumors; 22 metachronous tumors) by whole Exomeseq NGS. Overall, primary and metachronous tumors have a similar number of indels in coding genes. The repertoire of detected indels is only partially shared (27%) between the two categories of tumors. The 209 indels selected for the NOUS-209 vaccine are instead highly shared (95%) between primary and metachronous tumors. Moreover, the analysis of 8 patients for which both the primary and the metachronous tumor were available confirmed the presence of the 209 mutations both in the first and the second tumor. Therefore, the NOUS 209 vaccine has the potential to prevent tumor occurrence both in previvors and survivors by inducing a broad T cell immune response against recurrent FSP. Citation Format: Lorenzo De Marco, Elisa Micarelli, Joni Panula, Anna Morena D'Alise, Guido Leoni, Kalle E. Hokkanen, Eija Hämäläinen, Jukka-Pekka Mecklin, Elisa Scarselli, Toni Seppälä. Nous-209 off-the-shelf vaccine targets neoantigens mutations well represented both in primary and metachronous incident CRCs from Lynch syndrome patients [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B058.

Parvimonas micra forms a distinct bacterial network with oral pathobionts in colorectal cancer patients

BackgroundMounting evidence suggests a significant role of the gut microbiota in the development and progression of colorectal cancer (CRC). In particular, an over-representation of oral pathogens has been linked to CRC. The aim of this study was to further investigate the faecal microbial landscape of CRC patients, with a focus on the oral pathogens Parvimonas micra and Fusobacterium nucleatum.MethodsIn this study, 16S rRNA sequencing was conducted using faecal samples from CRC patients (n = 275) and controls without pathological findings (n = 95).ResultsWe discovered a significant difference in microbial composition depending on tumour location and microsatellite instability (MSI) status, with P. micra, F. nucleatum, and Peptostreptococcus stomatis found to be more abundant in patients with MSI tumours. Moreover, P. micra and F. nucleatum were associated with a cluster of CRC-related bacteria including Bacteroides fragilis as well as with other oral pathogens such as P. stomatis and various Porphyromonas species. This cluster was distinctly different in the control group, suggesting its potential linkage with CRC.ConclusionsOur results suggest a similar distribution of several CRC-associated bacteria within CRC patients, underscoring the importance of considering the concomitant presence of bacterial species in studies investigating the mechanisms of CRC development and progression.

Solitary Loss of PMS2 in a patient with Colon carcinoma

Abstract Introduction/Objective In the United States, there are about 150,000 new cases of Colorectal cancer (CRC) and about 50,000 CRC related deaths each year. Hereditary nonpolyposis colorectal cancer (Lynch Syndrome) accounts for 2% - 4% of CRC. It is characterized by germline mutations in mismatch repair (MMR) genes - MLH1, MSH2, MSH6 and PMS2. Patients with Lynch syndrome have up to an 80% lifetime risk (LTR) of CRC and up to 60% LTR of endometrial cancer. Lynch syndrome patients also have an associated LTR of ovarian cancer (38%), upper urologic tract cancer (18%), gastric cancer (13%), small bowel cancer (6%), hepatobiliary tract cancer (4%), and brain tumors (3% - usually glioblastoma). Methods/Case Report A 76-year-old man with history of moderately differentiated colorectal adenosarcoma involving the transverse colon and a recently diagnosed grade group 5 (Gleason 4 + 5) prostate adenocarcinoma, currently being managed at an outside hospital. The case was sent to UAB for DNA MMR/microsatellite instability (MSI) status evaluation testing. Immunostaining showed loss of PMS2 and intact expression of MLH1, MSH2 and MSH6. These results were confirmed by the IdyIIa MSI assay which detected microsatellite instability in 5 of 7 markers and negative for BRAF V600E variant confirming microsatellite instable tumor. Results (if a Case Study enter NA) NA Conclusion Solitary loss of PMS2 in colonic adenocarcinoma is uncommon and may be caused by an underlying germline mutation of MLH-1 or PMS2, thus could represent Lynch Syndrome. Our patient’s age doesn’t favor Lynch syndrome. Next step would be to perform MLH-1 promoter methylation to confirm sporadic nature of carcinoma. Somatic methylation of the MLH1 promoter occurs in approximately 80% of CRC with defective MMR. Prostate cancer is not currently considered a part of Lynch syndrome.

Exploring Shared Genetic Features and Molecular Mechanisms between Non-Alcoholic Steatohepatitis and Hepatocellular Carcinoma through Bioinformatics.

Hepatocellular Carcinoma (HCC) is one of the most common malignant tumors in the world, characterized by high incidence, high malignancy, and low survival rate. Currently, 1/4 of adults in the world suffer from Non-Alcoholic Fatty Liver Disease (NAFLD), with an incidence rate of 27% in Asia. We used TCGA and GEO public database data sets to conduct weighted gene coexpression network analysis to identify relevant gene modules, defined the intersection of tumorigenesis-related modules and NASH development-related modules as shared genes, and then used single-factor Cox, LASSO, and multivariate Cox regression analysis screened out core shared genes and verified their prognostic value. We further investigated the relationship between core shared genes and immune infiltration, tumor mutational load, and drug sensitivity. Finally, RT-qPCR was used to verify its mRNA expression in different cell lines. We identified Karyopherin α 2 (KPNA2) as the core shared gene between NASH and HCC. Patients were divided into low-risk groups and high-risk groups based on the expression of KPNA2. The prognosis of the low-risk group was significantly better than that of the highrisk group. Furthermore, we found significant differences in tumor immune cell infiltration, somatic mutations, microsatellite instability, and drug sensitivity between different expression groups. There are very few studies on the molecular mechanism of the relationship between NAFLD and HCC. Our study demonstrates that KPNA2 is a potential therapeutic target and immune-related biomarker for patients with NAFLD and HCC.

Tertiary lymphoid structures' pattern and prognostic value in primary adenocarcinoma of jejunum and ileum.

To date, there have been no reports on tertiary lymphoid structures (TLS) in primary adenocarcinoma of jejunum and ileum. In this study, we employed digital pathology image analysis software to classify and quantify TLS, and evaluated the maturity of TLS using immunohistochemistry. Molecular genetics and immunotherapy biomarker detection were performed using next-generation sequencing technology, such as tumor mutational burden (TMB) and microsatellite instability (MSI). The aim of this study was to investigate the presence, location, maturity, association with immunotherapy biomarkers, and prognostic value of TLS in primary adenocarcinoma of jejunum and ileum. Compared to secondary follicle-like TLS (SFL-TLS), intra-tumoral TLS (IT-TLS) were more likely to manifest as early TLS (E-TLS) (P = 0.007). Compared to IT-TLS, SFL-TLS had a higher propensity to occur at the invasive margin(IM) (P = 0.032) and showed a trend towards being more prevalent at the tumor periphery (P = 0.057). In terms of immunotherapy biomarkers, there was a higher trend of IM-TLS density in PD-L1(22C3) score CPS < 1 group compared to PD-L1(22C3) score CPS ≥ 1 group (P = 0.071). TMB-H was significantly associated with MSI-H (P = 0.040). Univariate survival analysis demonstrated a correlation between high SFL-TLS group and prolonged disease free survival (DFS) (P = 0.047). There was also a trend towards prolonged DFS in the E-TLS-high group compared to the E-TLS-low group (P = 0.069). The peri-tumoral TLS (PT-TLS)-high group showed a trend of prolonged overall survival (OS) compared to the PT-TLS-low group (P = 0.090). In conclusion, the majority of TLS were located at the invasive margin and tumor periphery, predominantly consisting of mature TLS, while IT-TLS were mainly immature. Notably, TMB was closely associated with MSI and PD-L1, indicating potential predictive value for immunotherapy in primary adenocarcinoma of jejunum and ileum.

Poor compliance with germline testing recommendations in colorectal cancer patients undergoing molecular residual disease testing.

Approximately 15% of colorectal cancers (CRCs) are associated with germline mutations. There is increasing adoption of DNA-based assays for molecular residual disease (MRD) and growing evidence supporting its clinical utility, particularly for CRC by oncologists in the U.S. We assessed the uptake of germline multi-gene panel testing (MGPT) for hereditary cancer in CRC patients receiving MRD analyses in community oncology settings. This retrospective study included 80 patients receiving care for CRC through community oncology practices who were referred for MRD testing at a commercial laboratory (January-March 2022). Clinical data, including test requisition forms, pathology reports, and clinical notes were reviewed. Documentation of tumor microsatellite instability and/or immunohistochemical (IHC) testing for mismatch repair (MMR) deficiency, age of CRC diagnosis, family history of cancer, and any order or recommendation for MGPT were assessed. Overall, 5/80 (6.3%) patients in the study have documented germline MGPT; 65/80 (81.3%) patients have documented MMR testing of their colorectal tumor. Among the 5 cases with abnormal MMR IHC, 2 have MGPT. Of the 33 patients meeting the 2021 National Comprehensive Cancer Network (NCCN) criteria for genetic/familial high-risk assessment, only 2 have MGPT. Our real-world data suggest that many CRC patients receiving MRD testing and meeting NCCN (v. 2021) criteria for germline MGPT may not be receiving evaluation beyond routine MMR status. Process and educational improvements are needed in community health settings to increase access and uptake of germline testing among CRC patients regardless of age at diagnosis or MMR status.

Clinicopathological Characteristics and Outcomes of Colorectal Cancer With Heterogenous Staining of Mismatch Repair Protein.

Scant data are available on heterogenous staining of mismatch repair protein in colorectal cancer. This study aimed to improve insights into clinicopathologic features and prognosis of colorectal cancer harboring heterogenous mismatch repair protein staining. A single-center retrospective observational study. This study was conducted in a tertiary referral center in China between 2014 and 2018. Colorectal cancers with heterogenous staining of mismatch repair protein were included. Clinicopathologic and molecular features, and survival outcomes were analyzed. A total of 151 out of 6721 colorectal cancers (2.2%) exhibited heterogenous staining for at least one mismatch repair protein, with intraglandular heterogeneity being the most common pattern (89.4%). Heterogenous MLH1 staining was significantly associated with distant metastasis (p = 0.03), while heterogenous MSH2 staining was associated with left-sided (p = 0.03) and earlier pT stage tumors (p = 0.02). The rates of microsatellite instability-high, KRAS and BRAF mutation were 12.6%, 47.3% and 3.4%, respectively. Microsatellite instability-high was significantly associated with higher intraglandular MSH6 heterogeneity frequency (p < 0.001) and decreased MSH6 expression level (< 27.5%, p = 0.01). BRAF mutation was associated with the coexistence of intraglandular and clonal heterogeneity (p = 0.003) and decreased PMS2 expression level (p = 0.01). Multivariable analysis revealed that progression-free survival was significantly associated with tumor stage (p = 0.003), stroma fraction (p = 0.004), and heterogenous PMS2 staining (p = 0.02). Overall survival was linked to tumor stage (p = 0.006) and BRAF mutation (p = 0.01). The limitations of this study include the absence of testing for MLH1 promoter methylation and mismatch repair gene mutations, its retrospective design, and insufficient data related to direct comparison with deficient mismatch repair and proficient mismatch repair colorectal cancer. Heterogenous mismatch repair protein staining in colorectal cancer exhibits distinct associations with tumor location, stage, microsatellite instability, BRAF mutation and prognosis. It is recommended to report MSH6 heterogeneity as it may indicate microsatellite instability-high. See Video Abstract.

Elevated Microsatellite Alterations at Selected Tetranucleotide Repeats (EMAST) in Penile Squamous Cell Carcinoma-No Evidence for a Role in Carcinogenesis.

Penile squamous cell carcinoma (pSCC) is a rare malignancy with a global incidence ranging from 0.1 to 0.7 per 100,000 males. Prognosis is generally favorable for localized tumors, but metastatic pSCC remains challenging, with low survival rates. The role of novel biomarkers, such as tumor mutational burden (TMB) and microsatellite instability (MSI), in predicting the response to immune checkpoint inhibitors (ICIs) has been investigated in various cancers. However, MSI has not been observed in pSCC, limiting immunotherapy options for this patient subgroup. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) are a distinct form of genomic instability associated with deficient MSH3 expression, which has been proposed as a potential biomarker in several cancers. This study investigates EMAST and MSH3 expression in a cohort of 78 pSCC cases using PCR, fragment analysis and immunohistochemistry. For the detection of EMAST, the stability of five microsatellite markers (D9S242, D20S82, MYCL1, D8S321 and D20S85) was analyzed. None of the cases showed an instability. As for MSH3 immunohistochemistry, all analyzable cases showed retained MSH3 expression. These results strongly suggest that neither EMAST nor MSH3 deficiency is involved in the carcinogenesis of pSCC and do not represent reliable predictive biomarkers in this entity. Furthermore, these findings are in full agreement with our previous study showing a very low frequency of MSI and further support the thesis that EMAST and MSI are strongly interconnected forms of genomic instability. Further research is needed to explore novel therapeutic targets and predictive biomarkers for immunotherapy in this patient population.

Mitochondrial-related genes as prognostic and metastatic markers in breast cancer: insights from comprehensive analysis and clinical models.

Breast cancer (BC) constitutes a significant peril to global women's health. Contemporary research progressively suggests that mitochondrial dysfunction plays a pivotal role in both the inception and advancement of BC. However, investigations delving into the correlation between mitochondrial-related genes (MRGs) and the prognosis and metastasis of BC are still infrequent. Utilizing data from the TCGA database, we employed the "limma" R package for differential expression analysis. Subsequently, both univariate and multivariate Cox regression analyses were executed, alongside LASSO Cox regression analysis, to pinpoint prognostic MRGs and to further develop the prognostic model. External validation (GSE88770 merged GSE425680) and internal validation were further conducted. Our investigation delved into a broad spectrum of analyses that included functional enrichment, metabolic and immune characteristics, immunotherapy response prediction, intratumor heterogeneity (ITH), mutation, tumor mutational burden (TMB), microsatellite instability (MSI), cellular stemness, single-cell, and drug sensitivity analysis. We validated the protein and mRNA expressions of prognostic MRGs in tissues and cell lines through immunohistochemistry and qRT-PCR. Moreover, leveraging the GSE102484 dataset, we conducted differential gene expression analysis to identify MRGs related to metastasis, subsequently developing metastasis models via 10 distinct machine-learning algorithms and then selecting the best-performing model. The division between training and validation cohorts was set at 70% and 30%, respectively. A prognostic model was constructed by 9 prognostic MRGs, which were DCTPP1, FEZ1, KMO, NME3, CCR7, ISOC2, STAR, COMTD1, and ESR2. Patients within the high-risk group experienced more adverse outcomes than their counterparts in the low-risk group. The ROC curves and constructed nomogram showed that the model exhibited an excellent ability to predict overall survival (OS) for patients and the risk score was identified as an independent prognostic factor. The functional enrichment analysis showed a strong correlation between metabolic progression and MRGs. Additional research revealed that the discrepancies in outcomes between the two risk categories may be attributed to a variety of metabolic and immune characteristics, as well as differences in intratumor heterogeneity (ITH), tumor mutational burden (TMB), and cancer stemness indices. ITH, TIDE, and IPS analyses suggested that patients possessing a low-risk score may exhibit enhanced responsiveness to immunotherapy. Additionally, distant metastasis models were established by PDK4, NRF1, DCAF8, CHPT1, MARS2 and NAMPT. Among these, the XGBoost model showed the best predicting ability. In conclusion, MRGs significantly influence the prognosis and metastasis of BC. The development of dual clinical prediction models offers crucial insights for tailored and precise therapeutic strategies, and paves the way for exploring new avenues in understanding the pathogenesis of BC.

Abstract C165: Interrogating the Tumor and Immune Microenvironment of Endometrial Cancers Among a Diverse Cohort of Cases

Abstract Endometrial cancer (EC) is the sixth most common gynecological malignancy, with an increasing incidence worldwide over the last two decades. African American women are more likely to be diagnosed with endometrial cancer than Caucasian women. Unfortunately, African American women are more frequently diagnosed with high-grade EC, which occurs 2-3 times more often compared to their white and Hispanic counterparts. Additionally, African American women have higher mortality rates from EC than Caucasian women, highlighting a significant cancer disparity among these patients. Uterine EC disparities are induced by complex ecosystems composed of cellular niches with distinct genotypes, phenotypes, and spatial transcriptomic landscapes. In estrogen-dependent EC tumorigenesis, the endometrium undergoes uncontrollable proliferation, progressing from normal to atypical hyperplasia and ultimately to carcinoma. The heterogeneity of EC tumors complicates therapeutic targeting, rendering EC a challenging disease to cure. This study aims to investigate the genetic and transcriptomic features found in the tumor microenvironment of African American patients with EC. Previous research has shown that the molecular classification of EC tumors can be categorized as estrogen-driven, hypermutant, microsatellite instable, or lacking a specific molecular profile. Current models do not adequately reflect the oncogenic origin and pathological progression in patients. The cohort of EC cases includes primary, metastatic, and normal tumor tissues classified as Uterine Endometrial Adenocarcinoma, along with two Serous Papillary cases with varying tumor grades (low to high grade). Spatial transcriptomics and whole exome sequencing were performed on these samples. Spatial transcriptomics will identify the alterations in gene expression and the spatial landscape of the cell neighborhoods driving tumor heterogeneity. Whole exome sequencing will provide insight into the germline and somatic variants present in EC, offering a deeper understanding of the potential genetic drivers in African American patients. The genes expressed across the EC tumor landscape are implicated in cell proliferation, epithelial- mesenchymal transition, DNA damage response, and immune response. The analysis will also show the transition of normal to malignant endometrium harboring high tumor mutational burden and microsatellite instability when comparing paired samples. This comprehensive approach aims to elucidate the genetic and transcriptomic underpinnings contributing to the disparities observed in African American patients with EC, ultimately informing better-targeted therapies and improving outcomes. Citation Format: Danyelle Paine, John Carpten. Interrogating the Tumor and Immune Microenvironment of Endometrial Cancers Among a Diverse Cohort of Cases [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C165.

Characterization of a ferroptosis-related gene signature predicting survival and immunotherapeutic response in lung adenocarcinoma.

Lung cancer remains the leading cause of cancer-related death worldwide, and drug resistance represents the main obstacle responsible for the poor mortality and prognosis. Here, to identify a novel gene signature for predicting survival and drug response, we jointly investigated RNA sequencing data of lung adenocarcinoma patients from TCGA and GEO databases, and identified a ferroptosis-related gene signature. The signature was validated in the validation set and two external cohorts. The high-risk group had a reduced survival than the low-risk group (P < 0.05). Moreover, the established gene signature was associated with tumor mutation burden, microsatellite instability, and response to immune checkpoint blockade. In addition, four candidate oncogenes (RRM2, SLC2A1, DDIT4, and VDAC2) were identified to be candidate oncogenes using in silico and wet experiments, which could serve as potential therapeutic targets. Collectively, this study developed a novel ferroptosis-related gene signature for predicting prognosis and drug response, and identified four candidate oncogenes for lung adenocarcinoma.

Prognostic aging gene-based score for colorectal cancer: unveiling links to drug resistance, mutation burden, and personalized treatment strategies

ObjectiveColorectal cancer (CRC) is characterized by high incidence and mortality rates worldwide. In this study, we present a novel aging-related gene-based risk scoring system (Aging score) as a predictive tool for CRC prognosis. Method: We identified prognostic aging-related genes using univariate Cox regression analysis, revealing key biological processes in CRC progression. We then constructed a robust prognostic model using LASSO and multivariate Cox regression analyses, including four critical genes: CAV1, FOXM1, MAD2L1, and WT1. Result: The Aging score demonstrated high prognostic performance across the training, testing, and entire TCGA-CRC datasets, proving its reliability. High-risk patients identified by the Aging score had significantly shorter overall survival times than low-risk patients, indicating its potential for patient stratification and personalized treatment. The Aging score remained an independent prognostic factor compared to age, gender, and tumor stage. Additionally, the score was linked to tumor mutation burden and microsatellite instability, indicators of immune checkpoint inhibitor response. High-risk patients also showed higher estimated IC50 values for common chemotherapeutic drugs, suggesting possible treatment resistance. Conclusion: Our findings highlight the Aging score's potential to enhance clinical decision-making and pave the way for personalized CRC management.

A comprehensive prognostic and immunological implications of PFKP in pan-cancer

BackgroundPhosphofructokinase P (PFKP) is a key rate-limiting enzyme in glycolysis, playing a crucial role in various pathophysiological processes. However, its specific function in tumors remains unclear. This study aims to evaluate the expression and specific role of PFKP across multiple tumor types (Pan-cancer) and to explore its potential clinical significance as a therapeutic target in cancer treatment.MethodsWe analyzed the expression of PFKP, immune cell infiltration, and patient prognosis across various cancers using data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Additionally, we conducted a series of experiments in lung cancer cells, including Western blot, CCK-8 assay, colony formation assay, transwell migration assay, scratch wound healing assay, LDH release assay, and flow cytometry, to evaluate the impact of PFKP on tumor cells.ResultsPFKP was found to be highly expressed in most cancers and identified as a prognostic risk factor. Elevated PFKP expression is associated with poorer clinical outcomes, particularly in lung adenocarcinoma (LUAD). Receiver operating characteristic (ROC) curve analysis indicated that PFKP can effectively differentiate between cancerous and normal tissues. The expression of PFKP in most tumors showed significant correlations with tumor mutational burden (TMB), microsatellite instability (MSI), immune score, and immune cell infiltration. In vitro experiments demonstrated that PFKP overexpression promotes lung cancer cell proliferation and migration while inhibiting apoptosis, whereas PFKP deficiency results in the opposite effects.ConclusionPFKP acts as an oncogene involved in tumorigenesis and may influence the immune microenvironment within the tumor. Our findings suggest that PFKP could serve as a potential biomarker for predicting prognosis and the efficacy of immunotherapy in tumors.

Investigation of the Relationship Between DNA Mismatch Repair Genes and Microsatellite Instability in Solid Tumors

Aim: In this study, we aimed to detect the MSI status and somatic mutations in MMR genes (MSH2, MSH6, MLH1, PMS2) of a total of 55 solid tumors diagnosed with colorectal, endometrium and ovarian cancer by NGS method and to reveal the relationship between them. Material and Method: DNA isolation was performed by taking 10-micron sections from paraffin-embedded tissue samples of 55 patients diagnosed with kolorektal, endometrium ve ovarian solid tümörlerinin and Kapa NGS DNA extraction kit was used for sequence analysis. The purity and concentration of the DNA obtained was measured by Qubit fluoremeter, and NadPrep DNA Universal Library Preparation Kit was used for high quality library preparation. Bioinformatics analyses were performed on the Genomize Seq platform. The MSI value was analysed by Roche Navify Mutation Caller software and percentage MSI values were determined using the MSIsensor2 pipeline for secondary analysis of NGS. Results: All ovarian tumors were in the MSI-Stable category. The average MSI value was 2.01. One sample had an MSI of zero. In addition, no mutations in the MSH2 and MLH1 genes were detected in any of the ovarian tumors. 3 of 4 endometrial tumors were in the MSI-Stable category, and 1 tumor was in the MSI-low (MSI value: 13.2) category. No variants were detected in the MSH2 and PMS2 genes in endometrial tumors. 2 of the 41 colorectal tumors (Case4, Case16) were in the MSI-High category. No variants were detected in the MMR genes in 19 tumors. Conclusion: Although frame-shift and stop-gain mutations were detected in 23 tumors that would cause protein deficiency in MMR genes, MSI-H was not detected, as expected, except for two colorectal tumors. Therefore, the results of our study emphasise the need to define new predictive biomarkers clinically within the framework of algorithms to predict response to immunotherapy and determine prognosis.

CD24 affects the immunosuppressive effect of tumor-infiltrating cells and tumor resistance in a variety of cancers

BackgroundCluster of differentiation 24 (CD24) is a highly glycosylated glycosylphosphatidylinositol (GPI)-anchored surface protein, expressed in various tumor cells, as a "don't eat me" signaling molecule in tumor immune. This study aimed to investigate the potential features of CD24 in pan-cancer.MethodsThe correlations between 22 immune cells and CD24 expression were using TIMER analysis. R package “ESTIMATE” was used to predict the proportion of immune and stromal cells in pan-cancer. Spearman's correlation analysis was performed to evaluate the relationships between CD24 expression and immune checkpoints, chemokines, mismatch repair, tumor mutation burden and microsatellite instability, and qPCR and western blot were conducted to assess CD24 expression levels in liver hepatocellular carcinoma (LIHC). In addition, loss of function was performed for the biological evaluation of CD24 in LIHC.ResultsCD24 expression was positively correlated with myeloid cells, including neutrophils and myeloid-derived suppressor cells, in various tumors, such as BLCA, HNSC-HPV, HNSC, KICH, KIRC, KIRP, TGCT, THCA, THYM, and UCEC. In contrast, anti-tumor NK cells and NKT cells showed a negative association with CD24 expression in BRCA-Her2, ESCA, HNSC-HPV, KIRC, THCA, and THYM. The top three tumors with the highest correlation between CD24 and ImmuneScore were TGCT, THCA, and SKCM. Functional enrichment analysis revealed CD24 expression was negatively associated with various immune-related pathways. Immune checkpoints and chemokines also exhibited inverse correlations with CD24 in CESC, CHOL, COAD, ESCA, READ, TGCT, and THCA. Additionally, CD24 was overexpressed in most tumors, with high CD24 expression in BRCA, LIHC, and CESC correlating with poor prognosis. The TIDE database indicated tumors with high CD24 expression, particularly melanoma, were less responsive to PD1/PD-L1 immunotherapy. Finally, CD24 knockdown resulted in impaired proliferation and cell cycle progression in LIHC.ConclusionCD24 participates in regulation of immune infiltration, influences patient prognosis and serves as a potential tumor marker.

227TiP A phase II, open label, randomized, non-comparative cohorts study of adjuvant atezolizumab or atezolizumab plus tiragolumab in solid tumors with resectable disease with intermediate-high risk of recurrence and high tumor mutational burden (TMB-H) or microsatellite instability (MSI-H)

227TiP A phase II, open label, randomized, non-comparative cohorts study of adjuvant atezolizumab or atezolizumab plus tiragolumab in solid tumors with resectable disease with intermediate-high risk of recurrence and high tumor mutational burden (TMB-H) or microsatellite instability (MSI-H)

Pan-cancer analysis reveals copper transporters as promising potential targets

BackgroundCopper transport proteins (SLC31A1, ATP7A, ATP7B) regulate copper levels in the body and may be involved in tumor development. However, their comprehensive expression and function across various cancers remain unclear. MethodsThe expressions of copper transporters in 33 tumors and normal tissues were analyzed using TCGA, GTEx, CCLE, ULCAN, and HPA databases. Cox regression assessed their impact on patient survival. Gene alterations were explored using cBioPortal. Spearman correlation tests were performed to investigate the associations between copper transporters and tumor mutation burden (TMB), microsatellite instability (MSI), and infiltration of immune cells. Gene functions were analyzed using STRING and GeneMANIA databases. Drug sensitivity was assessed using GSCALite database. ATP7B expression in lung squamous cell carcinoma (LUSC) was validated by immunohistochemical staining. ResultsCopper transporters exhibited variable expression patterns across various cancer types, indicating their potential dual role as either oncogenes or tumor suppressor genes, depending on the cancer type. Significant associations were found between these transporters and tumor stage, as well as prognosis in most tumors studied. Pathway analysis identified links between copper transporters and tumor-related pathways like apoptosis and RAS/MAPK. Copy number variation (CNV) analysis revealed varying degrees of gene amplification and deletion of copper transporters in most tumors. Copper transporters exhibited strong correlations with immune features, including TMB, MSI, and immune-infiltrating cells, suggesting their potential role in guiding immunotherapy. They were also associated with sensitivity to various chemotherapeutic and immunotherapeutic drugs. Immunohistochemical tests validated the correlation between elevated ATP7B level and worse progression-free survival (PFS) in LUSC. ConclusionCopper transporters may serve as potential tumor markers and therapeutic targets.

Identification of new subtypes of breast cancer based on vasculogenic mimicry related genes and a new model for predicting the prognosis of breast cancer

Breast cancer is a malignant tumor that poses a serious threat to women's health, and vasculogenic mimicry (VM) is strongly associated with bad prognosis in breast cancer. However, the relationship between VM and immune infiltration in breast cancer and the underlying mechanisms have not been fully studied. On the basis of the Cancer Genome Atlas (TCGA), Fudan University Shanghai Cancer Center (FUSCC) database, GSCALite database, and gene set enrichment analysis (GSEA) datasets, we investigated the potential involvement of VM-related genes in the development and progression of breast cancer. We analyzed the differential expression, mutation status, methylation status, drug sensitivity, tumor mutation burden (TMB), microsatellite instability (MSI), immune checkpoints, tumor microenvironment (TME), and immune cell infiltration levels associated with VM-related genes in breast cancer. We created two VM subclusters out of breast cancer patients using consensus clustering, and discovered that patients in Cluster 1 had better survival outcomes compared to those in Cluster 2. The infiltration levels of T cells CD4 memory resting and T cells CD8 were higher in Cluster 1, indicating an immune-active state in this cluster. Additionally, we selected three prognostic genes (LAMC2, PIK3CA, and TFPI2) using Lasso, univariate, and multivariate Cox regression and constructed a risk model, which was validated in an external dataset. The prognosis of patients is strongly correlated with aberrant expression of VM-related genes, which advances our knowledge of the tumor immune milieu and enables us to identify previously unidentified breast cancer subtypes. This could direct more potent immunotherapy approaches.