Similar immune responses to alpha1-oleate and Bacillus Calmette-Guérin treatment in patients with bladder cancer.

BACKGROUND: The molecular content of urine is defined by filtration in the kidneys and by local release from tissues lining the urinary tract. Pathological processes and different therapies change the molecular composition of urine and a variety of markers have been analyzed in patients with bladder cancer. The response to BCG immunotherapy and chemotherapy has been extensively studied and elevated urine concentrations of IL-1RA, IFN-α, IFN-γ TNF-α, and IL-17 have been associated with improved outcome. METHODS: In this study, the host response to intravesical alpha 1-oleate treatment was characterized in patients with non-muscle invasive bladder cancer by proteomic and transcriptomic analysis. RESULTS: Proteomic profiling detected a significant increase in multiple cytokines in the treatment group compared to placebo. The innate immune response was strongly activated, including IL-1RA and pro-inflammatory cytokines in the IL-1 family (IL-1α, IL-1ß, IL-33), chemokines (MIP-1α, IL-8), and interferons (IFN-α2, IFN-γ). Adaptive immune mediators included IL-12, Granzyme B, CD40, PD-L1, and IL-17D, suggesting broad effects of alpha 1-oleate treatment on the tumor tissues. CONCLUSIONS: The cytokine response profile in alpha 1-oleate treated patients was similar to that reported in BCG treated patients, suggesting a significant overlap. A reduction in protein levels at the end of treatment coincided with inhibition of cancer-related gene expression in tissue biopsies, consistent with a positive treatment effect. Thus, in addition to killing tumor cells and inducing cell detachment, alpha 1-oleate is shown to activate a broad immune response with a protective potential.

In silico analysis and experimental validation shows negative correlation between miR-1183 and cell cycle progression gene 1 expression in colorectal cancer.

MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate gene expression by binding to the 3' untranslated regions (UTR) of target genes. Aberrant expression of miRNAs can lead to disease, including cancer. Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Among several factors, differential expression of miRNA can have serious consequences on disease progression. This study was designed to computationally identify and experimentally verify strong miRNA candidates that could influence CRC progression. In silico analysis of publicly available gene expression microarray datasets revealed significant upregulation of miR-1183 in CRC. Comparison of mRNA microarray expression data with predicted miR-1183 targets led to the identification of cell cycle progression gene 1 (CCPG1) as strong, negatively correlated miR-1183 target. Expression analysis by means of quantitative PCR validated the inverse correlation between miR-1183 and CCPG1 in colorectal cancer tissues. CCPG1 indirectly modulates the cell cycle by interacting with the PH/DH domain of Dbs (Rho-specific guanine nucleotide exchange factor). Interestingly, the computational analysis also showed that miR-1183 is upregulated in liver and gastric cancer. This finding is notable as the liver and stomach are the primary metastatic sites for colorectal cancer and hepatocellular carcinoma respectively. This novel finding highlights the broader implications of miR-1183 dysregulation beyond primary CRC, potentially serving as a valuable prognostic marker and a therapeutic target for both primary and metastatic CRC.

Dysregulated claudin expression significantly effect breast cancer disease progression.

Background: In this study, the role of claudins in cancer progression was explored among breast cancer-affected women. Methodology: Two cohorts (discovery and validated) of breast cancer-affected women were used. In discovery cohort, 90 freshly excised breast tumor tissues along with adjacent cancer free specimens were collected at the time of surgery. These specimens were processed for RNA isolation and complementary DNA synthesis. After designing primers for claudin 3, claudin 4, and claudin 7, these sequences were synthesized from Macrogen, Korea. Claudin expression in respective tumors and controls was assessed using quantitative reverse transcription polymerase chain reaction. Any probable correlation of these molecules with various clinicopathological parameters was explored. For validation, a publicly available dataset of 2088 breast cancer patients was accessed. Claudin expression of these patients was analyzed for given clinical parameters and compared with earlier findings of discovery cohort. Results: Discovery cohort comprised 17% luminal A, 63% luminal B, 8% human epidermal growth factor receptor 2 enrich, and 12% triple-negative breast cancer tumor. High claudin 3 expression was significantly correlated with tumor size >2 cm and menopausal status. Claudin 7 expression was upregulated among poorly differentiated tumor patients. Both claudins 3/4 showed significant correlation with tumor grade, stage, size, and metastasis. Claudin-low subtype was also found in 18% of the cohort. Conclusion: Claudins impart a significant role in cell differentiation and disease progression. Hence, claudin cluster can be ascertained as the disease biomarkers for breast cancer.

Genomic Relevance of FGFR2 on the Prognosis of HCV-Induced Hepatocellular Carcinoma Patients.

The Fibroblast Growth Factor Receptors (FGFRs) are known to regulate cancer metabolism in different tumor types, including hepatocellular carcinoma (HCC). Several risk factors are associated with HCC, of which viral infections (Hepatitis B and C) and cirrhosis are prominent. In Pakistan as well as in highly developed countries like the United States, hepatitis C virus HCV infections are most commonly reported in HCC. Here, we aimed to investigate the clinical relevance of FGFR receptors in HCC and their role in HCV-positive HCC cases. 264 HCC samples along with their clinical information and 96 normal liver samples were collected. qPCR was done to estimate the expression of FGFR1, FGFR2, FGFR3 and FGFR4. Three independent HCV-induced HCC cohorts (containing 293 HCC samples) were used for validation. According to in vitro results, FGFR1 was upregulated in HCV+ HCC patients. However, in all three independent cohorts of HCC, significant a down-regulation of FGFR1 was observed. FGFR2 overexpression was observed in the in vitro cohort as well as in three independent HCC cohorts. Interestingly, a strong correlation of FGFR2 expression was observed between cirrhosis and HCV in all four HCC cohorts. Our study suggested that FGFR2 expression can be used to classify HCC patients based on HCV infection. This FGFR2-based classification may lead to new therapeutic strategies against HCV-positive HCC subtypes.

Molecular classification of hepatocellular carcinoma: prognostic importance and clinical applications.

Hepatocellular carcinoma (HCC) is a lethal human malignancy with a very low overall and long-term survival rate. Poor prognostic outcomes are predominantly associated with HCC due to a huge landscape of heterogeneity found in the deadliest disease. However, molecular subtyping of HCC has significantly improved the knowledge of the underlying mechanisms that contribute towards the heterogeneity and progression of the disease. In this review, we have extensively summarized the current information available about molecular classification of HCC. This review can be of great significance for providing the insight information needed for development of novel, efficient and personalized therapeutic options for the treatment of HCC patients globally.

Effect of MHC Linked 7-Gene Signature on Delayed Hepatocellular Carcinoma Recurrence.

Dysregulated immune response significantly affects hepatocellular carcinoma's (HCC) prognosis. Human Leukocyte Antigens are key in devising immune responses against HCC. Here, we investigated how HLAs modulate HCC development at the transcriptomic level. RNA-seq data of 576 patients from two independent cohorts was retrieved. The clinicopathological relevance of all HLA genes was investigated using Fisher-Exact, correlation, and Kaplan-Meier and cox regression survival tests. Clustering of ~800 immune-related genes against HLAs was completed using a ward-agglomerative method. Networks were generated using 40 HLA associated unique genes and hub genes were investigated. HLAs including HLA-DMA, HLA-DMB, HLA-DOA and HLA-DRB6 were associated with delayed recurrence in both discovery (204 HCC cases) and validation (372 HCC cases) cohorts. Clustering analyses revealed 40 genes associated with these four HLAs in both cohorts. A set of seven genes (NCF4, TYROBP, LCP2, ZAP70, PTPRC, FYN and WAS) was found co-expressed at gene-gene interaction level in both cohorts. Furthermore, survival analysis revealed seven HLA-linked genes as predictors of delayed recurrence. Multivariate analysis also predicted that mean expression of 7-gene is an independent predictor of delayed recurrence in both cohorts. We conclude that the expression of 7-gene signature may lead to improved patient prognosis. Further studies are required for consideration in clinical practice.

Targeted Inhibition of Fibroblast Growth Factor Receptor 1-GLI Through AZD4547 and GANT61 Modulates Breast Cancer Progression.

The underlying mechanism of fibroblast growth factor receptor 1 (FGFR1) mediated carcinogenesis is still not fully understood. For instance, FGFR1 upregulation leads to endocrine therapy resistance in breast cancer patients. The current study aimed to identify FGFR1-linked genes to devise improved therapeutic strategies. RNA-seq and microarray expression data of 1,425 breast cancer patients from two independent cohorts were downloaded for the analysis. Gene Set Enrichment Analysis (GSEA) was performed to identify differentially expressed pathways associated with FGFR1 expression. Validation was done using 150 fresh tumor biopsy samples of breast cancer patients. The clinical relevance of mRNA and protein expression of FGFR1 and its associated genes were also evaluated in mouse embryonic fibroblasts (MEFs) and breast cancer cell line (MDA-MB-231). Furthermore, MDA-MB-231 cell line was treated with AZD4547 and GANT61 to identify the probable role of FGFR1 and its associated genes on cells motility and invasion. According to GSEA results, SHH pathway genes were significantly upregulated in FGFR1 patients in both discovery cohorts of breast cancer. Statistical analyses using both discovery cohorts and 150 fresh biopsy samples revealed strong association of FGFR1 and GLI1, a member of SHH pathway. The increase in the expression of these molecules was associated with poor prognosis, lymph node involvement, late stage, and metastasis. Combined exposures to AZD4547 (FGFR1 inhibitor) and GANT61 (GLI1 inhibitor) significantly reduced cell proliferation, cell motility, and invasion, suggesting molecular crosstalk in breast cancer progression and metastasis. A strong positive feedback mechanism between FGFR1-GLI1 axis was observed, which significantly increased cell proliferation and metastasis. Targeting FGFR1-GLI1 simultaneously will significantly improve the prognosis of breast cancer in patients.

Metadherin (MTDH) overexpression significantly correlates with advanced tumor grade and stages among colorectal cancer patients.

BACKGROUND: Colorectal cancer is the 4th leading cause of cancer related deaths affecting both men and women worldwide. In the present study, any probable role of MTDH mRNA expression in CRC tumorigenesis was explored using both discovery and validation cohorts. METHODS AND RESULTS: After prior ethical and biosafety approvals, tumor tissue samples along with their adjacent controls were collected for this study from Pakistani patients diagnosed with colorectal cancer. RNA was isolated using Trizol reagent, followed by cDNA synthesis. Transcript analysis of MTDH was performed by using qPCR. Moreover, genome-wide expression of MTDH was also determined through micro-array data analysis using BRB-array tools software. MTDH expression was significantly high in tumor tissue samples (p < 0.05) compared to their respective controls. Likewise, results of microarray analysis also revealed overamplification of MTDH in tumor samples as compared to controls. Expression of MTDH was also found to be positively correlated with KI-67 index (p < 0.05) and were observed to be significantly upregulated in advance tumor grade (p < 0.05) and stage (p < 0.05). However, no association of MTDH overexpression with age and gender could be established. CONCLUSION: Hence, it can be concluded that MTDH is a core element that plays a pivotal role in colorectal tumorigenesis irrespective of patient's age and gender. Molecular insight into the tumor microenvironment revealed MTDH as a niche, representing distinctive framework for cancer progression, thus, making it an innovative target strategy for colorectal cancer treatment.

Genomic relevance of FGF14 and associated genes on the prognosis of pancreatic cancer.

BACKGROUND: Fibroblast (FGFs) and insulin (IGF) growth factor pathways are among 10 most recurrently altered genomic pathways in pancreatic ductal adenocarcinoma (PDAC). However, the prognostic and therapeutic relevance of FGF and IGF pathways in PDAC is largely unknown. METHODS: We investigated the relationship between fibroblast and insulin pathway gene expression and clinicopathological features in three independent transcriptomic cohorts of 532 PDAC patients. Furthermore, we have examined the coexpressed genes specific to the prognostic marker identified from these cohorts. Statistical tests including Fisher-exact\Chi-square, Kaplan-Meier, Pearson Correlation and cox regression analyses were performed. Additionally, pathway analysis of gene-specific co-expressed genes was also performed. RESULTS: The dysregulation of six genes including FGF9, FGF14, FGFR1, FGFR4, IGF2BP2 and IGF2BP3 were significantly associated with different clinical characteristics (including grade, stage, recurrence and nodes) in PDAC cohorts. 11 genes (including FGF9, FGF13, FGF14, FGF17, FGFR1, FGFRL1, FGFBP3, IGFBP3, IGF2BP2, IGF2BP3 and IGFBPL1) showed association with overall survival in different PDAC cohorts. Interestingly, overexpression of FGF14 was found associated with better overall survival (OS) in all three cohorts. Of note, multivariate analysis also revealed FGF14 as an independent prognostic marker for better OS in all three cohorts. Furthermore, FMN2 and PGR were among the top genes that correlated with FGF14 in all 3 cohorts. Of note, overexpression of FMN2 and PGR was found significantly associated with good overall survival in PDAC patients, suggesting FMN2 and PGR can also act as potential markers for the prediction of prognosis in PDAC patients. CONCLUSION: FGF14 may define a distinct subset of PDAC patients with better prognosis. Moreover, FGF14-based sub-classification of PDAC suggests that FMN2 and PGR can be employed as good prognostic markers in PDAC and this classification may lead to new therapeutic approaches.

Increased YAP1 expression is significantly associated with breast cancer progression, metastasis and poor survival.

YAP1 plays a key role as a transcriptional coactivator in the Hippo pathway. Based on conflicting reports regarding YAP1 function in cancer, this study discerned its role in breast carcinogenesis. First, a systematic review of salient breast cancer studies targeting YAP1 dysregulation was performed. Additionally, freshly excised tumor specimens of approximately 200 breast cancer patients were processed for quantification of YAP1 expression at mRNA and protein levels using quantitative PCR and immunohistochemistry, respectively. YAP1 expression was nine folds higher in tumors versus controls and significantly associated with metastasis (p < 0.05) and poor survival in Pakistani breast cancer patients. These findings establish the role of YAP1 overexpression in tumorigenesis and metastasis. Hence, YAP1 inhibition may be considered a possible therapeutic strategy.

Lay abstract Breast cancer incidence and prevalence are rapidly increasing across the globe, especially in countries with poor screening interventions, culminating in delayed diagnosis and greater mortality. Furthermore, for the adequate treatment of breast cancer, treatment plans must be individualized. In this context, the present study was devised to add to the existing pool of information with regard to breast cancer. In addition, the authors wanted to see whether YAP1 (the gene of interest) significantly contributes to breast cancer progression and its spread to distant areas of the body. Also, the authors aimed to study the effect of this gene on survival in breast cancer patients. Knowing the role of YAP1 in breast cancer, it is imperative to make use of this gene in devising treatment strategies for the proper management of breast cancer patients.

Reverse transcriptase loop-mediated isothermal amplification (RT-LAMP)-based diagnosis: A potential alternative to quantitative real-time PCR based detection of the novel SARS-COV-2 virus.

The sudden outbreak of the novel Coronavirus infectious disease (COVID-19) resulted in significant challenges to global health systems. One of the primary challenges is rapid, reliable, and accurate detection of the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) virus among the suspected COVID-19-infected individuals. At present, quantitative real-time PCR (qRT-PCR) is a widely used diagnostic method. However, it requires expensive instruments and expertise in the interpretation of results. These constraints reflect the significant need for the development of alternative diagnostic options. This study will validate the use and efficiency of the reverse transcriptase loop-mediated isothermal amplification (RT-LAMP) assay as a potential alternative for the detection of COVID-19. For this purpose, a cohort of 297 suspected COVID-19 patients was tested using both the RT-LAMP assay and the conventional RT-PCR method. For the RT-LAMP assay, three genes (orf-1ab, N, and S) were identified as the target sites for the detection of COVID-19. Based on a comparative assessment, 117 out of 124 positive COVID-19 cases were observed using the RT-LAMP technique with an overall 91.45% sensitivity. Interestingly, where a consensus on 163 individuals free of SARS-Cov-2 was observed, RT-LAMP specificity was 90%. Based on these findings, the robustness of the technique, and the reduced dependency on expensive instrumentation, RT-LAMP-based COVID-19 detection is strongly recommended as a potential alternative assay.

FGF19-FGFR4 Signaling in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the sixth most common type of cancer, with an increasing mortality rate. Aberrant expression of fibroblast growth factor 19-fibroblast growth factor receptor 4 (FGF19-FGFR4) is reported to be an oncogenic-driver pathway for HCC patients. Thus, the FGF19-FGFR4 signaling pathway is a promising target for the treatment of HCC. Several pan-FGFR (1-4) and FGFR4-specific inhibitors are in different phases of clinical trials. In this review, we summarize the information, recent developments, binding modes, selectivity, and clinical trial phases of different available FGFR4/pan-FGF inhibitors. We also discuss future perspectives and highlight the points that should be addressed to improve the efficacy of these inhibitors.

Phylogenetic analyses of human 1/2/8/20 paralogons suggest segmental duplications during animal evolution.

Susumu Ohno hypothesized that the diversity of vertebrate gene families and genome is due to two rounds of whole genome duplications (also referred as 2R hypothesis). The quadruplicate paralogous blocks present on 1/2/8/20 chromosomes are taken as one of the evidences in favor of the 2R. In this study, we investigated that whether 2R has shaped the vertebrate evolution using gene families residing on chromosomes 1/2/8/20. Evolutionary history of 22 gene families (11 from the current study and 11 from the previous study) was evaluated by the phylogenetic analysis with triplicated or quadruplicated distribution on these human chromosomes 1/2/8/20. The phylogenetic analysis was performed using high-quality whole genomic sequence data of multiple species with neighbor-joining (NJ) and maximum likelihood (ML) methods. The phylogenetic tree topology of these gene families revealed variable duplication time points during invertebrate-vertebrate evolution. Topology comparison approach categorized 22 gene families into three groups. Tree topologies of ten gene families fell into Group 1 (duplications prior to invertebrate-vertebrate split), four in Group 2 (i.e., (AB) (C) (D), topology incongruent with 2R) and eight in Group 3 (((AB) (CD)), 2R congruent topology). Therefore, taken together the current and previous data of 1/2/8/20 paralogons, we propose that, in addition to whole genome duplications events, current developmental, morphological and genomic complexity of the vertebrate genomes may also have originated through segmental duplications occurring at varying time points during the course of animal evolution.

Characterization of Hepatocellular Carcinoma Patients with FGF19 Amplification Assessed by Fluorescence in situ Hybridization: A Large Cohort Study.

BACKGROUND: FGF19 amplification is a relatively novel type of genetic aberration that has been proposed to be a driver of hepatocarcinogenesis. Selective inhibitors of FGFR4, a receptor of FGF19, have been developed as targeted therapies for hepatocellular carcinoma (HCC). Despite the role of FGF19 in mediating HCC progression, the clinicopathological characterization of patients exhibiting FGF19 amplification remains unclear. Immunohistochemical staining is the simplest and most widely used method of identifying aberrations in the FGF19 gene, although its specificity is very low. METHODS: This study investigated the prognostic significance of FGF19 amplification in a large cohort of 989 HCC patients using fluorescence in situ hybridization (FISH), which has a high degree of specificity. In addition, FISH data from formalin-fixed, paraffin-embedded sections were compared with copy number variation (CNV) data obtained from fresh frozen sections to validate the use of FISH as a diagnostic tool. RESULTS: FGF19 amplifications were detected by FISH in 51 (5.15%) of the 989 patients, and were independently associated with poor survival and a higher risk of tumor recurrence, as well as with poor prognostic factors such as a high α-fetoprotein level, hepatitis B or C virus infection, a large tumor size, microvascular invasion, and necrosis. In addition, FGF19 amplification was associated with TP53 mutation, and was mutually exclusive with CTNNB1 mutation. The results of the FISH and CNV analyses exhibited a significant concordance rate of 96% (κ = 0.618, p < 0.001). CONCLUSIONS: These data indicate that FGF19 amplification represents a unique molecular subtype associated with poor prognostic characteristics, which supports the hypothesis that the FGF19-FGFR4 signaling pathway plays an important role in hepatocarcinogenesis. We have also demonstrated that FISH is a viable alternative to CNV analysis, offering a number of advantages in the clinical setting.

IPCT: Integrated Pharmacogenomic Platform of Human Cancer Cell Lines and Tissues.

: (1) Motivation: The exponential increase in multilayered data, including omics, pathways, chemicals, and experimental models, requires innovative strategies to identify new linkages between drug response information and omics features. Despite the availability of databases such as the Cancer Cell Line Encyclopedia (CCLE), the Cancer Therapeutics Response Portal (CTRP), and The Cancer Genome Atlas (TCGA), it is still challenging for biologists to explore the relationship between drug response and underlying genomic features due to the heterogeneity of the data. In light of this, the Integrated Pharmacogenomic Database of Cancer Cell Lines and Tissues (IPCT) has been developed as a user-friendly way to identify new linkages between drug responses and genomic features, as these findings can lead not only to new biological discoveries but also to new clinical trials. (2) Results: The IPCT allows biologists to compare the genomic features of sensitive cell lines or small molecules with the genomic features of tumor tissues by integrating the CTRP and CCLE databases with the REACTOME, cBioPortal, and Expression Atlas databases. The input consists of a list of small molecules, cell lines, or genes, and the output is a graph containing data entities connected with the queried input. Users can apply filters to the databases, pathways, and genes as well as select computed sensitivity values and mutation frequency scores to generate a relevant graph. Different objects are differentiated based on the background color of the nodes. Moreover, when multiple small molecules, cell lines, or genes are input, users can see their shared connections to explore the data entities common between them. Finally, users can view the resulting graphs in the online interface or download them in multiple image or graph formats. (3) Availability and Implementation: The IPCT is available as a web application with an integrated MySQL database. The web application was developed using Java and deployed on the Tomcat server. The user interface was developed using HTML5, JQuery v.3.1.0 , and the Cytoscape Graph API v.1.0.4. The IPCT can be accessed at http://ipct.ewostech.net. The source code is available at https://github.com/muhammadshoaib/ipct.

3D printing approaches for cardiac tissue engineering and role of immune modulation in tissue regeneration.

Conventional tissue engineering, cell therapy, and current medical approaches were shown to be successful in reducing mortality rate and complications caused by cardiovascular diseases (CVDs). But still they have many limitations to fully manage CVDs due to complex composition of native myocardium and microvascularization. Fabrication of fully functional construct to replace infarcted area or regeneration of progenitor cells is important to address CVDs burden. Three-dimensional (3D) printed scaffolds and 3D bioprinting technique have potential to develop fully functional heart construct that can integrate with native tissues rapidly. In this review, we presented an overview of 3D printed approaches for cardiac tissue engineering, and advances in 3D bioprinting of cardiac construct and models. We also discussed role of immune modulation to promote tissue regeneration.

Comparative genomic analysis of collagen gene diversity.

Collagen gene family, comprising 30% of the total protein mass in mammals, is the major part of extracellular matrix. To understand the complexity of collagen gene family, detailed sequence, phylogenetic and synteny analyses of 44 collagen genes were performed. According to sequence analysis results, Fibril-associated collagen with interrupted triple helices (FACITs) were identified as the most recently evolved vertebrate-specific collagens while Fibril-forming collagens and Collagen VI, VII, XXVI, and XXVIII were the most ancient collagens, originating at the time of choanoflagellates. Network-forming collagens were entirely conserved from arthopods to homo sapiens, except one gene loss event. Of note, bird specific gene dispensability of COL1A1, COL3A1, COL5A3 and COL11A2 genes was observed in Fibril-forming collagens. According to phylogenetic analysis, gene duplications in collagen family occurred at variable time points during invertebrate to vertebrate evolution. However, majority of gene duplications in FACITs and network-forming collagens occurred at fish time point, suggesting large scale duplications at the root of vertebrate lineage. Lastly, synteny analysis identified 12 conserved blocks containing 27 collagen genes in vertebrate species. Interestingly, dysregulation of seven conserved blocks including block1 (COL11A1), block3 (COL3A1, COL5A2), block5 (COL6A5, COL6A6), block7 (COL1A2), block9 (COL4A1, COL4A2), block11 (COL6A1, COL6A2, COL18A1) and block12 (COL4A5, COL4A6) were also reported in different diseases including cancer. The current study revealed many critical insights into sequence, structural and functional diversity of collagen gene family. In future, by using this information we may be able to establish the clinical and pathological relevance of these conserved collagen blocks in different diseases.

FGFR1 expression defines clinically distinct subtypes in pancreatic cancer.

BACKGROUND: The clinical significance of fibroblast growth factor receptor 1 (FGFR1) protein expression in pancreatic cancer is largely unknown. In this study, we aimed investigate the clinical significance of FGFR1 expression in pancreatic cancer. METHODS: First, we investigated the relationship between FGFR pathway gene expression and clinicopathological data in three pancreatic cancer cohorts containing 313 cases. Subsequently, to confirm the findings from the discovery cohorts, we performed immunohistochemistry (IHC) of FGFR1 protein in a validation cohort of 205 pancreatic cancer cases. RESULTS: In discovery cohort 1, FGFR1 and Klotho beta (KLB) overexpression was associated with low tumor stage (P < 0.05), low tumor grade (P < 0.05), and better overall survival. Multivariate analysis predicted FGFR1 (P < 0.05) as a prognostic factor for better overall survival. In discovery cohorts 2 and 3, only FGFR1 overexpression was associated with better overall survival (P < 0.05). In the validation cohort, there were 15.7% and 61% strong and weak/moderate FGFR1-positive cases, respectively. FGFR1-positive cases showed better overall survival than FGFR1-negative cases (P < 0.05). Furthermore, multivariate analysis revealed FGFR1 positivity as an independent prognostic factor for better overall survival in pancreatic cancer patients (hazard ratio 0.677, 95% confidence interval 0.471-0.972, P = 0.035). CONCLUSIONS: FGFR1 expression, as estimated by IHC, may be used to define clinically distinct subtypes in pancreatic cancer. Moreover, FGFR1-based subclassification of pancreatic cancer may lead to new therapeutic approaches for the FGFR1-positive subtype.

Copy number profiling of Oncotype DX genes reveals association with survival of breast cancer patients.

Copy number variations (CNVs) are key contributors in breast cancer initiation and progression. However, to date, no CNV-based gene signature is developed for breast cancer. 21-gene Oncotype DX, a clinically validated signature, was identified using only RNA expression data in breast cancer patients. In this study, we evaluated whether CNVs of Oncotype DX genes can be used to predict the prognosis of breast cancer patients. Transcriptomic data of 547 and genomic data of 816 of breast cancer patients were downloaded from The Cancer Genome Atlas database. To establish the prognostic relevance between the CNVs of Oncotype DX genes and clinicopathological features, statistical analysis including Pearson Correlation, Fisher-exact, Chi square, Kaplan-Meier survival and Cox regression analyses were performed. 86% genes showed positive CNV-expression correlation. CNVs in 52% and 47.6% genes showed association with ER+ and PR+ status, respectively. 71% of the genes (including ERBB2, CTSV, CD68, GRB7, MKI67, MMP1, PGR, RPLP0, TFRC, BAG1, BCL2, BIRC5, FLNB, GSTM1 and SCUBE2) showed association with poor overall survival. 14% of the genes (including CTSV, RPLP0 and BIRC5) genes showed association with disease free survival. Cox regression analysis revealed ESR1, metastasis and node stage as independent prognostic factors for overall survival of breast cancer patients. The results suggested that CNV-based assay of Oncotype DX genes can be used to predict the survival of breast cancer patients. In future, identifying new gene signatures for better breast cancer prognosis using CNV level information will be worth investigating.

The clinical implications of G1-G6 transcriptomic signature and 5-gene score in Korean patients with hepatocellular carcinoma.

BACKGROUND: Efforts have been made to classify Hepatocellular Carcinoma (HCC) at surgically curable stages because molecular classification, which is prognostically informative, can accurately identify patients in need of additional early therapeutic interventions. Recently, HCC classification based French studies on the expression of 16 genes and 5 genes were proposed. In 16-gene classification, transcriptomic signatures (G1-G6) were used to classify HCC patients into clinical, genomic and pathway-specific subgroups. In 5-gene score classification, the good or poor prognosis of HCC patients was predicted. The patient's cohort in these studies was mainly from Caucasian and African populations. Here, we aimed to validate G1-G6 and 5-gene score signatures in 205 Korean HCC patients since genomic profiles of Korean patients are distinct from other regions. METHODS: Integrated analyses using whole-exome sequencing, copy number variation and clinical data was performed against these two signatures to find statistical correlations. Kaplan-Meier, univariate and multivariate COX regression analysis were performed for Disease-Specific Survival (DSS) and Recurrence-Free Survival (RFS). RESULTS: The G2 and G3 subgroups of transcriptomic signature were significantly associated with TP53 mutations while G5 and G6 subgroups were significantly associated with CTNNB1 mutations which is in concordance with original French studies. Similarly, the poor prognosis group of 5-gene score showed shorter DSS (p = 0.045) and early RFS (p = 0.023) as well as a significant association with microvascular invasion, tumor size (> 5 cm), elevated AFP levels, and RB1 mutations. However, the 5-gene score was not an independent prognostic factor for survival. CONCLUSION: The G1-G6 and 5-gene signatures showed significant concordance between genetic profiles of Korean HCC patients and patients in original French studies. Thus, G1-G6 and 5-gene score signatures can be targeted as potential therapeutic biomarkers against HCC patients worldwide.