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: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: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: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:Locally advanced rectal cancer (LARC) remains a medical challenge. Reliable biomarkers to predict which patients will significantly respond to neoadjuvant chemoradiotherapy (nCRT) have not been identified. We evaluated baseline genomic and transcriptomic features to detect differences that may help predict response to nCRT. Eligible LARC patients received nCRT (3D-LCRT 50.4 Gy plus capecitabine 825 mg/m2/bid), preceded by three cycles of CAPOX in high systemic-relapse risk tumors, and subsequent surgery. Frozen tumor biopsies at diagnosis were sequenced using a colorectal cancer panel. Transcriptomic data was used for pathway and cell deconvolution inferential algorithms, coupled with immunohistochemical validation. Clinical and molecular data were analyzed according to nCRT outcome. Pathways related to DNA repair and proliferation (p < 0.005), and co-occurrence of RAS and TP53 mutations (p = 0.001) were associated with poor response. Enrichment of expression signatures related to enhanced immune response, particularly B cells and interferon signaling (p < 0.005), was detected in good responders. Immunohistochemical analysis of CD20+ cells validated the association of good response with B cell infiltration (p = 0.047). Findings indicate that the presence of B cells is associated with successful tumor regression following nCRT in LARC. The prevalence of simultaneous RAS and TP53 mutations along with a proficient DNA repair system that may counteract chemoradio-induced DNA damage was associated with poor response.
| S-EPMC7464257 | biostudies-literature
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:Background: Neoadjuvant chemoradiotherapy (NCRT) is the treatment of choice in advanced rectal cancer, even though there are many patients who will not benefit from it. There are still no effective methods for predicting which patients will respond or not. The present study aimed to define the genomic profile of rectal tumors and to identify alterations that are predictive of response in order to optimize therapeutic strategies. Methods: Forty-eight candidates for NCRT were recruited and their pretherapy biopsies analyzed by array Comparative Genomic Hybridization (aCGH). Pathologic response was evaluated by tumor regression grade (TRG).Results: Both Smoothing and Hidden Markov Model (HMM) approaches identified similar alterations, with a prevalence of DNA gains. Non responsive patients had a different alteration profile from responsive ones, with a higher number of genome changes mainly located on 2q21, 7q21, 7q36, 13q12, 13q32-34, 16p13, 17p12 chromosomal regions. Conclusion: This exploratory study suggests that an in depth characterization of chromosomal alterations by aCGH would provide useful predictive information about response to NCRT and help to optimize therapy in rectal cancer patients.
2011-11-17 | GSE25885 | GEO
Project description:Background: Neoadjuvant chemoradiotherapy (NCRT) is the treatment of choice in advanced rectal cancer, even though there are many patients who will not benefit from it. There are still no effective methods for predicting which patients will respond or not. The present study aimed to define the genomic profile of rectal tumors and to identify alterations that are predictive of response in order to optimize therapeutic strategies. Methods: Forty-eight candidates for NCRT were recruited and their pretherapy biopsies analyzed by array Comparative Genomic Hybridization (aCGH). Pathologic response was evaluated by tumor regression grade (TRG).Results: Both Smoothing and Hidden Markov Model (HMM) approaches identified similar alterations, with a prevalence of DNA gains. Non responsive patients had a different alteration profile from responsive ones, with a higher number of genome changes mainly located on 2q21, 7q21, 7q36, 13q12, 13q32-34, 16p13, 17p12 chromosomal regions. Conclusion: This exploratory study suggests that an in depth characterization of chromosomal alterations by aCGH would provide useful predictive information about response to NCRT and help to optimize therapy in rectal cancer patients. 48 samples included in the study were analyzed on whole genome BAC arrays with the aim to characterize genomic alterations and correlate them with the tumor response to therapy. The case series was composed by 15%,81% and 4% of uT2, uT3 and uT4 tumors, respectively. At the diagnosis 56% of patients had uN0 tumors and 44% uN+. 30%,13%, 23% and 34% of patients reached/mantained respectively ypT0, ypT1, ypT2 and ypT3. With regard to response to NCRT, according to TRG criteria proposed by Dworak, two group were defined: non responders (TRG0-2= 56%) and responders (TRG3-4=44%). Clinical and pathological parameters: uT: pre-therapy stage determined by ultrasounds techniques uN: pre-therapy lymph node status determined by ultrasounds techniques ypT: pathologic stage after a neoadjuvant treatment ypN: pathologic lymph node status after a neoadjuvant treatment
2011-11-17 | E-GEOD-25885 | biostudies-arrayexpress
Project description:A total of 156 LARC patients (training cohort n = 60; validation cohort n = 96) were included in the study who underwent surgical resection post PCRT. By using univariate and multivariate logistic regression, we identified a 9-gene signature that differentiated between responders and non-responders. ; The novel 9-gene signature is robust in predicting response to PCRT in LARC patients. Tailored treatment approaches in good and poor responders to PCRT may improve the oncologic outcomes of patients with LARC.
2019-10-23 | GSE139255 | GEO
Project description:Neoadjuvant chemoradiation therapy (CRT) is a widely used preoperative treatment strategy for locally advanced rectal cancer (LARC). However, a few studies have evaluated the molecular changes caused by neoadjuvant CRT in these cancer tissues. Here, we aimed to investigate changes in immunotherapy-related immunogenic effects in response to preoperative CRT in LARC. We analyzed 60 pairs of human LARC tissues before and after irradiation from three independent LARC cohorts, including a LARC patient RNA sequencing (RNA-seq) dataset from our cohort and GSE15781 and GSE94104 datasets. Gene ontology analysis showed that preoperative CRT significantly enriched the immune response in LARC tissues. Moreover, gene set enrichment analysis revealed six significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways associated with downregulated genes, including mismatch repair (MMR) genes, in LARC tissues after CRT in all three cohorts. Radiation also induced apoptosis and downregulated various MMR system-related genes in three colorectal cancer cells. One patient with LARC showed a change in microsatellite instability (MSI) status after CRT, as demonstrated by the loss of MMR protein and PCR for MSI. Moreover, CRT significantly increased tumor mutational burden in LARC tissues. CIBERSORT analysis revealed that the proportions of M2 macrophages and CD8 T cells were significantly increased after CRT in both the RNA-seq dataset and GSE94104. Notably, preoperative CRT increased various immune biomarker scores, such as the interferon-γ signature, the cytolytic activity and the immune signature. Taken together, our findings demonstrated that neoadjuvant CRT modulated the immune-related characteristics of LARC, suggesting that neoadjuvant CRT may enhance the responsiveness of LARC to immunotherapy.
2023-05-31 | GSE233517 | GEO