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Naproxen Chemoprevention Promotes Immune Activation In Lynch Syndrome Colorectal Mucosa

ABSTRACT: Naproxen Chemoprevention Promotes Immune Activation In Lynch Syndrome Colorectal Mucosa

PROVIDER: PRJNA603524 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10980700_1.fastq.gz	Fastqsanger.gz
	SRR10980700_2.fastq.gz	Fastqsanger.gz
	SRR10980701_1.fastq.gz	Fastqsanger.gz
	SRR10980701_2.fastq.gz	Fastqsanger.gz
	SRR10980702_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Naproxen Chemoprevention Promotes Immune Activation In Lynch Syndrome Colorectal Mucosa

Project description:Lynch syndrome (LS) patients are at markedly increased risk for colorectal cancer. It is being increasingly recognized that the immune system plays an essential role in LS tumor development. Therefore, immune interception strategies are emerging as a novel way to prevent cancer in LS. This phase Ib, placebo-controlled, randomized clinical trial and a co-clinical trial using a LS mouse model and patient-derived organoids aims to evaluate the safety and tolerability as well as to discover novel molecular pathways involved in the activity of Naproxen as chemoprevention in LS patients.

2020-06-25 | GSE144381 | GEO

Expression of immune-related genes in the normal colorectal mucosa and colorectal carcinoma samples from Lynch syndrome individuals

Project description:Colorectal carcinomas arising in the context of Lynch syndrome, the most common inherited cancer syndrome, typically show deficiency of the DNA MMR (mismatch repair) system. Lack of functional MMR leads to accumulation of frameshift mutations at micosatellites (microsatellite instability, MSI). High load of highly immunogenic tumor-specific frameshift neoantigens results in strong immune response against Lynch syndrome MSI cancers. Previous studies have shown systemic immune responses against frameshift neoantigens in Lynch syndrome carriers long before tumor manifestation. In the present study, we analyzed the immune profile of normal colorectal mucosa in Lynch syndrome carriers without current or previous cancer history and in Lynch syndrome colorectal cancer patients, as well as of Lynch syndrome colorectal carcinomas. The unsupervised cluster analysis of gene expression data revealed a sharp differentiation between normal mucosa from Lynch syndrome individuals with and without manifest cancer as well as between normal mucosa in general and Lynch syndrome cancer tissue. Deconvolution analysis for predicting the prevalence of immune cell population among the three groups revealed 10 out of 14 investigated populations to be significantly different between the three tissue types (FDR=10%). In contrast to normal mucosa samples, tumor tissue showed overrepresentation of immune-suppressive cell populations, such as regulatory T cells and neutrophils. Taken together with the quantitative T cell density analysis on the basis of immunohistochemical T cell stainings, our data show strong immune infiltration of the normal colorectal mucosa in Lynch syndrome individuals even in the absence of a manifest cancer.

2022-03-14 | GSE178516 | GEO

Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa.

Project description:ObjectivePatients with Lynch syndrome (LS) are at markedly increased risk for colorectal cancer. It is being increasingly recognised that the immune system plays an essential role in LS tumour development, thus making an ideal target for cancer prevention. Our objective was to evaluate the safety, assess the activity and discover novel molecular pathways involved in the activity of naproxen as primary and secondary chemoprevention in patients with LS.DesignWe conducted a Phase Ib, placebo-controlled, randomised clinical trial of two dose levels of naproxen sodium (440 and 220 mg) administered daily for 6 months to 80 participants with LS, and a co-clinical trial using a genetically engineered mouse model of LS and patient-derived organoids (PDOs).ResultsOverall, the total number of adverse events was not different across treatment arms with excellent tolerance of the intervention. The level of prostaglandin E2 in the colorectal mucosa was significantly decreased after treatment with naproxen when compared with placebo. Naproxen activated different resident immune cell types without any increase in lymphoid cellularity, and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Naproxen demonstrated robust chemopreventive activity in a mouse co-clinical trial and gene expression profiles induced by naproxen in humans showed perfect discrimination of mice specimens with LS and PDOs treated with naproxen and control.ConclusionsNaproxen is a promising strategy for immune interception in LS. We have discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity.Trial registration numbergov Identifier: NCT02052908.

| S-EPMC7790993 | biostudies-literature

Naproxen in Preventing DNA Mismatch Repair Deficient Colorectal Cancer in Patients With Lynch Syndrome

Project description:This randomized phase Ib trial studies the side effects and best dose of naproxen in preventing deoxyribonucleic acid (DNA) mismatch repair deficient colorectal cancer in patients with Lynch syndrome. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of naproxen may keep cancer from forming in patients with Lynch syndrome.

| 2160055 | ecrin-mdr-crc

Genomic profiling of colorectal cancer from patients with Lynch syndrome and Familial colorectal cancer type X with comparison to sporadic microsatelite stable and instable colorectal cancer

Project description:Lynch syndrome and Familial colorectal cancer type X (FCCTX) are clinically diagnosed using the same criteria, but genomic differences exist between these two groups and the genomic profiles share similarities with their sporadic counterparts, mismatch repair (MMR) deficient and proficient tumors, respectively. Array-based comparative genomic hybridization was performed on 91 tumors, comprising 23 Lynch syndrome (AH), 23 FCCTX (AA), 23 sporadic MMR deficient (AM) and 22 sporadic MMR proficient tumors, in order to identify differences between Lynch syndrome and FCCTX.

2012-06-01 | E-GEOD-38405 | biostudies-arrayexpress

Naproxen chemoprevention induces proliferation of cytotoxic lymphocytes in Lynch Syndrome colorectal mucosa.

Project description:BackgroundRecent clinical trial data from Lynch Syndrome (LS) carriers demonstrated that naproxen administered for 6-months is a safe primary chemoprevention that promotes activation of different resident immune cell types without increasing lymphoid cellularity. While intriguing, the precise immune cell types enriched by naproxen remained unanswered. Here, we have utilized cutting-edge technology to elucidate the immune cell types activated by naproxen in mucosal tissue of LS patients.MethodsNormal colorectal mucosa samples (pre- and post-treatment) from a subset of patients enrolled in the randomized and placebo-controlled 'Naproxen Study' were obtained and subjected to a tissue microarray for image mass cytometry (IMC) analysis. IMC data was processed using tissue segmentation and functional markers to ascertain cell type abundance. Computational outputs were then used to quantitatively compare immune cell abundance in pre- and post-naproxen specimens.ResultsUsing data-driven exploration, unsupervised clustering identified four populations of immune cell types with statistically significant changes between treatment and control groups. These four populations collectively describe a unique cell population of proliferating lymphocytes within mucosal samples from LS patients exposed to naproxen.ConclusionsOur findings show that daily exposure of naproxen promotes T-cell proliferation in the colonic mucosa, which paves way for developing combination of immunoprevention strategies including naproxen for LS patients.

| S-EPMC10189148 | biostudies-literature

Expression of immune-related genes in the normal colorectal mucosa and colorectal carcinoma samples from Lynch syndrome individuals

Project description:Expression of immune-related genes in the normal colorectal mucosa and colorectal carcinoma samples from Lynch syndrome individuals

| PRJNA739468 | ENA

Genomic profiling of colorectal cancer from patients with Lynch syndrome and Familial colorectal cancer type X with comparison to sporadic microsatelite stable and instable colorectal cancer

2012-06-02 | GSE38405 | GEO

Lynch Syndrome Targeted Metagenome

Project description:Faecal Microbiota Characterization in Lynch Syndrome (LS) Patients With or Without Colorectal Neoplasia ( AAS-Lynch-Microbiote)

| PRJEB70919 | ENA

Identification and validation of miRNAs in colorectal cancer (CRC) in early age diagnosed patients without MMR defect

Project description:transcriptional profiling (miRNAs) of human biopsies of colorectal cancer tumors (Lynch Sindrome, Sporadic old, Sporadic young and normal mucosa)

2019-05-02 | GSE123040 | GEO

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