Genomic Signatures Reveal DNA Damage Response Deficiency in Brain Metastases of Colorectal Cancer
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ABSTRACT:
PROVIDER: EGAS00001003659 | EGA |
REPOSITORIES: EGA
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Project description:Brain metastasis (BM) of colorectal cancer (CRC) is rare but lethal and lacks effective therapies or a good understanding of its genomic landscapes. We conduct an analysis of whole-exome sequencing (WES, Illumina HiSeq 2500 sequencing platform) on 11 patient-matched BMs, primary CRC tumours, and adjacent normal tissues; and whole-genome sequencing (WGS, Illumina HiSeq X Ten platform) on 8 patient-matched BMs, primary CRC tumors, and adjacent normal tissues to uncover the whole-genome mutational landscape of colorectal cancer with brain metastasis.
| EGAD00001005030 | EGA
Project description:Basement membranes (BMs) are ubiquitous extracellular matrices whose composition remains elusive, limiting our understanding of BM regulation and function. By developing a bioinformatic and in vivo discovery pipeline, we define a network of over 220 human proteins localized to BMs. More than 100 BM-network genes associate with human phenotypes and by screening over 63,000 germline genomic sequences from families with rare disorders, we discovered novel predicted loss-of-function variants in MATN2. Biochemical analyses suggest that MATN2 interacts with many BM proteins, and we found that depletion of MATN2 affected levels of core BM components in human podocyte-derived extracellular matrix.
2022-05-31 | PXD029266 | Pride
Project description:We performed RNA-Seq on primary colorectal cancer (CRC) tissues and brain metastatic tissues from two CRC patients. Differential expression analysis was conducted to find genes associated with brain metastasis.
2019-06-06 | GSE132226 | GEO
Project description:Purpose: To identify the aberrant long non-coding RNA (lncRNA) and explore the predictive value of lncRNA on the risk of brain metastases (BMs) for patients with limited-stage small cell lung cancer (SCLC). Patients and Methods: We executed an array of lncRNA and mRNA chip assays on peripheral blood mononuclear cells of SCLC patients with BM comparing to others without BMs to identify the lncRNAs relating to BMs. Then validation was conducted in clinical data to confirm the relationship of lncRNAs and BMs furtherly. We estimated the cumulative incidence of BMs using the Kaplan-Meier method and differences between the groups were analyzed using the log-rank test. Results: The expression of 67 lncRNAs (27 up, 40 down) and 47 mRNAs (20 up, 27 down) were different significantly in BM groups comparing to the group without BMs (fold change ≥ 2.0, p value ≤0.05) which were found by lncRNA and mRNA chip assays initially. Four lncRNAs were verified by qRT-PCR to confirm the accuracy of the microarray data and then the results of 11 pairs of patients (11 patients with BMs, while 11 patients without BMs) showed that low expression of LncRNA XR_429159.1 was the high-risk factor of BM. Further clinical data showed that the BM incidence of 25 patients with low level LncRNA XR_429159.1 was 31% at 1-year, and that was 14.3% in the 18 patients with high level LncRNA XR_429159.1, p = 0.035. Conclusion: Our present study identified that low expression of lncRNA XR_429159.1 was the high-risk factor of BM in patients with limited-stage SCLC.
2021-04-16 | GSE161968 | GEO
Project description:Colorectal cancer (CRC) is currently the fourth leading etiology of brain metastasis (BM). Yet, mechanisms supporting the formation of CRC BM are mostly unknown. In order to identify drivers that lead to tropism and adaptation of CRC cells to the brain environment, we analyzed an extensive genomic database, consisting of over 36,000 human CRC primary and metastasis samples. Several genomic alterations specific for BM were noted, among them increased prevalence of insulin receptor substrate 2 (IRS2) amplification, observed in 7.6% of BM, compared to only 2.9% of primary tumors or other metastatic sites (p<7E-05). This observation was validated by Immunohistochemistry studies of human clinical samples, showing increased expression of IRS2 protein in BM. IRS2 is a cytoplasmic adaptor mediating effects of insulin and IGF-1 receptors and is involved in more aggressive behavior of different cancer types. In order to study the ability of IRS2 to promote growth of CRC cells under brain microenvironment conditions, we employed an in vitro system consisting of cultured human astrocytes or their conditioned media. Indeed, IRS2-overexpressed CRC cells survived better and formed larger 3D spheres when grown in brain-mimicking conditions, while IRS2-silenced CRC cells showed a mirror image. Similarly, In vivo studies, using intracranial CRC BM mouse model, demonstrated that IRS2-overexpressed cells generated larger brain lesions, while silencing IRS2 dramatically decreased tumor outgrowth and extended survival. Transcriptomic analysis revealed enrichment of oxidative phosphorylation (OXPHOS) and Wnt/β-catenin pathways by IRS2. Indeed, IRS2-expressing cells showed increased mitochondrial activity and glycolysis-independent viability. Furthermore, IRS2-expressing cells had increased β-catenin transcriptional activity, and either β-catenin inhibition or IRS2 inhibition in IRS2-expressing cells decreased their viability, β-catenin transcriptional activity, and mitochondrial activity. These data suggest involvement of IRS2 in modulating OXPHOS through β-catenin. Exploiting this mechanism as a potential vulnerability allowed us to develop novel treatment strategies against CRC BM. NT219 is a novel IRS1/2 inhibitor already being tested in clinical trials. Treatment of mice harboring CRC BM with NT219 and 5-flourouracil reduced tumor growth and prolonged mice survival. These data reveal, for the first time, the unique genomic profile of CRC BM and imply the IRS2 role in promoting CRC BM. These effects may be mediated, at least in part, by modulation of the β-catenin and OXPHOS pathway. These findings may pave the way for clinical trials evaluation this novel IRS2-based strategy for the treatment of CRC BM.
2022-05-16 | GSE203017 | GEO
Project description:This study aims to find the specific lncRNA molecule relating BMs from LADC in situ tumor to BM tumor tissue using gene chip technology and, combined with biological information database, through the competitive endogenous RNA (ceRNA) mechanism for microRNA (miRNA) related to specific lncRNA, to verify the possible target genes and therefore to explore the role and mechanism of specific lncRNA in BMs from LADC. By detecting the gene expression profiles of lncRNA and mRNA in cancer tissues of five cases of LADC and the paired paracancerous tissue samples, it was found that there were a large number of differentially expressed lncRNAs and mRNAs in LADC tissues and paracancerous tissues. By detecting the gene expression profiles of lncRNA and mRNA in three cases of BMs from LADC and matched paracancerous tissues, it was found that there were significant differences in the expression of lncRNAs and mRNAs between BM tumors of LADC and paracancerous tissues. These findings will provide a scientific basis for the early diagnosis and targeted therapy of BMs from LADC for application in further studies. Differential expression of lncRNAs and mRNAs in cancer tissues of three cases of BMs from LADC and the paired paracancerous tissue samples, it was found that there were a large number of differentially expressed lncRNAs and mRNAs in BMs tissues and paracancerous tissues.
2020-03-06 | GSE146460 | GEO
Project description:This study aims to find the specific lncRNA molecule relating BMs from LADC in situ tumor to BM tumor tissue using gene chip technology and, combined with biological information database, through the competitive endogenous RNA (ceRNA) mechanism for microRNA (miRNA) related to specific lncRNA, to verify the possible target genes and therefore to explore the role and mechanism of specific lncRNA in BMs from LADC. By detecting the gene expression profiles of lncRNA and mRNA in cancer tissues of five cases of LADC and the paired paracancerous tissue samples, it was found that there were a large number of differentially expressed lncRNAs and mRNAs in LADC tissues and paracancerous tissues. By detecting the gene expression profiles of lncRNA and mRNA in three cases of BMs from LADC and matched paracancerous tissues, it was found that there were significant differences in the expression of lncRNAs and mRNAs between BM tumors of LADC and paracancerous tissues. These findings will provide a scientific basis for the early diagnosis and targeted therapy of BMs from LADC for application in further studies. Differential expression of lncRNAs and mRNAs in cancer tissues of five cases of LADC and the paired paracancerous tissue samples, it was found that there were a large number of differentially expressed lncRNAs and mRNAs in LADC tissues and paracancerous tissues.
2020-03-06 | GSE146459 | GEO
Project description:Brain metastases (BM) of colorectal cancer (CRC) are rare but lethal, and an understanding of their genomic landscape is lacking. We conduct an analysis of whole-exome sequencing (WES) and whole-genome sequencing (WGS) data on 19 trios of patient-matched BMs, primary CRC tumors, and adjacent normal tissue. Compared with primary CRC, BM exhibits elevated mutational signatures of homologous recombination deficiency (HRD) and mismatch repair deficiency (MMRD). Further analysis reveals two DNA damage response (DDR) signatures could emerge early and are enhanced in BM tissues but are eliminated eventually in matched primary CRC tissues. BM-specific mutations in DDR genes and elevated microsatellite instability (MSI) levels support the importance of DDR in the brain metastasis of CRC. We also identify BM-related genes (e.g., SCN7A, SCN5A, SCN2A, IKZF1, and PDZRN4) that carry frequent BM-specific mutations. These results provide a better understanding of the BM mutational landscape and insights into treatment.
| S-EPMC6639368 | biostudies-literature
Project description:The bone marrow (BM) niche comprised of BM endothelial cells (BMECs) and LepR+ mesenchymal stromal cells (MSCs), plays a critical role in preserving the fitness of hematopoietic stem cells (HSCs). Aging is associated with defects in the BM niche that impair their ability to support HSC activity. However, mechanisms underlying age-related defects in the BM niche remain poorly understood. In this study, we identify BM niche derived Netrin-1 (NTN1) as a critical regulator of BM niche cell fitness during aging. Conditional deletion of NTN-1 specifically within BM MSCs or BMECs of young mice resulted in premature aging phenotypes within the BM niche including increased vascular leakiness, hypoxia, DNA damage and adiposity. On the other hand, supplementation of aged mice with NTN1 resulted in restoration of these hallmark niche defects and a rejuvenation of HSC activity. Mechanistically, we identify NTN1 as a critical regulator of DNA Damage Response (DDR) within BM niche cells and HSCs. In this experiment, RNA Seq analysis was performed on BM MSCs derived from young (3 month old) and aged (18 month old) mice to characterize transcriptional alterations within BM MSCs during aging.
2023-04-14 | GSE227144 | GEO
Project description:The bone marrow (BM) niche comprised of BM endothelial cells (BMECs) and LepR+ mesenchymal stromal cells (MSCs), plays a critical role in preserving the fitness of hematopoietic stem cells (HSCs). Aging is associated with defects in the BM niche that impair their ability to support HSC activity. However, mechanisms underlying age-related defects in the BM niche remain poorly understood. In this study, we identify BM niche derived Netrin-1 (NTN1) as a critical regulator of BM niche cell fitness during aging. Conditional deletion of NTN-1 specifically within BM MSCs or BMECs of young mice resulted in premature aging phenotypes within the BM niche including increased vascular leakiness, hypoxia, DNA damage and adiposity. On the other hand, supplementation of aged mice with NTN1 resulted in restoration of these hallmark niche defects and a rejuvenation of HSC activity. Mechanistically, we identify NTN1 as a critical regulator of DNA Damage Response (DDR) within BM niche cells and HSCs. In this experiment, RNA Seq analysis was performed on BM MSCs and BMECs following conditional deletion of NTN1 within BMECs or MSCs to characterize transcriptional alterations within BM niche cells resulting from a deficiency of niche derived NTN1.
2023-04-14 | GSE227143 | GEO