Assessing the genomic feature of Chinese patients with ampullary adenocarcinoma: potential therapeutic targets
Ontology highlight
ABSTRACT:
SUBMITTER: Dong Z
PROVIDER: S-EPMC10910796 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in both men and women in the United States, carrying a 5-year survival rate of approximately 5%, which is the poorest prognosis of any solid tumor type. Given the dismal prognosis associated with PDAC, a more thorough understanding of risk factors and genetic predisposition has important implications not only for cancer prevention, but also for screening techniques and the development of personalized therapies. While screening of the general population is not recommended or practicable with current diagnostic methods, studies are ongoing to evaluate its usefulness in people with at least 5- to 10-fold increased risk of PDAC. In order to help identify high-risk populations who would be most likely to benefit from early detection screening tests for pancreatic cancer, discovery of additional pancreatic cancer susceptibility genes is crucial. Thus, specific gene-based, gene-product, and marker-based testing for the early detection of pancreatic cancer are currently being developed, with the potential for these to be useful as potential therapeutic targets as well. The goal of this review is to provide an overview of the genetic basis for PDAC with a focus on germline and familial determinants. A discussion of potential therapeutic targets and future directions in screening and treatment is also provided.
| S-EPMC3939680 | biostudies-literature
Project description:IntroductionPancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis. The roles of the transcription factor special AT-rich binding protein-2 (SATB2) and β-catenin in PDAC have been a subject of controversy. We aimed to assess the diagnostic and prognostic impact of SATB2 and β-catenin in PDAC.MethodsWe analyzed 44 paraffin-embedded tissue blocks along with corresponding blood and pancreatic tissues. We evaluated SATB2 expression using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA). β-catenin was assessed using IHC and real-time polymerase chain reaction (qPCR).ResultsHigh SATB2 expression and low β-catenin expression were associated with a poor prognosis in PDAC, including advanced pathological tumor stage (pT-stage), pathological lymph node stage (pN-stage), and TNM stage. We found a positive correlation between SATB2 expression assessed by IHC and the concentration of SATB2 in both serum and tissue samples measured by ELISA. We observed a positive correlation between β-catenin expression assessed by IHC and β-catenin levels measured by qPCR.ConclusionsSATB2 and β-catenin could provide valuable insights into the development of pancreatic cancer, and targeting them may be beneficial for the prevention and treatment of PDAC. The levels of SATB2 in serum show promise for the diagnosis and tumor invasion of pancreatic cancer.
| S-EPMC11779791 | biostudies-literature
Project description:PurposeTumor genomic profiling is increasingly used to guide treatment strategy in patients with cancer. We integrated tumor genomic, clinical demographic, and treatment response data to assess how prospective tumor-normal sequencing impacted treatment selection in patients with cervical cancer.Experimental designCervical cancers were prospectively analyzed using the MSK-IMPACT (Memorial Sloan Kettering Cancer Center - Integrated Mutation Profiling of Actionable Cancer Targets) next-generation sequencing panel. Clinical data, including histology, stage at diagnosis, treatment history, clinical trial enrollment and outcomes, date of last follow-up, and survival status were obtained from medical records.ResultsA total of 177 patients with cervical cancer (squamous, 69; endocervical adenocarcinoma, 50; gastric type, 22; adenosquamous, 21; and other, 15) underwent MSK-IMPACT testing. The most prevalent genomic alterations were somatic mutations or amplifications in PIK3CA (25%), ERBB2 (12%), KMT2C (10%), and KMT2D (9%). Furthermore, 13% of patients had high tumor mutational burden (TMB >10 mut/Mb), 3 of which were also microsatellite instability-high (MSI-H). Thirty-seven percent of cases had at least one potentially actionable alteration designated as a level 3B mutational event according to the FDA-recognized OncoKB tumor mutation database and treatment classification system. A total of 30 patients (17%) were enrolled on a therapeutic clinical trial, including 18 (10%) who were matched with a study based on their MSK-IMPACT results. Twenty patients (11%) participated in an immune checkpoint inhibition study for metastatic disease; 2 remain progression free at >5 years follow-up.ConclusionsTumor genomic profiling can facilitate the selection of targeted/immunotherapies, as well as clinical trial enrollment, for patients with cervical cancer.
| S-EPMC10644000 | biostudies-literature
Project description:BackgroundIdentification of clinically relevant oncogenic drivers in advanced cancer is critical in selecting appropriate targeted therapy. Using next-generation sequencing (NGS)-based clinical cancer gene assay, we performed comprehensive genomic profiling (CGP) of advanced cases of lung adenocarcinoma.MethodsFormalin-fixed paraffin-embedded tumors from 51 lung adenocarcinoma patients whose tumors previously tested negative for EGFR/KRAS/ALK by conventional methods were collected, and CGP was performed via hybridization capture of 4,557 exons from 287 cancer-related genes and 47 introns from 19 genes frequently rearranged in cancer.ResultsGenomic profiles of all 51 cases were obtained, with a median coverage of 564x and a total of 190 individual genomic alterations (GAs). GAs per specimen was a mean of 3.7 (range 0-10).Cancer genomes are characterized by 50% (80/190) non-synonymous base substitutions, 15% (29/190) insertions or deletion, and 3% (5/190) splice site mutation. TP53 mutation was the most common GAs (15%, n=29/190), followed by CDKN2A homozygous loss (5%, n=10/190), KRAS mutation (4%, n=8/190), EGFR mutation (4%, n=8/190) and MDM2 amplification (2%, n=5/190). As per NCCN guidelines, targetable GAs were identified in 16 patients (31%) (BRAF mutation [n=1], EGFR mutation [n=8], ERBB2 mutation [n=4], MET amplification [n=1], KIF5B-RET rearrangement [n=2], CCDC6-RET rearrangement [n=1], CD74-ROS1 rearrangement [n=1], EZR-ROS1 rearrangement [n=5], and SLC34A2-ROS1 rearrangement [n=1]).ConclusionFifty eight percent of patients wild type by standard testing for EGFR/KRAS/ALK have GAs identifiable by CGP that suggest benefit from target therapy. CGP used when standard molecular testing for NSCLC is negative can reveal additional avenues of benefit from targeted therapy.
| S-EPMC5029692 | biostudies-literature
Project description:ObjectiveThe aim of this study was to predict the long-term survival probability of patients with ampullary adenocarcinoma (AAC), which would provide a theoretical basis for the long-term care of these patients.MethodsData on patients with AAC during 2004-2015 were obtained from the Surveillance, Epidemiology, and End Results database, which were split at a 7:3 ratio into two independent cohorts: training and testing cohorts. Differences in survival between the two groups were tested using the Kaplan-Meier estimator and log-rank test methods. We constructed six survival analysis methods: the American Joint Committee on Cancer TNM stage, Cox Proportional Hazards regression, CoxTime, DeepSurv, XGBoost Survival Embeddings, and Random Survival Forest. The performances of these models were evaluated using the C-index, receiver operating characteristic (ROC), and calibration curves.ResultsThis study included 2,935 patients with AAC. Univariate Cox regression analyses of the training cohort indicated that race, marital status at diagnosis, scope of regional lymph node surgery, tumor grade, summary stage, American Joint Committee on Cancer stage, TNM stage T, and TNM stage N were important factors affecting survival (P < 0.05). The results of the C-index indicated that DeepSurv performed the best among the six models, with the highest C-index of 0.731. The areas under the ROC curves of the DeepSurv model at the 1-year, 3-year, 5-year, and 10-year time points were 0.823, 0.786, 0.803, and 0.813, respectively. The calibration curve indicated that DeepSurv performed well, with good calibration.ConclusionsMachine learning models such as DeepSurv have a stronger performance in the survival analysis of patients with AAC.
| S-EPMC9583040 | biostudies-literature
Project description:UnlabelledBrain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched brain metastases, primary tumors, and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically informative alterations in the brain metastases not detected in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were genetically homogenous. Distal extracranial and regional lymph node metastases were highly divergent from brain metastases. We detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases.SignificanceDecisions for individualized therapies in patients with brain metastasis are often made from primary-tumor biopsies. We demonstrate that clinically actionable alterations present in brain metastases are frequently not detected in primary biopsies, suggesting that sequencing of primary biopsies alone may miss a substantial number of opportunities for targeted therapy.
| S-EPMC4916970 | biostudies-literature
Project description:Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10-8) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.
| S-EPMC7749177 | biostudies-literature
Project description:BackgroundDuodenal papilla carcinoma (DPC) is a rare malignancy of the gastrointestinal tract with high recurrence rate, and the pathogenesis of this highly malignant neoplasm is yet to be fully elucidated. This study aims to identify key genes to further understand the biology and pathogenesis underlying the molecular alterations driving DPC, which could be potential diagnostic or therapeutic targets.MethodsTumor samples of three DPC patients were collected and integrating RNA-seq analysis of tumor tissues and matched normal tissues were performed to discover differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were carried out to understand the potential bio-functions of the DPC differentially expressed genes (DEGs). Protein-protein interaction (PPI) network was constructed for functional modules analysis and identification of hub genes. qRT-PCR of clinical samples was conducted to validate the expression level of the hub genes.ResultsA total of 110 DEGs were identified from our RNA-seq data, GO and KEGG analyses showed that the DEGs were mainly enriched in multiple cancer-related functions and pathways, such as cell proliferation, IL-17signaling pathway, Jak-STAT signaling pathway, PPAR signaling pathway. The PPI network screened out five hub genes including IL-6, LCN2, FABP4, LEP and MMP1, which were identified as core genes in the network and the expression value were validated by qRT-PCR. The hub genes identified in this work were suggested to be potential therapeutic targets of DPC.DiscussionThe current study may provide new insight into the exploration of DPC pathogenesis and the screened hub genes may serve as potential diagnostic indicator and novel therapeutic target.
| S-EPMC7789135 | biostudies-literature
Project description:AbstractThis study is to identify potential biomarkers and therapeutic targets for lung adenocarcinoma (LUAD).GSE6044 and GSE118370 raw data from the Gene Expression Omnibus database were normalized with Robust Multichip Average. After merging these two datasets, the combat function of sva packages was used to eliminate batch effects. Then, limma packages were used to filtrate differentially expressed genes. We constructed protein-protein interaction relationships using STRING database and hub genes were identified based on connectivity degrees. The cBioportal database was used to explore the alterations of the hub genes. The promoter methylation of cyclin dependent kinase 1 (CDK1) and polo-like Kinase 1 (PLK1) and their association with tumor immune infiltration in patients with LUAD were investigated using DiseaseMeth version 2.0 and TIMER databases. The Cancer Genome Atlas-LUAD dataset was used to perform gene set enrichment analysis.We identified 10 hub genes, which were upregulated in LUAD, among which 8 were successfully verified in the Cancer Genome Atlas and Oncomine databases. Kaplan-Meier analysis indicated that the expressions of CDK1 and PLK1 in LUAD patients were associated with overall survival and disease-free survival. The methylation levels in the promoter regions of these 2 genes in LUAD patients were lower than those in normal lung tissues. Their expressions in LUAD were associated with tumor stages and relative abundance of tumor infiltrating immune cells, such as B cells, CD4+ T cells, and macrophages. Moreover, cell cycle, DNA replication, homologous recombination, mismatch repair, P53 signaling pathway, and small cell lung cancer signaling were significantly enriched in CDK1 and PLK1 high expression phenotype.CDK1 and PLK1 may be used as potential biomarkers and therapeutic targets for LUAD.
| S-EPMC8360490 | biostudies-literature
Project description:The AlkB family consists of Fe(II)- and α-ketoglutarate-dependent dioxygenases that can catalyze demethylation on a variety of substrates, such as RNA and DNA, subsequently affecting tumor progression and prognosis. However, their detailed functional roles in lung adenocarcinoma (LUAD) have not been clarified in a comprehensive manner. In this study, several bioinformatics databases, such as ONCOMINE, TIMER, and DiseaseMeth, were used to evaluate the expression profiles and prognostic significance of the AlkB family (ALKBH1-8 and FTO) in LUAD. The expression levels of ALKBH1/2/4/5/7/8 were significantly increased in LUAD tissues, while the expression levels of ALKBH3/6 and FTO were decreased. The main functions of differentially expressed AlkB homologs are related to the hematopoietic system and cell adhesion molecules. We also found that the expression profiles of the AlkB family are highly correlated with infiltrating immune cells (i.e., B cells, CD8 + T cells, CD4 + T cells, macrophages, neutrophils and dendritic cells). In addition, DNA methylation analysis indicated that the global methylation levels of ALKBH1/2/4/5/6/8 and FTO were decreased, while the global methylation levels of ALKBH3/7 were increased. In addition, the patients with upregulated ALKBH2 have significantly poor overall survival (OS) and post-progressive survival (PPS). Taken together, our work could provide insightful information about aberrant AlkB family members as potential biomarkers for the diagnostic and prognostic evaluation of LUAD. Especially, ALKBH2 could be served as a therapeutic candidate for treating LUAD.
| S-EPMC8209387 | biostudies-literature