Increased BRCA1 mRNA: An independent prognostic variable in completely resected chemo-naive non-small cell lung cancer (NSCLC) patients (p)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7551-7551
Author(s):  
R. Rosell ◽  
E. Jassem ◽  
M. Skrzypski ◽  
M. Taron ◽  
P. Mendez ◽  
...  
Keyword(s):  
Adjuvant Chemotherapy ◽  
Epithelial Mesenchymal Transition ◽  
Excision Repair ◽  
Cox Model ◽  
Distant Metastases ◽  
Genetic Alterations ◽  
Stage I ◽  
Mesenchymal Transition ◽  
Real Time Quantitative Pcr ◽  
Resected Nsclc

7551 Background: Following surgical resection in operable NSCLC, 5-year survival is 60% in stage I, 39% in stage IIB and 23% in stage IIIA, with relapse commonly as distant metastases. The average benefit of adjuvant chemotherapy is 5%, ranging from nil in stage I to 15% in stage II-IIIA. Caretaker genes involved in keeping genetic alterations to a minimum include the nucleotide excision repair genes ERCC1 and myeloid zinc finger 1 (MZF1), which mediates ERCC1 expression, and other stability genes, such as BRCA1, which control processes involving large portions of chromosomes. Thioredoxin-1 (TRX1) is a redox protein overexpressed in NSCLC that is correlated with poor prognosis, and TWIST contributes to metastasis by promoting epithelial-mesenchymal transition. Methods: In order to identify p with a high risk of relapse, we investigated the expression of these 5 transcripts in frozen resected tumors from 126 resected NSCLC p by real-time quantitative PCR. Gene expression was normalized using β-actin and 18SrRNA expression as internal references. Results: Adenocarcinoma (adeno), 33 p; squamous cell carcinoma (SCC), 93 p. Stage: IA, 18 p; IB, 53 p; IIB, 33 p; IIIA, 22 p. Tumoral transcript expression with β-actin: ERCC1, 1.23; MZF1, 0.53; BRCA1, 3.65; TRX1, 1.82; TWIST, 7.75. A strong correlation was observed between the expression of ERCC1, MZF1 and BRCA1 (P<0.001). Expression of each of the 5 transcripts was higher in SCC than in adeno (P<0.001). Median survival (MS): low ERCC1 (<1.5) = not reached (NR), high ERCC1 = 33 months (m) (P=0.21); low MZF1 (<0.5) = NR, high MZF1 = 33 m (P=0.04); low BRCA1 (<5) = NR, high BRCA1 = 22 months (m) (P=0.01); low TRX1 (<0.8) = NR, high TRX1 = 39.5 m (P=0.02); no differences in MS according to levels of TWIST. In a multivariate Cox model for survival, BRCA1 and stage emerged as independent prognostic variables ( Table ). Conclusion: Increased BRCA1 is associated with shorter survival, and BRCA1 assessment could be useful for customizing adjuvant chemotherapy. No significant financial relationships to disclose. [Table: see text]

Association of miR-141 and miR-200c with time to recurrence (TTR) and overall survival (OS) in resected non-small-cell lung cancer (NSCLC) adenocarcinoma (ADC) patients (p).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7547-7547
Author(s):  
Marc Campayo ◽  
Alfons Navarro ◽  
Rut Tejero ◽  
Maria L Cabanas ◽  
Laureano Molins ◽  
...  
Keyword(s):  
Surgical Resection ◽  
Prognostic Value ◽  
Epithelial Mesenchymal Transition ◽  
Early Stage ◽  
Stage I ◽  
Mesenchymal Transition ◽  
Early Stage Nsclc ◽  
Time To Recurrence ◽  
Resected Nsclc

7547 Background: Surgical resection remains the standard curative treatment for early-stage NSCLC, but nearly 50% of p experience recurrence, highlighting the need for novel diagnostic and therapeutic strategies. Moreover, treatments in NSCLC are often histology-dependent, underlining the need for histology-related markers. MicroRNAs (miRNAs) are promising molecular markers in cancer, with marked differences in expression according to histology. miR-200 family members have been associated in vitro with the regulation of epithelial-mesenchymal transition. We have examined their impact on outcome in resected NSCLC p. Methods: We analyzed miRNA expression using TaqMan assays in 160 tumor samples from NSCLC p who had undergone surgical resection and correlated our findings with TTR and OS. Results: p characteristics: age, 67 (51-83); 140 male; 96 (60%) stage I, 34 (21.3%) stage II, 30 (18.7%) stage III; 77(48.1%) ADC, 71(44.4%) squamous cell carcinoma (SCC); 16 (9.1%) received adjuvant treatment. With a median follow-up of 28 months (m), 64 p (40%) had relapsed. TTR for the 107 p with high miR-200c was 26.7 m vs 100.2 m for the 52 p with low miR-200c (P=0.032). OS for p with high miR-200c was 71.2 m vs. 125 m for p with low miR-200c (P=0.01). TTR for 112 p with high miR-141 was 26.7 m vs. 100.2 m for 46 p with low miR-141 (P=0.06). OS for p with high miR-141 was 72 m vs. 118 m for p with low miR-141 (P=0.02). Interestingly, neither miR-200c nor miR-141 correlated with TTR or OS in SCC p. In contrast, in ADC p, the prognostic value of both miRNAs increased: miR-200c (TTR, P=0.01; OS, P<0.0001) and miR-141 (TTR, P=0.003; OS, P<0.0001). This prognostic value was maintained in the subgroup of stage I p: miR-200c (TTR, P=0.011; OS, P<0.001) and miR-141 (TTR, P=0.018; OS, P<0.001). In the multivariate analysis, miR-200c and miR-141 emerged as an independent prognostic factor for OS (OR: 3.2, P=0.006; OR:2.5, P=0.02, respectively) together with age>65 (OR: 3.3, P=0.001) and stage I (OR: 0.3, P=0.004). Conclusions: miR-200c and miR-141 expression is associated with TTR and OS in resected ADC but not in SCC NSCLC p.

scholarly journals Epithelial-Mesenchymal Transition Phenotype, Metformin, and Survival for Colorectal Cancer Patients with Diabetes Mellitus II

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Yaodu Wang ◽  
Zhiyang Wu ◽  
Likuan Hu
Keyword(s):  
Diabetes Mellitus ◽  
Colorectal Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Disease Free Survival ◽  
Multivariate Regression Analysis ◽  
Stage I ◽  
Clinicopathological Parameters ◽  
Mesenchymal Transition ◽  
Patients With Diabetes ◽  
E Cadherin

Objectives. We aimed to explore the association between metformin treatment and epithelial-mesenchymal transition (EMT) phenotype and further appraise the prognostic values of metformin and EMT markers E-cadherin and vimentin for colorectal cancer (CRC) in clinical practice. Methods. We collected specimens and evaluated clinicopathological parameters of 102 stage I to III CRC patients with prediagnosed type 2 diabetes mellitus (DM II). Expression of E-cadherin and vimentin in tumors was detected by immunohistochemistry (IHC), and statistical analysis was performed using SPSS 19.0. Results. In correlation tests, we found a lower tumor cell EMT degree (more E-cadherin (P=0.014) and less vimentin (P=0.011) expression in patients who used metformin, and the expression of E-cadherin and vimentin was associated with serum CA19-9 (P=0.048, P=0.009), tumor invasive depth (T) (P<0.001, P=0.045), and lymph invasion (N) (P=0.013, P=0.001). In Cox multivariate regression analysis, E-cadherin was identified as a prognostic factor for disease-free survival (DFS) (P=0.038) and metformin use (P=0.015P=0.044) and lymph invasion (P=0.016P=0.023) were considered as the prognostic factors for both DFS and overall survival (OS). Conclusion. Our study suggested that metformin may impede the EMT process and improve survival for stage I–III CRC patients with DM II.

scholarly journals Single-cell transcriptomic analysis of the tumor ecosystems underlying initiation and progression of papillary thyroid carcinoma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Weilin Pu ◽  
Xiao Shi ◽  
Pengcheng Yu ◽  
Meiying Zhang ◽  
Zhiyan Liu ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Single Cell ◽  
Epithelial Mesenchymal Transition ◽  
Distant Metastases ◽  
Developmental Trajectory ◽  
Papillary Thyroid ◽  
Normal Morphology ◽  
Mesenchymal Transition ◽  
Therapeutic Implications

AbstractThe tumor ecosystem of papillary thyroid carcinoma (PTC) is poorly characterized. Using single-cell RNA sequencing, we profile transcriptomes of 158,577 cells from 11 patients’ paratumors, localized/advanced tumors, initially-treated/recurrent lymph nodes and radioactive iodine (RAI)-refractory distant metastases, covering comprehensive clinical courses of PTC. Our data identifies a “cancer-primed” premalignant thyrocyte population with normal morphology but altered transcriptomes. Along the developmental trajectory, we also discover three phenotypes of malignant thyrocytes (follicular-like, partial-epithelial-mesenchymal-transition-like, dedifferentiation-like), whose composition shapes bulk molecular subtypes, tumor characteristics and RAI responses. Furthermore, we uncover a distinct BRAF-like-B subtype with predominant dedifferentiation-like thyrocytes, enriched cancer-associated fibroblasts, worse prognosis and promising prospect of immunotherapy. Moreover, potential vascular-immune crosstalk in PTC provides theoretical basis for combined anti-angiogenic and immunotherapy. Together, our findings provide insight into the PTC ecosystem that suggests potential prognostic and therapeutic implications.

scholarly journals Ubiquilin Networking in Cancers

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1586
Author(s):  
Salinee Jantrapirom ◽  
Luca Lo Piccolo ◽  
Dumnoensun Pruksakorn ◽  
Saranyapin Potikanond ◽  
Wutigri Nimlamool
Keyword(s):  
Cell Cycle ◽  
Genetic Variants ◽  
Epithelial Mesenchymal Transition ◽  
Excision Repair ◽  
Cancer Therapies ◽  
Cellular Functions ◽  
Mesenchymal Transition ◽  
Wide Range ◽  
Nucleotide Excision

Ubiquilins or UBQLNs, members of the ubiquitin-like and ubiquitin-associated domain (UBL-UBA) protein family, serve as adaptors to coordinate the degradation of specific substrates via both proteasome and autophagy pathways. The UBQLN substrates reveal great diversity and impact a wide range of cellular functions. For decades, researchers have been attempting to uncover a puzzle and understand the role of UBQLNs in human cancers, particularly in the modulation of oncogene’s stability and nucleotide excision repair. In this review, we summarize the UBQLNs’ genetic variants that are associated with the most common cancers and also discuss their reliability as a prognostic marker. Moreover, we provide an overview of the UBQLNs networks that are relevant to cancers in different ways, including cell cycle, apoptosis, epithelial-mesenchymal transition, DNA repairs and miRNAs. Finally, we include a future prospective on novel ubiquilin-based cancer therapies.

scholarly journals ARID1A, a SWI/SNF subunit, is critical to acinar cell homeostasis and regeneration and is a barrier to transformation and epithelial-mesenchymal transition in the pancreas

Gut ◽  
2018 ◽  
Vol 68 (7) ◽  
pp. 1245-1258 ◽  
Author(s):  
Wenjia Wang ◽  
Scott C Friedland ◽  
Bing Guo ◽  
Michael R O’Dell ◽  
William B Alexander ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Cell Lines ◽  
Genetic Alterations ◽  
Homozygous Deletion ◽  
Ductal Adenocarcinoma ◽  
Interaction Domain ◽  
Mesenchymal Transition ◽  
Poorly Differentiated

ObjectiveHere, we evaluate the contribution of AT-rich interaction domain-containing protein 1A (ARID1A), the most frequently mutated member of the SWItch/sucrose non-fermentable (SWI/SNF) complex, in pancreatic homeostasis and pancreatic ductal adenocarcinoma (PDAC) pathogenesis using mouse models.DesignMice with a targeted deletion of Arid1a in the pancreas by itself and in the context of two common genetic alterations in PDAC, Kras and p53, were followed longitudinally. Pancreases were examined and analysed for proliferation, response to injury and tumourigenesis. Cancer cell lines derived from these models were analysed for clonogenic, migratory, invasive and transcriptomic changes.ResultsArid1a deletion in the pancreas results in progressive acinar-to-ductal metaplasia (ADM), loss of acinar mass, diminished acinar regeneration in response to injury and ductal cell expansion. Mutant Kras cooperates with homozygous deletion of Arid1a, leading to intraductal papillary mucinous neoplasm (IPMN). Arid1a loss in the context of mutant Kras and p53 leads to shorter tumour latency, with the resulting tumours being poorly differentiated. Cancer cell lines derived from Arid1a-mutant tumours are more mesenchymal, migratory, invasive and capable of anchorage-independent growth; gene expression analysis showed activation of epithelial-mesenchymal transition (EMT) and stem cell identity pathways that are partially dependent on Arid1a loss for dysregulation.ConclusionsARID1A plays a key role in pancreatic acinar homeostasis and response to injury. Furthermore, ARID1A restrains oncogenic KRAS-driven formation of premalignant proliferative IPMN. Arid1a-deficient PDACs are poorly differentiated and have mesenchymal features conferring migratory/invasive and stem-like properties.

scholarly journals Molecular Events in Primary and Metastatic Colorectal Carcinoma: A Review

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Rani Kanthan ◽  
Jenna-Lynn Senger ◽  
Selliah Chandra Kanthan
Keyword(s):  
Colorectal Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Cpg Island ◽  
Genetic Alterations ◽  
Tumour Suppressor Genes ◽  
Metastatic Colorectal Carcinoma ◽  
Cpg Island Methylator Phenotype ◽  
Mesenchymal Transition ◽  
Sequence Of Events ◽  
Molecular Events

Colorectal cancer (CRC) is a heterogeneous disease, developing through a multipathway sequence of events guided by clonal selections. Pathways included in the development of CRC may be broadly categorized into (a) genomic instability, including chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP), (b) genomic mutations including suppression of tumour suppressor genes and activation of tumour oncogenes, (c) microRNA, and (d) epigenetic changes. As cancer becomes more advanced, invasion and metastases are facilitated through the epithelial-mesenchymal transition (EMT), with additional genetic alterations. Despite ongoing identification of genetic and epigenetic markers and the understanding of alternative pathways involved in the development and progression of this disease, CRC remains the second highest cause of malignancy-related mortality in Canada. The molecular events that underlie the tumorigenesis of primary and metastatic colorectal carcinoma are detailed in this manuscript.

Adjuvant chemotherapy outcome in unselected single-center non-small cell lung cancer (NSCLC) population.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20089-e20089
Author(s):  
Marie Florescu ◽  
Normand Blais ◽  
Mustapha Ali Tehfe ◽  
Mathieu Gravel
Keyword(s):  
Overall Survival ◽  
Adjuvant Chemotherapy ◽  
Stage I ◽  
Observation Group ◽  
Positive Margins ◽  
Resected Nsclc ◽  
Number Of Patients ◽  
Significant Difference ◽  
Improvement In Survival ◽  
Nsclc Patients

e20089 Background: Adjuvant chemotherapy with Cisplatinum/Vinorelbine is an established regimen since a decade in selected resected NSCLC population in order to improve DFS and overall survival. However, the outcome of patients treated outside the research protocols is not as good as in clinical trials. Methods: We retrospectively reviewed 209pts resected stage I to III NSCLC patients using our SARDO database, treated in our University hospital between 2006 and 2015 with a median follow-up of 13mos. Any adjuvant chemotherapy was recorded. Results: Amongst 209 resected NSCLC patients, 185pts (89%) had negative margins and 24pts (11%) have positive margins resection. The observation group and the chemotherapy group in both settings were well-balanced in terms of demographic, co-morbidities and tumor characteristics. As expected, the median overall survival (mOS) in negative margins was significantly better than in positive margins patients (43mos vs 24mos p = 0.029). In negative margins patients, no survival benefit was seen in stage I (A and B) (57 mos for chemo group vs 77 mos for observation group p = 0,217) and stage III (A and B) (39mos mOS for chemo group vs 40mos for observation group, p = 0.37), but a trend for improved mOS was seen in stage II (52 mos for chemo group vs 38 mos for observation group, p = 0.114), also consistent with mPFS results for each group. However, for the small number of patients with positive margins, a significant improvement in survival was seen in chemotherapy arm (mOS 37mos) compared to observational arm (mOS 11mos p = 0,039). No significant difference in survival was seen between Carbo/Taxol regimen and Cisplatinum/Vinorelbine regimen (43 mos vs 38 mos p = 0,658). Conclusions: In our unselected population, adjuvant chemotherapy did not show the improvement in survival expected with margin negative resected NSCLC. In positive resected NSCLC, adjuvant chemotherapy benefit was statistically significant, emphasizing need to treatment to these patients.

scholarly journals Integrated Multi-Omics Data Reveals the Molecular Subtypes of Prostate Cancer

2021 ◽  
Author(s):  
Jialin Meng ◽  
Xiaofan Lu ◽  
Chen Jin ◽  
Yujie Zhou ◽  
Qintao Ge ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Clustering Algorithms ◽  
Molecular Classification ◽  
Genetic Alterations ◽  
High Response Rate ◽  
Omics Data ◽  
Oncogenic Signaling ◽  
Mesenchymal Transition ◽  
Molecular Features

Prostate cancer (PCa), the second most common male malignancy, is the fifth leading cause of cancer-related death and places notable burdens on medical resources. Most of the previous subtypes only focused on one or fewer types of data or ignored the genomic heterogeneity among PCa patients with diverse genetic backgrounds. Therefore, it is essential to precisely identify the specific molecular features and judge potential clinical outcomes based on multi-omics data. In the current study, we first identified the PCa multi-omics classification (PMOC) system based on the multi-omics, including mRNA, miRNA, lncRNA, DNA methylation, and gene mutation, using a total of ten state-of-the-art clustering algorithms. The PMOC1 subtype, also called the inflammatory subtype, contains the highest expression levels of immune checkpoint proteins, moderate activated immune-associated pathways. The PMOC2 tumor-activated subtype demonstrated the worst prognosis, which might be impacted by the activated cell cycle and DNA repair pathways, and also characterized by the most genetic alterations of mutant TP53, mutant APC and copy number alteration of 8q24.21 region. The PMOC3 subtype is likely to be a balance subtype, with the activated oncogenic signaling pathways, including hypoxia, angiogenesis, epithelial mesenchymal transition, and PI3K/AKT pathways. As well as with the activated proinflammatory pathways, including IL6/JAK/STAT3, IL2/STAT5, Notch and TNF-α signaling. Additionally, PMOC3 subtype also linked with the activation of the androgen response and the high response rate of ARSI treatment. Taken together, we defined the PMOC system for PCa patients via multi-omics data and consensus results of ten algorithms, this multi-omics consensus PCa molecular classification can further assist in the precise clinical treatment and development of targeted therapy.

scholarly journals Gastric Cancer in Young Adults: A Different Clinical Entity from Carcinogenesis to Prognosis

2020 ◽  
Vol 2020 ◽  
pp. 1-13 ◽  
Author(s):  
Jian Li
Keyword(s):  
Gastric Cancer ◽  
Young Adults ◽  
Epithelial Mesenchymal Transition ◽  
Early Stage ◽  
The United States ◽  
Genetic Alterations ◽  
Mesenchymal Transition ◽  
Screening Programs ◽  
Life Years ◽  
Advanced Stages

Approximately 5.0% of gastric cancer (GC) patients are diagnosed before the age of 40 and are not candidates for screening programs in most countries and regions. The incidence of gastric cancer in young adults (GCYA) has declined over time in most countries except in the United States. Genetic alterations, environmental factors, and lifestyle may predispose some young adults to GC. According to molecular classifications, the cancer of most GCYA patients belongs to the genomically stable or microsatellite stable/epithelial-mesenchymal transition subtype, with the common genetic aberrations being mutations in CDH1. What characterizes GCYA are a higher prevalence in females, more aggressive tumor behaviors, diagnosis at advanced stages, fewer comorbidities and being better treatment candidates, and a similar or better survival outcome when compared with older patients. Considering the greater loss of life-years in younger patients, lowering the incidence of GC and diagnosing at a relatively early stage are the two most effective ways to decrease GC mortality. To achieve these goals, the low awareness of GCYA among general people, policy-makers, clinicians, and researchers should be changed.

Gene expression levels of ribonucleotide reductase subunit M1 (RRM1), tyrosyl-DNA phosphodiesterase (Tdp1), nuclear factor of activated T-cells (NFAT), and BubR1 mRNA expression in completely resected chemo-naive non-small cell lung cancer (NSCLC) patients

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18016-18016
Author(s):  
I. Chaib ◽  
E. Jassem ◽  
M. Spkrzypski ◽  
R. Rosell ◽  
M. Taron ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Cox Model ◽  
Chromosome Instability ◽  
Mrna Levels ◽  
Internal Reference ◽  
Activated T Cells ◽  
Real Time Quantitative Pcr ◽  
Resected Nsclc ◽  
Actin Expression

18016 Background: A relationship between gene transcripts and survival in operable NSCLC is now emerging. RRM1 is involved in DNA repair, Tdp1 is implicated in the repair of CPT-induced topoisomerase damage, and NFAT promotes cancer invasion. BubR1 is a key spindle checkpoint gene, and altered BubR1 mRNA levels are associated with lymph node metastasis and chromosome instability. Methods: In order to identify p with a high risk of relapse, we examined the expression of these four genes in frozen resected tumors from 126 resected NSCLC p by real-time quantitative PCR. Gene expression was normalized using β-actin expression as internal reference. Results: Adenocarcinoma (adeno), 33 p; squamous cell carcinoma (SCC), 93 p. Stage: IA, 18 p; IB, 53 p; IIB, 33 p; IIIA, 22 p. Tumor transcript expression: RRM1, 2.10; Tdp1, 1.77; NFAT, 0.56; BubR1, 16.40. Expression of RRM1, Tdp1 and BubR1 was higher in SCC than in adeno (P<0.001). Median time to relapse (TTR) was longer for p with low levels of RRM1 (P=0.11), Tdp1 (P=0.86), NFAT (P=0.29), or BubR1 (P=0.44) (Table). A significant trend towards longer survival was also observed in stage I p with low RRM1 P=0.06). In a multivariate Cox model, tumor size > 4 cm and stage III predicted shorter TTR and survival. Conclusion: Increased mRNA expression of these genes is associated with shorter TTR; this knowledge could be useful for customizing adjuvant chemotherapy. [Table: see text] No significant financial relationships to disclose.

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