Comprehensive Characterization of Cachexia-Inducing Factors in Diffuse Large B-Cell Lymphoma Reveals a Molecular Subtype and a Prognosis-Related Signature

Abstract

BackgroundCachexia is defined as an involuntary decrease in body weight, which can increase the risk of death in cancer patients and reduce the quality of life. Cachexia-inducing factors (CIFs) have been reported in colorectal cancer and pancreatic adenocarcinoma, but their value in diffuse large B-cell lymphoma (DLBCL) requires further genetic research.MethodsWe used gene expression data from Gene Expression Omnibus to evaluate the expression landscape of 25 known CIFs in DLBCL patients and compared them with normal lymphoma tissues from two cohorts [GSE56315 (n = 88) and GSE12195 (n = 136)]. The mutational status of CIFs were also evaluated in The Cancer Genome Atlas database. Based on the expression profiles of 25 CIFs, a single exploratory dataset which was merged by the datasets of GSE10846 (n = 420) and GSE31312 (n = 498) were divided into two molecular subtypes by using the method of consensus clustering. Immune microenvironment between different subtypes were assessed via single-sample gene set enrichment analysis and the CIBERSORT algorithm. The treatment response of commonly used chemotherapeutic drugs was predicted and gene set variation analysis was utilized to reveal the divergence in activated pathways for distinct subtypes. A risk signature was derived by univariate Cox regression and LASSO regression in the merged dataset (n = 882), and two independent cohorts [GSE87371 (n = 221) and GSE32918 (n = 244)] were used for validation, respectively.ResultsClustering analysis with CIFs further divided the cases into two molecular subtypes (cluster A and cluster B) associated with distinct prognosis, immunological landscape, chemosensitivity, and biological process. A risk-prognostic signature based on CCL2, CSF2, IL15, IL17A, IL4, TGFA, and TNFSF10 for DLBCL was developed, and significant differences in overall survival analysis were found between the low- and high-risk groups in the training dataset and another two independent validation datasets. Multivariate regression showed that the risk signature was an independently prognostic factor in contrast to other clinical characteristics.ConclusionThis study demonstrated that CIFs further contribute to the observed heterogeneity of DLBCL, and molecular classification and a risk signature based on CIFs are both promising tools for prognostic stratification, which may provide important clues for precision medicine and tumor-targeted therapy.

Identification and Validation of the Pyroptosis-Related Molecular Subtypes of Lung Adenocarcinoma by Bioinformatics and Machine Learning

“…We applied integrated bioinformatics methods, including MCPcounter, xCell, quanTIseq, CIBERSORTx, single-sample gene set enrichment analysis (GSEA) to evaluate differences of immune status among different molecular subtypes ( Finotello et al, 2019 ; Cai et al, 2021 ; Yuan et al, 2021 ). Furthermore, the ‘‘pRRophetic’’ R package was used to predict the chemotherapy response of each sample based on Genomics of Drug Sensitivity in Cancer (GDSC) 3 , and the correlation between molecular subtypes and immune checkpoint genes was analyzed ( Geeleher et al, 2014 ; Kuang et al, 2021 ).…”

Identification of lactate regulation pattern on tumor immune infiltration, therapy response, and DNA methylation in diffuse large B-cell lymphoma

“…In this study, we embarked on a comprehensive analysis of histology-specific lactate-related gene expression data from DLBCL samples, and develop a novel prognostic gene signature. Compare with other four published models (13)(14)(15)(16), the clinical usefulness of our novel prognostic model was better. Our findings revealed a significant correlation between the prognostic lactate score and various key factors including patient outcomes, immune infiltration levels, and activation of cancer-related pathways in DLBCL.…”

Identification of PLA2G7 as a novel biomarker of diffuse large B cell lymphoma

“…The data generated in the present study further suggest that PLA2G7 expression may be associated with DLBCL tumor stromal and immune scores. Kua et al [ 31 , 32 ] reported that the CIBERSORT algorithm was used to analyze the DLBCL immune cell infiltration in the TME. As such, we explored the association between PLA2G7 expression and TIICs, revealing that patients expressing high levels of this gene also exhibited increased monocyte infiltration.…”