Transcription profiling of breast cancer tissue from 64 patients to identify transcriptional differences between subgroups of grade III invasive ductal breast cancers
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Natrajan Rachael
PROVIDER: S-ECPF-TABM-543 | biostudies-other |
REPOSITORIES: biostudies-other
Similar Datasets
Project description:To gain insights into the transcriptional differences between subgroups of grade III invasive ductal breast cancers, we performed gene expression profiling of a series of RNA extracted from microdissected frozen tissue from patients with breast cancer
2009-08-20 | E-TABM-543 | biostudies-arrayexpress
Project description:INTRODUCTION:The 19q12 locus is amplified in a subgroup of oestrogen receptor (ER)-negative grade III breast cancers. This amplicon comprises nine genes, including cyclin E1 (CCNE1), which has been proposed as its 'driver'. The aim of this study was to identify the genes within the 19q12 amplicon whose expression is required for the survival of cancer cells harbouring their amplification. METHODS:We investigated the presence of 19q12 amplification in a series of 313 frozen primary breast cancers and 56 breast cancer cell lines using microarray comparative genomic hybridisation (aCGH). The nine genes mapping to the smallest region of amplification on 19q12 were silenced using RNA interference in phenotypically matched breast cancer cell lines with (MDA-MB-157 and HCC1569) and without (Hs578T, MCF7, MDA-MB-231, ZR75.1, JIMT1 and BT474) amplification of this locus. Genes whose silencing was selectively lethal in amplified cells were taken forward for further validation. The effects of cyclin-dependent kinase 2 (CDK2) silencing and chemical inhibition were tested in cancer cells with and without CCNE1 amplification. RESULTS:19q12 amplification was identified in 7.8% of ER-negative grade III breast cancer. Of the nine genes mapping to this amplicon, UQCRFS1, POP4, PLEKHF1, C19ORF12, CCNE1 and C19ORF2 were significantly over-expressed when amplified in primary breast cancers and/or breast cancer cell lines. Silencing of POP4, PLEKHF1, CCNE1 and TSZH3 selectively reduced cell viability in cancer cells harbouring their amplification. Cancer cells with CCNE1 amplification were shown to be dependent on CDK2 expression and kinase activity for their survival. CONCLUSIONS:The 19q12 amplicon may harbour more than a single 'driver', given that expression of POP4, PLEKHF1, CCNE1 and TSZH3 is required for the survival of cancer cells displaying their amplification. The observation that cancer cells harbouring CCNE1 gene amplification are sensitive to CDK2 inhibitors provides a rationale for the testing of these chemical inhibitors in a subgroup of patients with ER-negative grade III breast cancers.
| S-EPMC3446387 | biostudies-literature
Project description:Protein tyrosine kinase 7 (PTK7) is a catalytically inactive receptor tyrosine kinase that is involved in development and tumorigenesis. PTK7 expression and its functional roles have been investigated in several human cancers, although controversial results have been obtained. In this study, we investigated the expression of PTK7 protein in invasive ductal breast cancer tissues, and analyzed its relationship with clinicopathologic parameters. Seventy-nine consecutive invasive breast cancer tissues were included in the study, and PTK7 protein was detected in invasive ductal breast cancers and normal breast epithelial cells by immunohistochemistry. Positive staining was noted in all normal breast epithelial cells and differential expression was observed in breast carcinomas. Thirty-eight of 79 samples (48.1%) were negative or stained weakly for PTK7 (-), 19 (24.1%) showed moderate staining (+), and 22 (27.8%) were strongly stained (++). PTK7 expression was negatively associated with tumor grade (P=0.025, r=-0.251), tumor-node-metastasis stage (P=0.004, r=-0.317), lymph node metastasis (P=0.002, r=-0.351), human epidermal growth factor receptor 2 expression (P=0.029, r=-0.245), and Ki67 expression (P=0.004, r=-0.317), and positively associated with estrogen receptor (ER) expression (P=0.037, r=0.235). No significant relationship was found between PTK7 expression and patient age or progesterone receptor (PR) expression. Our data indicated that PTK7 protein was down-regulated in breast cancer cells compared with healthy epithelial cells, and that PTK7 may be a tumor suppressor gene in breast cancer. Future studies should explore the molecular mechanisms underlying the down-regulation and functional roles of PTK7 in breast cancer.
| S-EPMC6945173 | biostudies-literature
Project description:Comparison of multiple grade 3 invasive ductal carcinomas arrayed against a common reference.
| S-ECPF-MEXP-1007 | biostudies-other
Project description:BackgroundLung adenocarcinomas (ADCs) show heterogeneous morphological patterns that are classified into five subgroups: lepidic predominant, papillary predominant, acinar predominant, micropapillary predominant and solid predominant. The morphological classification of ADCs has been reported to be associated with patient prognosis and adjuvant chemotherapy response. However, the molecular mechanisms underlying the morphology differences among different subgroups remain largely unknown.MethodsUsing the molecular profiling data from The Cancer Genome Atlas (TCGA) lung ADC (LUAD) cohort, we studied the molecular differences across invasive ADC morphological subgroups.ResultsWe showed that the expression of proteins and mRNAs, but not the gene mutations copy number alterations (CNA), were significantly associated with lung ADC morphological subgroups. In addition, expression of the FOXM1 gene (which is negatively associated with patient survival) likely plays an important role in the morphological differences among different subgroups. Moreover, we found that protein abundance of PD-L1 were associated with the malignancy of subgroups. These results were validated in an independent cohort.ConclusionsThis study provides insights into the molecular differences among different lung ADC morphological subgroups, which could lead to potential subgroup-specific therapies.
| S-EPMC7481608 | biostudies-literature
Project description:Although ductal carcinoma in situ (DCIS) precedes invasive ductal carcinoma (IDC), the related genomic alterations remain unknown. To identify the genomic landscape of DCIS and better understand the mechanisms behind progression to IDC, we performed whole-exome sequencing and copy number profiling for six cases of pure DCIS and five pairs of synchronous DCIS and IDC. Pure DCIS harbored well-known mutations (e.g., TP53, PIK3CA and AKT1), copy number alterations (CNAs) and chromothripses, but had significantly fewer driver genes and co-occurrence of mutation/CNAs than synchronous DCIS-IDC. We found neither recurrent nor significantly mutated genes with synchronous DCIS-IDC compared to pure DCIS, indicating that there may not be a single determinant for pure DCIS progression to IDC. Of note, synchronous DCIS genomes were closer to IDC than pure DCIS. Among the clinicopathologic parameters, progesterone receptor (PR)-negative status was associated with increased mutations, CNAs, co-occurrence of mutations/CNAs and driver mutations. Our results indicate that although pure DCIS has already acquired some drivers, more changes are needed to progress to IDC. In addition, IDC-associated DCIS is more aggressive than pure DCIS at genomic level and should really be considered IDC. Finally, the data suggest that PR-negativity could be used to predict aggressive breast cancer genotypes.
| S-EPMC4480702 | biostudies-literature
Project description:Introduction:Meningiomas are the most common brain tumor, with prevalence of approximately 3%. Histological grading has a major role in determining treatment choice and predicting outcome. While indolent grade 1 and aggressive grade 3 meningiomas exhibit relatively homogeneous clinical behavior, grade 2 meningiomas are far more heterogeneous, making outcome prediction challenging. We hypothesized two subgroups of grade 2 meningiomas which biologically resemble either World Health Organization (WHO) grade 1 or WHO grade 3. Our aim was to establish gene expression signatures that separate grade 2 meningiomas into two homogeneous subgroups: a more indolent subtype genetically resembling grade 1 and a more aggressive subtype resembling grade 3. Methods:We carried out an observational meta-analysis on 212 meningiomas from six distinct studies retrieved from the open-access platform Gene Expression Omnibus. Microarray data was analyzed with systems-level gene co-expression network analysis. Fuzzy C-means clustering was employed to reclassify 34 of the 46 grade 2 meningiomas (74%) into a benign "grade 1-like" (13/46), and malignant "grade 3-like" (21/46) subgroup based on transcriptomic profiles. We verified shared biology between matching subgroups based on meta-gene expression and recurrence rates. These results were validated further using an independent RNA-seq dataset with 160 meningiomas, with similar results. Results:Recurrence rates of "grade 1-like" and "grade 3- like" tumors were 0 and 75%, respectively, statistically similar to recurrence rates of grade 1 (17%) and 3 (85%). We also found overlapping biological processes of new subgroups with their adjacent grades 1 and 3. Conclusion:These results underpin molecular signatures as complements to histological grading systems. They may help reshape prediction, follow-up planning, treatment decisions and recruitment protocols for future and ongoing clinical trials.
| S-EPMC7674612 | biostudies-literature
Project description:INTRODUCTION:PTEN is a tumor suppressor gene that inhibits cell proliferation by inhibiting the phosphoinositide 3-kinase (PI3?K) signaling pathway. The significance of PTEN mutations resulting in variable PTEN expression and their impact on prognosis of breast cancer is not well established. The objective of our study was to correlate the immunohistochemical expression of PTEN in the four major subtypes of breast carcinoma (Luminal A, Luminal B, HER2 positive, and Triple Negative) in a population of 202 African-American (AA) females with other clinicopathological factors. MATERIALS AND METHODS:Tissue microarrays (TMAs) were constructed from FFPE tumor blocks from primary ductal breast carcinomas in 202 African-American females. Five micrometer sections were stained with a mouse monoclonal antibody against PTEN. The sections were evaluated for the intensity of cytoplasmic and nuclear reactivity. Bivariate analysis was done via ?2 analysis and survivability data was calculated via the generation of Kaplan-Meier curves (SPSS v19). RESULTS:Loss of PTEN expression was associated with ER negative (p?=?0.021), PR negative (p?=?0.024) and triple negative (p?=?0.0024) breast ductal cancers. It was marginally associated with distant metastasis (p?=?0.074). There was no association between PTEN loss and recurrence-free survival or overall survival. CONCLUSION:In our study, a statistically significant association between PTEN loss and the triple negative breast cancers (TNBC) was found in AA women. PTEN inhibits PI3?K resulting in decreased activation of downstream effector, mammalian target of rapamycin (mTOR). Loss of PTEN results in cell proliferation through activation of mTOR. Targeted therapy with mTOR inhibitors might be useful in the treatment of TNBC.
| S-EPMC5963715 | biostudies-literature
Project description:Invasive breast cancer was histopathologically confirmed on 47 samples obtained by core or incisional biopsy. Keywords: other
2005-12-06 | E-GEOD-2048 | biostudies-arrayexpress
Project description:Our aim was to investigate whether molecular classification can be used to refine prognosis in grade 3 endometrial endometrioid carcinomas (EECs). Grade 3 EECs were classified into 4 subgroups: p53 abnormal, based on mutant-like immunostaining (p53abn); MMR deficient, based on loss of mismatch repair protein expression (MMRd); presence of POLE exonuclease domain hotspot mutation (POLE); no specific molecular profile (NSMP), in which none of these aberrations were present. Overall survival (OS) and recurrence-free survival (RFS) rates were compared using the Kaplan-Meier method (Log-rank test) and univariable and multivariable Cox proportional hazard models. In total, 381 patients were included. The median age was 66 years (range, 33 to 96?y). Federation Internationale de Gynecologie et d'Obstetrique stages (2009) were as follows: IA, 171 (44.9%); IB, 120 (31.5%); II, 24 (6.3%); III, 50 (13.1%); IV, 11 (2.9%). There were 49 (12.9%) POLE, 79 (20.7%) p53abn, 115 (30.2%) NSMP, and 138 (36.2%) MMRd tumors. Median follow-up of patients was 6.1 years (range, 0.2 to 17.0?y). Compared to patients with NSMP, patients with POLE mutant grade 3 EEC (OS: hazard ratio [HR], 0.36 [95% confidence interval, 0.18-0.70]; P=0.003; RFS: HR, 0.17 [0.05-0.54]; P=0.003) had a significantly better prognosis; patients with p53abn tumors had a significantly worse RFS (HR, 1.73 [1.09-2.74]; P=0.021); patients with MMRd tumors showed a trend toward better RFS. Estimated 5-year OS rates were as follows: POLE 89%, MMRd 75%, NSMP 69%, p53abn 55% (Log rank P=0.001). Five-year RFS rates were as follows: POLE 96%, MMRd 77%, NSMP 64%, p53abn 47% (P=0.000001), respectively. In a multivariable Cox model that included age and Federation Internationale de Gynecologie et d'Obstetrique stage, POLE and MMRd status remained independent prognostic factors for better RFS; p53 status was an independent prognostic factor for worse RFS. Molecular classification of grade 3 EECs reveals that these tumors are a mixture of molecular subtypes of endometrial carcinoma, rather than a homogeneous group. The addition of molecular markers identifies prognostic subgroups, with potential therapeutic implications.
| S-EPMC5893364 | biostudies-literature