ABSTRACT
BACKGROUND: Colorectal cancer (CRC) is the leading cause of cancer deaths, and treatment, especially in the metastatic stage, is challenging. Immune checkpoint inhibitors (ICIs) have revolutionized CRC treatment, but response varies, emphasizing the need for effective biomarkers. This study explores SPEN mutations as potential biomarkers. METHODS: Using data from the Memorial Sloan Kettering Cancer Center (MSKCC) and The Cancer Genome Atlas (TCGA)-Colorectal Cancer, this research applied bioinformatics tools and statistical analysis to SPEN (Split Ends) mutant and wild-type CRC patients treated with ICIs. Focus areas included mutation rates, immune cell infiltration, and DNA damage response pathways. RESULTS: The SPEN mutation rate was found to be 13.8% (15/109 patients) in the MSKCC cohort and 6.65% (35/526 patients) in the TCGA cohort. Our findings indicate that CRC patients with SPEN mutations had a longer median overall survival (OS) than the wild-type group. These patients also had higher tumor mutational burden (TMB), microsatellite instability (MSI) scores, and programmed death-ligand 1 (PD-L1) expression. SPEN mutants also exhibited increased DNA damage response (DDR) pathway mutations and a greater presence of activated immune cells, like M1 macrophages and CD8+ T cells, while wild-type patients had more resting/suppressive immune cells. Furthermore, distinct mutation patterns, notably with TP53, indicated a unique molecular subtype in SPEN-mutated CRC. CONCLUSIONS: We conclude that SPEN mutations might improve ICI efficacy in CRC due to increased immunogenicity and an inflammatory tumor microenvironment. SPEN mutations could be predictive biomarkers for ICI responsiveness, underscoring their value in personalized therapy and highlighting the importance of genomic data in clinical decisions. This research lays the groundwork for future precision oncology studies.
ABSTRACT
Introduction: Hepatocellular carcinoma (HCC) is one of the most invasive cancers with a low 5-year survival rate. Pyroptosis, a specialized form of cell death, has shown its association with cancer progression. However, its role in the prognosis of HCC has not been fully understood. Methods: In our study, clinical information and mRNA expression for 1076 patients with HCC were obtained from the five public cohorts. Pyroptotic clusters were generated by unsupervised clustering based on 40 pyroptosis-related genes (PRGs) in the TCGA and ICGC cohort. A pyroptosis-related signature was constructed using least absolute shrinkage and selection operator (LASSO) regression according to differentially expressed genes (DEGs) of pyroptotic clusters. The signature was then tested in the validation cohorts (GES10142 and GSE14520) and subsequently validated in the CPTAC cohort (n=159) at both mRNA and protein levels. Response to sorafenib was explored in GSE109211. Results: Three clusters were identified based on the 40 PRGs in the TCGA cohort. A total of 24 genes were selected based on DEGs of the above three pyroptotic clusters to construct the pyroptotic risk score. Patients with the high-risk score showed shorter overall survival (OS) compared to those with the low-risk score in the training set (P<0.001; HR, 3.06; 95% CI, 2.22-4.24) and the test set (P=0.008; HR, 1.61; 95% CI, 1.13-2.28). The predictive ability of the risk score was further confirmed in the CPTAC cohort at both mRNAs (P<0.001; HR, 2.99; 95% CI, 1.67-5.36) and protein levels (P<0.001; HR, 2.97; 95% CI 1.66-5.31). The expression of the model genes was correlated with immune cell infiltration, angiogenesis-related genes, and sensitivity to antiangiogenic therapy (P<0.05). Discussion: In conclusion, we established a prognostic signature of 24 genes based on pyroptosis clusters for HCC patients, providing insight into the risk stratification of HCC.
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BACKGROUND: Metastasis of pancreatic cancer to the colon is rare and the features need to be further elucidated. Herein, we report a rare case of pancreatic cancer with simultaneous liver and colon metastases. CASE SUMMARY: A 48-year-old man with intrahepatic space-occupying lesions based on a computed tomography scan was admitted to our hospital for further treatment. Abdominal magnetic resonance imaging revealed a 6.4 cm × 4.2 cm mass in the tail of the pancreas and multiple low-density masses in the liver parenchyma. In addition, a mass of 2.2 cm × 1.6 cm with surface congestive erosions in the sigmoid colon was detected by colonoscopy. Histopathological examination of biopsies from both the liver and colon lesions revealed a moderately to poorly differentiated adenocarcinoma. Immunohistochemical staining of the colon tumor was positive for cytokeratin (CK) 7 and CK, but negative for colorectal adenocarcinoma-related markers CK 20, CDX2, and SATB2, thus indicating that the metastasis originated from the pancreas. Next-generation sequencing for genomic profiling of the liver and colon metastases both found mutations in KRAS (p.G12D) and TP53 (c.376-1delG), with microsatellite stable and low tumor mutational burden without actionable or cancer-predisposing gene mutations detected. The patient was subsequently treated with 12 cycles of FOLFIRINOX which led to a sustainable response, followed by ongoing maintenance treatment with irinotecan plus fluorouracil. CONCLUSION: For this rare case, careful evaluation of histopathological and immunohistochemical staining results are required. The genomic profiling of colon lesions was revealed for the first time, and FOLFIRINOX showed good treatment efficacy in this patient.
ABSTRACT
Dysregulated intratumoral immune reactions are shaped by complex networks of cytokines, which coordinate with tumor cells to determine tumor progression and aggressiveness. In lung adenocarcinoma (LUAD), the role of intratumoral cytokine gene expression for stratifying prognosis has not been systematically investigated. Using high-dimensional datasets of cancer specimens from clinical patients in The Cancer Genome Atlas (TCGA), we explored the transcript abundance and prognostic impact of 27 clinically evaluable cytokines in 500 LUAD tumor samples according to clinicopathological features and two common driver mutations (EGFR and KRAS). We found that reduced expression of IL12B presented as the single prognostic factor for both poor overall survival (OS) and recurrence free survival (RFS) with high hazard ratios. Moreover, we identified that elevated expression of IL6, CXCL8 and CSF3 were additional independent predictors of poor RFS in LUAD patients. Their prognostic significance was further strengthened by their ability to stratify within clinicopathological factors. Notably, we prioritized high risk cytokines for patients with or without mutations in EGFR and KRAS. Our results provide integrative associations of cytokine gene expression with patient survival and tumor recurrence and demonstrate the necessity and validity of relating clinicopathological and genetic disposition factors for precise and personalized disease prognosis.
