Pre-existing tumoral B cell infiltration and impaired genome maintenance correlate with response to chemoradiotherapy in locally advanced rectal cancer (LARC)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE150082 | GEO | 2020/08/24
REPOSITORIES: GEO
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Project description:Most patients with locally advanced rectal cancer (LARC) present incomplete pathological response (pIR) to neoadjuvant chemoradiotherapy (nCRT). Despite the efforts to predict treatment response using tumor-molecular features, as differentially expressed genes, no molecule has proved to be a strong biomarker. The tumor secretome analysis is a promising strategy for biomarkers identification, which can be assessed using transcriptomic data. Here, we performed transcriptomic-based secretome analysis to select potentially secreted proteins using an in silico approach. The tumor expression profile of 28 LARC biopsies carefully selected and collected before nCRT was compared with normal rectal tissues (NT). The expression profile showed no significant differences between cases with complete (pCR) and incomplete response to nCRT. Genes with increased expression (pCR = 106 and pIR = 357) were used for secretome analysis based on public databases (Vesiclepedia, Human Cancer Secretome Database and Plasma and Proteome Database). Seventeen potentially secreted candidates (pCR=1, pIR=13 and 3 in both groups) were further investigated in two independent datasets (TCGA and GSE68204) confirming their over-expression in LARC. The potential secreted biomarkers were also confirmed as associated with the nCRT response (GSE68204). These putative proteins are candidates to be assessed in liquid biopsies aiming a personalized treatment in LARC patients.
2019-07-01 | GSE123390 | GEO
Project description:To characterize potential biomarkers and underlying mechanisms that prompt pathological complete response (pCR) rate of neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC) patients.LARC patients from two hospitals were enrolled with pre-nCRT biopsy tissues examined by pressure cycling technology (PCT) combined with data-independent acquisition (DIA) mass spectrometry. Tumor regression grade (TRG) evaluation was performed with the surgical tissues after nCRT to estimate the efficacy of nCRT. Proteins up regulated in pCR patients were highlighted and immune infiltration analysis was carried out. The candidate biomarker FOSL2 (FOS Like 2, AP-1 Transcription Factor Subunit), was selected and verified its role in vitro and vivo. We then performed gene expression profiling analysis using data obtained from RNA-seq of 2 different cells with or without chemoradiotherapy.
2025-09-09 | GSE213009 | GEO
Project description:Locally advanced rectal cancer (LARC) patients have been treated with a pre-operative multimodal regimen based on 5-fluorouracil and radiotherapy (nCRT) followed by surgery. Patients that achieve pathological complete response (pCR) present better overall survival and lower rates of recurrence. Substantial evidence indicate that these patients could be spared of surgery, while near 70% of cases present incomplete response (pIR), varying from partial response to stable-disease/progression. Markers capable of distinguishing pIR from pCR have the potential to address alternative treatment strategies. Herein, we evaluated the ability of predicting response to nCRT by DNA methylation analysis in pre-treatment biopsies of LARC.
2021-06-08 | GSE132668 | GEO
Project description:Locally advanced rectal cancer (LARC) exhibits heterogeneous responses to neoadjuvant chemoradiotherapy (nCRT), patients resistant to nCRT failing to benefit from to nCRT. The aim of this pilot study is to identify proteins associated with LARC nCRT-resistance. This pilot study retrospectively enrolled 4 representative nCRT-resistant (stable disease/progressive disease) and 4 nCRT-sensitive (complete response/partial response) patients, of which a total of 15 formalin-fixed paraffin-embedded tumor tissues (before and after nCRT) were subjected to data-independent acquisition mass spectrometry for proteomic analysis. Spectronaut software was employed for protein identification and quantification. Principal component analysis (PCA) was used to visualize intergroup differences in detected proteins. Differently abundant proteins in resistant patients (fold change ≥ 1.2 or ≤ 0.83 compare to sensitive patients) were selected for analysis using hierarchical clustering, cluster of orthologous groups, subcellular location, gene ontology, and pathway enrichment assay. A total of 39052 peptides and 6006 proteins were identified. PCA showed PCA clear separation among four groups: pre-treatment sensitive (B_S), pre-treatment resistant (B_R), post-treatment sensitive (P_S), and post-treatment resistant (P_R). Intergroup comparisons revealed before nCRT, 133 proteins were upregulated in the resistant group compared to the sensitive group, mainly localized in cytoplasm (33.08%), secreted (24.81%), and nucleus (24.06%), with functions enriched in cell junctions and metabolic related pathways. Post nCRT, 290 proteins were upregulated in the resistant group compared to the sensitive group, mainly localized in the nucleus (36.55%) and cytoplasm (23.10%), with functions enriched in replication, transcription, translation, and metabolic pathways. This study characterized DAP signatures of LARC with nCRT resistance, specific DAPs in resistant tumor provide references for mechanistic studies on treatment resistance, could be potential biomarker for response and therapeutic targets after further validation in larger cohorts.
2025-10-17 | PXD069647 |
Project description:Pre-existing tumoral B cell infiltration and impaired genome maintenance correlate with response to chemoradiotherapy in locally advanced rectal cancer (LARC)
| PRJNA631046 | ENA
Project description:Locally Advanced Rectal cancer (LARC) is treated using neoadjuvant chemoradiotherapy (nCRT) followed by surgery. On average 15% of tumors at surgery will present a pathological complete response (pCR). Increasing pCR can be done at the cost of treatment intensification usually combining nCRT and chemotherapy which comes with higher toxicity. However, many LARC patients do not respond to the current neoadjuvant treatments while experiencing important treatment related side effects. Predicting pCR following nCRT opens the door to non-surgical management - the watch and wait strategy and avoid escalation as well as sparring non-responders from nCRT in patients not eligible for intensification. Using RNA expression data, several groups have defined predictive signatures, however, none have made it into clinical practice. A comprehensive differential expression analysis was conducted across six Gene Expression Omnibus (GEO) datasets, followed by integration with four microarray datasets for refinement. A machine learning approach was employed to identify a 186-gene signature predictive of response to nCRT, validated using cross-validation. Gene set enrichment analysis (GSEA) was performed to explore biological pathways associated with treatment response. Spatial transcriptomic profiling of pre-treatment biopsies further examined gene expression in tumor and stroma compartments and identified eight compartment-specific genes significantly associated with response, with tumor-associated genes showing greater predictive value than stroma-associated genes. This study identifies a novel 186-gene signature associated with nCRT response in LARC, with potential clinical utility in guiding personalized treatment. Further validation in larger cohorts and exploration of spatial biomarkers are needed to confirm its clinical relevance.
2025-09-25 | GSE279942 | GEO
Project description:Rectal cancer (RC) accounts for one-third of colorectal cancer (CRC), and 40% of these are locally advanced rectal cancer (LARC) at diagnosis. The use of neoadjuvant chemoradiotherapy (nCRT) significantly reduces the rate of local recurrence compared to adjuvant therapy or surgery alone. However, after nCRT, up to 40-60% of patients show a poor pathological response, while only about 20% achieve a pathological complete response. In this scenario, the identification of novel predictors of tumor response to nCRT are urgently needed to reduce LARC mortality, and to spare poorly responding patients from unnecessary treatments. Therefore, by combining gene and microRNA expression datasets with proteomic data from LARC patients, we developed an integrated network centered on seven hub-genes putatively involved in the response to nCRT. In an independent validation cohort of LARC patients, we confirmed the differential expression of NFKB1, TRAF6 and STAT3 depending on a response to nCRT. In addition, the functional enrichment analysis also revealed that these genes are strongly related to hallmarks of cancer and inflammation, whose dysfunction may causatively affect LARC patient’s response to nCRT. Furthermore, by constructing the transcription factor-module network, we hypothesized a protective role of POU2F3 gene, which could be used as a new drug target in LARC patients. Finally, we identified and in vitro tested entinostat, a histone deacetylase (HDAC) inhibitor, as a chemical compound that could be combined with classical therapeutic regimen in order to design more efficient therapeutic strategies in LARC.
2023-01-05 | PXD035408 | Pride
Project description:Long course radiotherapy plus neoadjuvant chemotherapy followed by resection total mesorecta excision has accepted widespread recognized in the treatment of locally advanced rectal cancer (LARC). Tislelizumab, an anti-PD1(programmed death 1) humanized IgG4 (Immunoglomin G4) monoclonal antibody, has been demonstrated with clinical activity and is approved for treating recurrent/refractory classical Hodgkin lymphoma and locally advanced/metastatic urothelial carcinoma in China.
The aim of This NCRT-PD-1-LARC trial is to evaluate the efficacy and safety of long course neoadjuvant chemoradiotherapy plus tislelizumab followed by total mesorecta excision for LARC. This NCRT-PD-1-LARC trial will be a prospective, multicenter and phase Ⅱ clinical trial designed to evaluate the safety and efficacy of LARC patients treated with long course neoadjuvant chemoradiotherapy plus tislelizumab followed by total mesorecta excision. It will consecutively enroll 50 stage II/III LARC patients (cT3N0M0 and cT1-3N1-2M0) with the tumor distal location ≤ 10cm from anal verge at 7 centers in China. The enrolled patients will receive long course radiotherapy (50 Gy/25 f, 2 Gy/f, 5 days/week) and three 21-day cycles capecitabine (1000 mg/m2, bid, po, day1-14) plus three 21-day cycles tislelizumab (200 mg, iv.gtt, day8), followed by total mesorecta excision 6-12 week after the end of radiotherapy. The primary efficacy endpoint will be the pathological complete response (pCR) rate, which is defined as absence of viable tumor cells in the primary tumor and lymph nodes.
| 2379428 | ecrin-mdr-crc
Project description:Introduction: Neoadjuvant chemoradiotherapy (nCRT) was the foundation treatment for locally advanced rectal cancer (LARC). The nCRT can improve the efficacy of immunotherapy on account of its in-situ vaccine effect. Objective: The aim is to identify stable and reliable transcriptome signatures to predict the efficacy of immune checkpoint blockade (ICB) in patients with LARC. Methods: Immunophenotyping was established by using xCell immune cell infiltration abundance and consistent clustering in GSE39582 and verified in several data sets. The effects of immunophenotyping, follicular regulatory T cells, tumor associated fibroblasts (CAF) and tertiary lymphoid structures (TLS) signatures on the efficacy of ICB were analyzed by using IMvigor210, GSE91061 and an independent Daping Hospital (DPH) cohort. Results: There are four stable and repeatable immune subtypes in rectal cancer, among which C1 is low immune infiltration type, C2 is high interstitial infiltration type, C3 is high immune infiltration type and C4 is ion channel type. C2 is mainly characterized by high infiltration CAF, C3 is characterized by high infiltration of cytotoxic T lymphocytes, high expression of PD-L1 and TLS. In rectal cancer patients receiving nCRT, immunophenotyping was not significantly associated with pathological remission rate, but immunophenotyping was an independent prognostic factor of RFS. In IMvigor210 patients treatment with atezolizumab, the pathological remission rates of C1, C2, C3 and C4 were 23.86%, 10.94%, 33.33% and 23.08% respectively (χ2 = 8.981, P = 0.029), which were 11.76%, 50.00%, 42.86% and 0.0% respectively in the GSE91061 patients treatment with nivolumab (Fisher's exact probability, P = 0.018). Both follicular regulatory T cells and CAF showed a further impact on the ICB therapeutic efficacy of C2 and C3 subtype. In addition, both GSE91404 and DPH cohorts showed that nCRT treatment induced a significant increase in the expression of TNFRSF9 and abundance of macrophages in C3 subtype. Conclusion: Our data suggest that there are four immune types of rectal cancer, which are related to the prognosis of patients. Among them, C3 and some C2 subtypes represents the patients who may benefit from ICB after nCRT treatment.
2022-09-17 | GSE213331 | GEO
Project description:Neoadjuvant chemoradiotherapy (CRT) followed by surgery is the standard treatment for locally advanced rectal cancer (LARC). However, there are no good predictive methods. This study investigated whether specific lncRNA expression is associated with response to CRT. Tissue biopsies were obtained from patients before CRT. LncRNA expression was analyzed using one-color microarrays technique comparing signatures between good respondersand poor responders, as measured by tumour regression grade (TRG).
2020-02-22 | GSE145666 | GEO