Identification of tumor heterogeneity associated with KRAS/TP53 co-mutation status in lung adenocarcinoma based on single-cell RNA sequencing
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SUBMITTER: Ye Y
PROVIDER: S-EPMC10915312 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe main objective of this study was to analyze the effects of KRAS/TP53 mutation status and tumor sideness on the immune microenvironment of colorectal cancer using integrated scRNA-seq data.MethodsA total of 78 scRNA-seq datasets, comprising 42 treatment-naive colorectal tumors, 13 tumor adjacent tissues and 23 normal mucosa tissues were included. Standardized Seurat procedures were applied to identify cellular components with canonical cell marks. The batch-effect was assessed and corrected using harmony algorithm. The scMetabolism algorithm was used for single-cell metabolic analysis. The results and clinical significance were further validated using immunofluorescent-staining and TCGA-COAD datasets. Immune-infiltration scores of bulk-RNA-seq data were estimated using ssGSEA. The presto-wilcoxauc algorithm was used to identify differentially enriched genes or pathways across different subgroups. Two-sided p-value less than 0.05 was considered statistically significant.ResultsWe refined the landscape of functional immune cell subtypes, especially T cells and myeloid cells, across normal mucosa, tumor adjacent and tumor tissue. The existence and function of two states of exhausted CD8+ T (Tex) subtypes in colorectal cancer, and FOLR2+ LYVE1+ macrophages indicating unfavorable prognosis in colorectal cancer were identified and validated. The diverse tumor mutation status reshaped the immune cell function and immune checkpoint ligands/receptors (ICLs/ICRs) expression pattern. Importantly, the KRAS/TP53 dual mutations significantly reduced the major energy metabolic functions in immune cells, and promoted the cell-to-cell communications towards immunosuppression in colorectal cancers. The results revealed LAG3, CD24-SIGLEC10 and HBEGF-CD9 pathways as potential therapeutic targets for dual mutant colorectal cancers.ConclusionsWe revealed that the immune microenvironment underwent a gradual remodeling with an enrichment of immunosuppressive myeloid cells from normal mucosa to tumor regions in colorectal cancers. Moreover, we revealed the metabolic heterogeneity of tumor-infiltrating immune cells and suggested that the KRAS/TP53 dual mutation may impair antitumor immunity by reducing T and myeloid cell energy metabolism and reshaping cellular interactions toward immunosuppression.
| S-EPMC9510840 | biostudies-literature
Project description:BackgroundPredictive biomarkers in use for immunotherapy in advanced non-small cell lung cancer are of limited sensitivity and specificity. We analysed the potential of activating KRAS and pathogenic TP53 mutations to provide additional predictive information.MethodsThe study cohort included 713 consecutive immunotherapy patients with advanced lung adenocarcinomas, negative for actionable genetic alterations. Additionally, two previously published immunotherapy and two surgical patient cohorts were analyzed. Therapy benefit was stratified by KRAS and TP53 mutations. Molecular characteristics underlying KRASmut/TP53mut tumours were revealed by the analysis of TCGA data.ResultsAn interaction between KRAS and TP53 mutations was observed in univariate and multivariate analyses of overall survival (Hazard ratio [HR] = 0.56, p = 0.0044 and HR = 0.53, p = 0.0021) resulting in a stronger benefit for KRASmut/TP53mut tumours (HR = 0.71, CI 0.55-0.92). This observation was confirmed in immunotherapy cohorts but not observed in surgical cohorts. Tumour mutational burden, proliferation, and PD-L1 mRNA were significantly higher in TP53-mutated tumours, regardless of KRAS status. Genome-wide expression analysis revealed 64 genes, including CX3CL1 (fractalkine), as specific transcriptomic characteristic of KRASmut/TP53mut tumours.ConclusionsKRAS/TP53 co-mutation predicts ICI benefit in univariate and multivariate survival analyses and is associated with unique molecular tumour features. Mutation testing of the two genes can be easily implemented using small NGS panels.
| S-EPMC11300455 | biostudies-literature
Project description:MUC16/CA125 is one of the few oldest cancer biomarkers still used in current clinical practice. As mesothelium is an abundant source of MUC16 and a major contributor to stromal heterogeneity in PDAC, we investigated the regulation of MUC16 in tumor and stromal compartments individually. The trajectories constructed using the single-cell transcriptomes of stromal cells from KPC tumors demonstrated continuity in the trajectory path between MUC16-expressing mesothelial cells and other CAF subsets. Further, the tumor tissues of MUC16 whole-body knockout (KPCM) showed dysregulation in the markers of actomyosin assembly and fibroblast differentiation (iCAF and myCAF), indicating that MUC16 has an extra-tumoral role in controlling CAF differentiation. Although we found mesothelium-derivative stromal cells to be bystanders in normal pancreas, the proportion of these cells was higher in invasive PDAC, particularly in TP53 deficient tumors. Moreover, we also detail the regulation of MUC16, KRAS, and SOX9 by TP53 family members (TP53 and TP63) using multi-omics data from knockout models, PDAC cell lines, and human PDAC tissues.
| S-EPMC9936860 | biostudies-literature
Project description:BackgroundGastric cancer (GC) and gastroesophageal junction adenocarcinomas (GEJ) are molecularly diverse. TP53 is the most frequently altered gene with approximately 50% of patients harboring mutations. This qualitative study describes the distinct genomic alterations in GCs and GEJs stratified by TP53 mutation status.Patients and methodsTumor DNA sequencing results of 324 genes from 3741 patients with GC and GEJ were obtained from Foundation Medicine. Association between gene mutation frequency and TP53 mutation status was examined using Fisher's exact test. Functional gene groupings representing molecular pathways suggested to be differentially mutated in TP53 wild-type (TP53WT) and TP53 mutant (TP53MUT) tumors were identified. The association of the frequency of tumors containing a gene mutation in the molecular pathways of interest and TP53 mutation status was assessed using Fisher's exact test with a P-value of <.01 deemed statistically significant for all analyses.ResultsTP53 mutations were noted in 61.6% of 2946 GCs and 81.4% of 795 GEJs (P < .001). Forty-nine genes had statistically different mutation frequencies in TP53WT vs. TP53MUT patients. TP53WT tumors more likely had mutations related to DNA mismatch repair, homologous recombination repair, DNA and histone methylation, Wnt/B-catenin, PI3K/Akt/mTOR, and chromatin remodeling complexes. TP53MUT tumors more likely had mutations related to fibroblast growth factor, epidermal growth factor receptor, other receptor tyrosine kinases, and cyclin and cyclin-dependent kinases.ConclusionThe mutational profiles of GCs and GEJs varied according to TP53 mutation status. These mutational differences can be used when designing future studies assessing the predictive ability of TP53 mutation status when targeting differentially affected molecular pathways.
| S-EPMC8982441 | biostudies-literature
Project description:IntroductionAnti-EGFR targeted therapy is of increasing importance in advanced colorectal cancer and prior KRAS mutation testing is mandatory for therapy. However, at which occasions this should be performed is still under debate. We aimed to assess in patients with locally advanced rectal cancer whether there is intra-specimen KRAS heterogeneity prior to and upon preoperative chemoradiotherapy (CRT), and if there are any changes in KRAS mutation status due to this intervention.Materials and methodsKRAS mutation status analyses were performed in 199 tumor samples from 47 patients with rectal cancer. To evaluate the heterogeneity between different tumor areas within the same tumor prior to preoperative CRT, 114 biopsies from 34 patients (mean 3 biopsies per patient) were analyzed (pre-therapeutic intratumoral heterogeneity). For the assessment of heterogeneity after CRT residual tumor tissue (85 samples) from 12 patients (mean 4.2 tissue samples per patient) were analyzed (post-therapeutic intratumoral heterogeneity) and assessment of heterogeneity before and after CRT was evaluated in corresponding patient samples (interventional heterogeneity). Primer extension method (SNaPshot™) was used for initial KRAS mutation status testing for Codon 12, 13, 61, and 146. Discordant results by this method were reevaluated by using the FDA-approved KRAS Pyro Kit 24, V1 and the RAS Extension Pyro Kit 24, V1 Kit (therascreen® KRAS test).ResultsFor 20 (43%) out of the 47 patients, a KRAS mutation was detected. With 12 out of 20, the majority of these mutations affected codon 35. We did not obtained evidence that CRT results in changes of the KRAS mutation pattern. In addition, no intratumoral heterogeneity in the KRAS mutational status could be proven. This was true for both the biopsies prior to CRT and the resection specimens thereafter. The discrepancy observed in some samples when using the SNaPshot™ assay was due to insufficient sensitivity of this technique upon massive tumor regression by CRT as application of the therascreen® KRAS test revealed concordant results.ConclusionOur results indicate that the KRAS mutation status at the primary tumor site of rectal cancer is homogenous. Its assessment for therapeutic decisions is feasible in pre-therapeutic biopsies as well as in post-therapeutic resected specimens. The amount of viable tumor cells seems to be an important determinant for assay sensitivity and should thus be considered for selection of the analytical method.
| S-EPMC4827807 | biostudies-literature
Project description:We determined prognostic impact of KRAS, BRAF, PIK3CA and TP53 mutation status and mutation heterogeneity among 164 colorectal cancer (CRC) patients undergoing liver resections for metastatic disease. Mutation status was determined by Sanger sequencing of a total of 422 metastatic deposits. In univariate analysis, KRAS (33.5%), BRAF (6.1%) and PIK3CA (13.4%) mutations each predicted reduced median time to relapse (TTR) (7 vs. 22, 3 vs. 16 and 4 vs. 17 months; p < 0.001, 0.002 and 0.023, respectively). KRAS and BRAF mutations also predicted a reduced median disease-specific survival (DSS) (29 vs. 51 and 16 vs. 49 months; p <0.001 and 0.008, respectively). No effect of TP53 (60.4%) mutation status was observed. Postoperative, but not preoperative chemotherapy improved both TTR and DSS (p < 0.001 for both) with no interaction with gene mutation status. Among 94 patients harboring two or more metastatic deposits, 13 revealed mutation heterogeneity across metastatic deposits for at least one gene. Mutation heterogeneity predicted reduced median DSS compared to homogeneous mutations (18 vs. 37 months; p = 0.011 for all genes; 16 vs. 26 months; p < 0.001 analyzing BRAF or KRAS mutations separately). In multivariate analyses, KRAS or BRAF mutations consistently predicted poor TRR and DSS. Mutation heterogeneity robustly predicted DSS but not TTR, while postoperative chemotherapy improved both TTR and DSS. Our findings indicate that BRAF and KRAS mutations as well as mutation heterogeneity predict poor outcome in CRC patients subsequent to liver resections and might help guide treatment decisions.
| S-EPMC5071774 | biostudies-literature
Project description:KRAS and TP53 mutations are the two most common driver mutations in patients with lung adenocarcinoma (LUAD), and they appear to reduce latency and increase metastatic proclivity when a KRAS and TP53 co-mutation (KRAS/TP53-mut) occurs. However, the molecular mechanism involved is unclear. N6-methyladenosine (m6A), the most abundant RNA modification in mammal mRNAs, plays a critical role in tumorigenesis. Here, we used genomic and transcriptomic data and found that only LUAD patients with KRAS/TP53-mut, but not an individual mutation, appeared to exhibit poor overall survival when compared with patients without KRAS and TP53 mutation (wildtype). Subsequently, we analyzed the differential expression of the 15-m6A-related genes in LUAD with different mutations and found that YTHDF1 was the most upregulated in KRAS/TP53-mut patients and associated with their adverse prognosis. Bioinformatics and experimental evidence indicated that elevated YTHDF1 functionally promoted the translation of cyclin B1 mRNA in an m6A-dependent manner, thereby facilitating the tumor proliferation and poor prognosis of LUAD with KRAS/TP53-mut. Furthermore, the concurrent increase in YTHDF1 and cyclin B1 was confirmed by immunohistochemistry staining in patients with co-occurring KRAS/TP53 mutations. YTHDF1 was correlated with an unfavorable clinical stage and tumor size. Collectively, we identified and confirmed a novel "YTHDF1-m6A-cyclin B1 translation" axis as an essential molecular pathway for the prognosis of KRAS/TP53-mut LUAD.
| S-EPMC8305181 | biostudies-literature
Project description:BackgroundAlthough the molecular features of pancreatic ductal adenocarcinoma (PDAC) have been well described, the impact of detailed gene mutation subtypes on disease progression remained unclear. This study aimed to evaluate the impact of different TP53 mutation subtypes on clinical characteristics and outcomes of patients with PDAC.MethodsWe included 639 patients treated with PDAC in Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine between Jan 2019 and Jun 2021. The genomic alterations of PDAC were analyzed, and the association of TP53 mutation subtypes and other core gene pathway alterations with patients' clinical characteristics were evaluated by Chi-squared test, Kaplan-Meier method and Cox regression model.ResultsTP53 missense mutation was significantly associated with poor differentiation in KRASmut PDAC (50.7% vs. 36.1%, P = 0.001). In small-sized (≤ 2 cm) KRASmut tumors, significantly higher LNs involvement (54.8% vs. 23.5%, P = 0.010) and distal metastic rate (20.5% vs. 2.9%, P = 0.030) were observed in those with TP53 missense mutation instead of truncating mutation. Compared with TP53 truncating mutation, missense mutation was significantly associated with reduced DFS (6.6 [5.6-7.6] vs. 9.2 [5.2-13.3] months, HR 0.368 [0.200-0.677], P = 0.005) and OS (9.6 [8.0-11.1] vs. 18.3 [6.7-30.0] months, HR 0.457 [0.248-0.842], P = 0.012) in patients who failed to receive chemotherapy, while higher OS (24.2 [20.8-27.7] vs. 23.8 [19.0-28.5] months, HR 1.461 [1.005-2.124], P = 0.047) was observed in TP53missense cases after chemotherapy.ConclusionsTP53 missense mutation was associated with poor tumor differentiation, and revealed gain-of-function properties in small-sized KRAS transformed PDAC. Nonetheless, it was not associated with insensitivity to chemotherapy, highlighting the neoadjuvant therapy before surgery as the potential optimized strategy for the treatment of a subset of patients.
| S-EPMC10691048 | biostudies-literature
Project description:ObjectivesThis study assessed the preoperative prediction of TP53 status based on multiparametric magnetic resonance imaging (mpMRI) radiomics extracted from two-dimensional (2D) and 3D images.Methods57 patients with pancreatic cancer who underwent preoperative MRI were included. The diagnosis and TP53 gene test were based on resections. Of the 57 patients included 37 mutated TP53 genes and the remaining 20 had wild-type TP53 genes. Two radiologists performed manual tumour segmentation on seven different MRI image acquisition sequences per patient, including multi-phase [pre-contrast, late arterial phase (ap), portal venous phase, and delayed phase] dynamic contrast enhanced (DCE) T1-weighted imaging, T2-weighted imaging (T2WI), Diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC). PyRadiomics-package was used to generate 558 two-dimensional (2D) and 994 three-dimensional (3D) image features. Models were constructed by support vector machine (SVM) for differentiating TP53 status and DX score method were used for feature selection. The evaluation of the model performance included area under the curve (AUC), accuracy, calibration curves, and decision curve analysis.ResultsThe 3D ADC-ap-DWI-T2WI model with 11 selected features yielded the best performance for differentiating TP53 status, with accuracy = 0.91 and AUC = 0.96. The model showed the good calibration. The decision curve analysis indicated that the radiomics model had clinical utility.ConclusionsA non-invasive and quantitative mpMRI-based radiomics model can accurately predict TP53 mutation status in pancreatic cancer patients and contribute to the precision treatment.
| S-EPMC8165316 | biostudies-literature
Project description:BackgroundCell-free DNA (cfDNA) has arisen as an alternative target for evaluating somatic mutations in cancer. KRAS mutation status is critical for targeted therapy in colorectal adenocarcinoma (CRAC). We evaluated KRASG12/G13 mutations in cfDNA extracted from serum and compared the results with KRASG12/G13 mutations detected in tissue samples. We assessed the clinical significance of KRASG12/G13 mutation in serum in regard to recurrence and metastasis of CRAC.MethodsA total of 146 CRAC patients were enrolled, and KRASG12/G13 mutations were evaluated in 146 pairs of serum and tissue samples. In addition, 35 pairs of primary and metastatic CRAC tissue samples were evaluated for KRASG12/G13 mutational status.ResultsDetection of KRASG12/13 mutation from serum and tissue had a 55% concordance rate, and serum detection had a sensitivity of 39.8%. Detection of the KRASG12/13 mutation yielded a 14% discordance rate between primary and metastatic tissue. CRAC patients with mutant KRASG12/13 mutation in serum but wild-type KRASG12/13 in tissue had concurrent KRASG12/13-mutant metastatic tumors, indicating spatial genetic heterogeneity. Changes in serum KRASG12/G13 mutation status during postoperative follow-up were associated with recurrence. Conclusion: Although serum detection of the KRASG12/13 mutation cannot substitute for detection in tissue, serum testing can support the interpretation of a CRAC patient's status in regard to concurrent metastasis. Dynamic changes in serum KRASG12/13 mutation status during follow-up indicated that cfDNA from serum represents a potential source for monitoring recurrence in CRAC patients.
| S-EPMC7873888 | biostudies-literature