P53 mutation, deprivation and poor prognosis in primary breast cancer.
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ABSTRACT:
SUBMITTER: Baker L
PROVIDER: S-EPMC2837559 | biostudies-other | 2010 Feb
REPOSITORIES: biostudies-other
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Project description:Breast cancer is the second most common malignancy in women and considered as a severe health burden. PEG3 mutations have been observed in several cancers. However, the associations of PEG3 mutation with tumor mutation burden (TMB) and prognosis in breast cancer have not been investigated. In our study, the somatic mutation data of 986 breast cancer patients from The Cancer Genome Atlas (TCGA) were analyzed. It showed that PEG3 had a relatively high mutation rate (2%). After calculated the TMB in PEG3 mutant and PEG3 wild-type groups, we found the TMB value was significantly higher in PEG3 mutant samples than that in PEG3 wild-type samples (P = 5.6e-07), which was independent of the confounding factors including age, stage, mutations of BRCA1, BRCA2 and POLE (odd ratio, 0.45; 95% CI, 0.20-0.98; P=0.044). Survival analysis revealed that PEG3 mutant samples had inferior survival outcome compared with the PEG3 wild-type samples after adjusted for the confounding factors above (hazard ratio, 0.27; 95% CI: 0.12-0.57; P<0.001). These results illustrated that PEG3 mutation was associated with high TMB and inferior prognosis, suggesting PEG3 mutation might play a guiding role in prognosis prediction and immunotherapy selection in breast cancer.
| S-EPMC7419805 | biostudies-literature
Project description:Background: This study aimed to investigate the TP53 mutation, its potential immune features, its prognostic value, and its impact on immune infiltration in patients with breast cancer (BC). Methods: We downloaded the somatic mutation data and clinicopathologic features of BC patients from the TCGA GDC database, UCSC Xena platform, and International Cancer Genome Consortium (ICGC) database. The association between the TP53 mutation, clinicopathology features, and overall survival (OS) in BC patients was analyzed. We evaluated the potential role of the TP53 mutation in the immune therapy response, including the tumor mutation burden (TMB), microsatellite instability (MSI), and tumor immune dysfunction and exclusion (TIDE). Moreover, ESTIMATE was employed to assess the ImmuneScore and StromalScore in BC patients. We also explored immunocyte infiltration related to the TP53 mutation and its potential mechanism. Immunohistochemistry (IHC) was performed to validate the association between the expression of CXCL1, CXCL10, and CCL20 and TP53 status. Results: We found that the TP53 mutation was significantly associated with the shorter OS (p = 0.038) and was also an independent predictive factor of OS for BC patients (p < 0.001). Compared to that in the wild type group, the TP53-mutant group showed a higher TMB value (P< 0.001), MSI value (p = 0.077), and TIDE value (p < 0.001) with respect to BC patient immunotherapy. In addition, the ImmuneScore and StromalScore were both significantly increased in the TP53-mutant group (ImmuneScore: p < 0.001; StromalScore: p = 0.003). The results of CIBERSORT suggested that the TP53 mutation significantly promoted the infiltration of Tregs, T helper cells, and M0-type macrophages. KEGG and GSEA enrichment results suggested that the IL-17 signaling pathway and antigen processing and presentation pathways were significantly enriched in the TP53-mutant group. Importantly, based on IHC results of immune-related hub-genes, the chemokines CXCL1, CXCL10, and CCL20 were significantly upregulated in the TP53-mutant group in BC patients. Conclusion: These results indicate that a TP53 mutation might serve as a biomarker for BC prognosis and is related to immunocyte infiltration in the tumor microenvironment.
| S-EPMC8669954 | biostudies-literature
Project description:Using microarray analysis, we identified a unique ras superfamily gene, termed RERG (ras-related and estrogen-regulated growth inhibitor), whose expression was decreased or lost in a significant percentage of primary human breast tumors that show a poor clinical prognosis. Importantly, high RERG expression correlated with expression of a set of genes that define a breast tumor subtype that is estrogen receptor-positive and associated with a slow rate of tumor cell proliferation and a favorable prognosis for these cancer patients. RERG mRNA expression was induced rapidly in MCF-7 cells stimulated by beta-estradiol and repressed by tamoxifen treatment. Like Ras, RERG protein exhibited intrinsic GDP/GTP binding and GTP hydrolysis activity. Unlike Ras proteins, RERG lacks a known recognition signal for COOH-terminal prenylation and was localized primarily in the cytoplasm. Expression of RERG protein in MCF-7 breast carcinoma cells resulted in a significant inhibition of both anchorage-dependent and anchorage-independent growth in vitro and inhibited tumor formation in nude mice. These features of RERG are strikingly different from most Ras superfamily GTP-binding pro-teins and suggest that the loss of RERG expression may contribute to breast tumorigenesis.
| S-ECPF-SMDB-1443 | biostudies-other
Project description:Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women worldwide. Long non-coding RNAs (lncRNAs) are a class of non-coding RNAs in the human genome that involves in breast cancer development and progression. Here, we identify a lncRNA, LINC00978, which is upregulated in breast cancer cell lines and tissues compared with corresponding controls. Furthermore, LINC00978 expression is negatively associated with hormone receptor (HR) status in 195 breast cancer patients studied (p?=?0.033). Kaplan-Meier survival analysis shows that patients with high LINC00978 expression have poorer disease-free survival (DFS) than those with low LINC00978 expression (p?=?0.012), and multivariate analysis identifies LINC00978 as an independent prognostic factor in breast cancer (p?=?0.008, hazard ratio [HR]?=?2.270, 95% confidence interval [CI] 1.237-4.165). Our study indicates that LINC00978 may be an oncogene in breast cancer, and can serve as a potential biomarker to predict prognosis in breast cancer patients.
| S-EPMC5126584 | biostudies-literature
Project description:IntroductionNormal function of the p53 network is lost in most cancers, often through p53 mutation. The clinical impact of p53 mutations in breast cancer remains uncertain, especially where p53 isoforms may modify the effects of these p53 mutations.MethodsExpression of p53? and p53? isoforms, the isoforms identified in normal breast tissue, was detected by reverse transcription polymerase chain reaction from a cohort of 127 primary breast tumours. Expression of p53? and p53? isoforms was analysed in relation to clinical markers and clinical outcomes (5 years) by binary logistic regression, Cox proportional hazards regression and Kaplan-Meier survival analyses.Resultsp53? and p53? were not randomly expressed in breast cancer. p53? was associated with tumour oestrogen receptor (ER) expression, and p53? was associated with mutation of the p53 gene. The patient group with the mutant p53 breast tumour-expressing p53? isoform had low cancer recurrence and an overall survival as good as that of patients with wild-type p53 breast cancer. Conversely, patients expressing only mutant p53, without p53? isoform expression, had a particularly poor prognosis.ConclusionsThe determination of p53? expression may allow the identification, independently of the ER status, of two subpopulations of mutant p53 breast cancer patients, one expressing p53? with a prognosis as good as the wild-type p53 breast cancer patients and a second one not expressing p53? with a particularly poor prognosis. The p53? isoform may provide an explanation of the hitherto inconsistent relationship between p53 mutation, treatment response and outcome in breast cancer.
| S-EPMC3109573 | biostudies-literature
Project description:Using microarray analysis, we identified a unique ras superfamily gene, termed RERG (ras-related and estrogen-regulated growth inhibitor), whose expression was decreased or lost in a significant percentage of primary human breast tumors that show a poor clinical prognosis. Importantly, high RERG expression correlated with expression of a set of genes that define a breast tumor subtype that is estrogen receptor-positive and associated with a slow rate of tumor cell proliferation and a favorable prognosis for these cancer patients. RERG mRNA expression was induced rapidly in MCF-7 cells stimulated by beta-estradiol and repressed by tamoxifen treatment. Like Ras, RERG protein exhibited intrinsic GDP/GTP binding and GTP hydrolysis activity. Unlike Ras proteins, RERG lacks a known recognition signal for COOH-terminal prenylation and was localized primarily in the cytoplasm. Expression of RERG protein in MCF-7 breast carcinoma cells resulted in a significant inhibition of both anchorage-dependent and anchorage-independent growth in vitro and inhibited tumor formation in nude mice. These features of RERG are strikingly different from most Ras superfamily GTP-binding pro-teins and suggest that the loss of RERG expression may contribute to breast tumorigenesis.
2005-06-22 | E-SMDB-1443 | biostudies-arrayexpress
Project description:BACKGROUND: To establish the contribution of eight founder alleles in three DNA damage repair genes (BRCA1, CHEK2 and NBS1) to prostate cancer in Poland, and to measure the impact of these variants on survival among patients. METHODS: Three thousand seven hundred fifty men with prostate cancer and 3956 cancer-free controls were genotyped for three founder alleles in BRCA1 (5382insC, 4153delA, C61G), four alleles in CHEK2 (1100delC, IVS2+1G>A, del5395, I157T), and one allele in NBS1 (657del5). RESULTS: The NBS1 mutation was detected in 53 of 3750 unselected cases compared with 23 of 3956 (0.6%) controls (odds ratio (OR)=2.5; P=0.0003). A CHEK2 mutation was seen in 383 (10.2%) unselected cases and in 228 (5.8%) controls (OR=1.9; P<0.0001). Mutation of BRCA1 (three mutations combined) was not associated with the risk of prostate cancer (OR=0.9; P=0.8). In a subgroup analysis, the 4153delA mutation was associated with early-onset (age ≤ 60 years) prostate cancer (OR=20.3, P=0.004). The mean follow-up was 54 months. Mortality was significantly worse for carriers of a NBS1 mutation than for non-carriers (HR=1.85; P=0.008). The 5-year survival for men with an NBS1 mutation was 49%, compared with 72% for mutation-negative cases. CONCLUSION: A mutation in NBS1 predisposes to aggressive prostate cancer. These data are relevant to the prospect of adapting personalised medicine to prostate cancer prevention and treatment.
| S-EPMC3566821 | biostudies-other
Project description:PURPOSE:Somatic mutations of the chromatin remodeling AT-rich interactive domain 1A (SWI-like) gene (ARID1A) have been identified in many human cancers, including breast cancer. The purpose of this study was to evaluate the nuclear expression of ARID1A in breast cancers by immunohistochemistry (IHC) and to correlate the findings to clinicopathologic variables including prognostic significance. METHODS:IHC was performed on tissue microarrays of 476 cases of breast cancer. Associations between ARID1A expression and clinicopathologic characteristics and molecular subtype were retrospectively analyzed. RESULTS:Low expression of ARID1A was found in 339 of 476 (71.2%) cases. Low expression of ARID1A significantly correlated with positive lymph node metastasis (p=0.027), advanced pathologic stage (p=0.001), low Ki-67 labeling index (p=0.003), and negative p53 expression (p=0.017). The ARID1A low expression group had significantly shorter disease-free and overall survival than the ARID1A high expression group (p<0.001 and p<0.001, respectively). Multivariate analysis demonstrated that low expression of ARID1A was a significant independent predictive factor for poor disease-free and overall survival in patients with breast cancer (disease-free survival: hazard ratio, 0.38, 95% confidence interval [CI], 0.20-0.73, p=0.004; overall survival: hazard ratio, 0.11, 95% CI, 0.03-0.46, p=0.003). In patients with luminal A type disease, patients with low ARID1A expression had significantly shorter disease-free and overall survival rates than patients with high ARID1A expression (p=0.022 and p=0.018, respectively). CONCLUSION:Low expression of ARID1A is an independent prognostic factor for disease-free and overall survival in breast cancer patients and may be associated with luminal A type disease. Although the biologic function of ARID1A in breast cancer remains unknown, low expression of ARID1A can provide valuable prognostic information.
| S-EPMC4705085 | biostudies-literature
Project description:Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype and the lack of specific signature makes difficult the development of targeted therapeutic strategy. We previously found that PRICKLE1, an evolutionary conserved protein acting as a regulator of vertebrate development, is upregulated in TNBC. Proteomic approaches allowed us to decipher the protein complex associated to PRICKLE1 in TNBC. Within that complex, we identified a large subset of proteins involved in the regulation of Rho-GTPase family members. We build a metagene with regulators of small G-protein activity and we found that this metagene is overexpressed in TNBC and is a poor prognosis marker. We analyzed the combination of the metagene expression and PRICKLE1 expression and identified that combined expression of ECT2 and PRICKLE1 provides a worst prognosis than PRICKLE1 expression alone in TNBC. ECT2 is a GEF for Rac1 and we showed that PRICKLE1 regulate the enzymatic activity of ECT2. Finally, we also observed that Ect2 and Prickle1 are functionally connected during evolution since both act synergistically to coordinate cellular movement during vertebrate gastrulation. Our results demonstrate the pivotal role of PRICKLE1 in TNBC and build the path for development of targeted therapeutic strategies to heal TNBC patients.
2019-10-15 | PXD011253 | Pride
Project description:ObjectiveTo explore the mutated genes in esophageal cancer (ESCA), and evaluate its relationship with tumor mutation burden (TMB) and prognosis of ESCA, and analyze the advantages of FAT3 as a potential prognostic marker in ESCA.MethodsThe somatic mutation landscape was analyzed according to ESCA samples from the TCGA and ICGC database. The differences of TMB between mutant type and wild type of frequently mutated genes were compared by Mann-Whitney U test. The association of gene mutations with prognosis was analyzed by Kaplan-Meier method. The relative abundance of 22 tumor-infiltrating lymphocyte subsets in ESCA was calculated by CIBERSORT algorithm.ResultsFAT3 was a high frequency mutation in both TCGA and ICGC samples from the somatic mutation landscape. Then, the mutation type of FAT3 had significantly higher TMB in patients with ESCA compared the wild type (P<0.05). Meanwhile, the prognosis of FAT3 mutation type was significantly worse in patients with ESCA(P<0.05), and the FAT3 mutation status might be an independent factor for prognosis of patients with ESCA (HR: 1.262-5.922, P=0.011). The GSEA analysis revealed the potential mechanism of FAT3 mutation on the occurrence and development of ESCA. Finally, naive B cells were significantly enriched in FAT3 mutation samples of the ESCA microenvironment (P<0.05).ConclusionsFAT3 mutation is related to TMB and poor prognosis in ESCA. FAT3 mutation may be a prognostic marker of ESCA, and reveal the potential mechanism of FAT3 mutation on ESCA.
| S-EPMC8018597 | biostudies-literature