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Cancer Discovery Dec 2023This article presents a review of recent major advances in precision oncology and the future implications of these advances, specifying the iterative progress achieved... (Review)
Review
This article presents a review of recent major advances in precision oncology and the future implications of these advances, specifying the iterative progress achieved from the end of 2022 through 2023. We discuss the different classes of precision oncology drugs and associated biomarkers as well as the improvements in clinical trial design that have enabled the efficient testing of these drugs.
Topics: Humans; Neoplasms; Precision Medicine; Medical Oncology; Biomarkers, Tumor
PubMed: 38084089
DOI: 10.1158/2159-8290.CD-23-1194 -
Nature Communications Aug 2023The immune system can monitor tumor development, and DNA methylation is involved in the body's immune response to tumors. In this work, we investigate whether DNA...
The immune system can monitor tumor development, and DNA methylation is involved in the body's immune response to tumors. In this work, we investigate whether DNA methylation alterations in peripheral blood mononuclear cells (PBMCs) could be used as markers for early detection of breast cancer (BC) from the perspective of tumor immune alterations. We identify four BC-specific methylation markers by combining Infinium 850 K BeadChips, pyrosequencing and targeted bisulfite sequencing. Based on the four methylation markers in PBMCs of BC, we develop an efficient and convenient multiplex methylation-specific quantitative PCR assay for the detection of BC and validate its diagnostic performance in a multicenter cohort. This assay was able to distinguish early-stage BC patients from normal controls, with an AUC of 0.940, sensitivity of 93.2%, and specificity of 90.4%. More importantly, this assay outperformed existing clinical diagnostic methods, especially in the detection of early-stage and minimal tumors.
Topics: Humans; Female; DNA Methylation; Breast Neoplasms; Leukocytes, Mononuclear; Biomarkers, Tumor; Early Detection of Cancer; Multiplex Polymerase Chain Reaction
PubMed: 37550304
DOI: 10.1038/s41467-023-40389-5 -
Genes Jun 2023Breast cancer is the second most frequent cancer in the world. It is a heterogeneous disease and the leading cause of cancer mortality in women. Advances in molecular... (Review)
Review
Breast cancer is the second most frequent cancer in the world. It is a heterogeneous disease and the leading cause of cancer mortality in women. Advances in molecular technologies allowed for the identification of new and more specifics biomarkers for breast cancer diagnosis, prognosis, and risk prediction, enabling personalized treatments, improving therapy, and preventing overtreatment, undertreatment, and incorrect treatment. Several breast cancer biomarkers have been identified and, along with traditional biomarkers, they can assist physicians throughout treatment plan and increase therapy success. Despite the need of more data to improve specificity and determine the real clinical utility of some biomarkers, others are already established and can be used as a guide to make treatment decisions. In this review, we summarize the available traditional, novel, and potential biomarkers while also including gene expression profiles, breast cancer single-cell and polyploid giant cancer cells. We hope to help physicians understand tumor specific characteristics and support decision-making in patient-personalized clinical management, consequently improving treatment outcome.
Topics: Humans; Female; Breast Neoplasms; Biomarkers, Tumor; Prognosis; Treatment Outcome; Transcriptome
PubMed: 37510269
DOI: 10.3390/genes14071364 -
International Journal of Biological... 2023Nucleolar and spindle-associated protein 1 (NUSAP1) is a microtubule-associated protein that plays a crucial role in mitosis. Despite initial reports suggesting a...
Nucleolar and spindle-associated protein 1 (NUSAP1) is a microtubule-associated protein that plays a crucial role in mitosis. Despite initial reports suggesting a potential involvement of NUSAP1 in tumor progression and malignant cell regulation, there has been no systematic analysis of its role in the tumor immune microenvironment, nor its predictive value for prognosis and immunotherapy response across different cancer types. In this study, we analyze NUSAP1 mRNA and protein expression levels in various human normal and tumor tissues, using data from TCGA, GTEx, CPTAC, HPA databases, and clinical samples. Our findings reveal that NUSAP1 is highly expressed in multiple tumor tissues across most cancer types and is primarily expressed in malignant and immune cells, according to single-cell sequencing data from the TISCH database. Prognostic analysis based on curated survival data from the TCGA database indicates that NUSAP1 expression levels can predict clinical outcomes for 26 cancer types. Furthermore, Gene Set Enrichment Analysis (GSEA) suggests that NUSAP1 promotes cell proliferation, tumor cell invasion, and regulation of anti-tumor response. Analysis of immune score, immune cell infiltration, and anti-cancer immunity cycle using ESTIMATE, TIMER, and TIP databases show that high NUSAP1 levels are associated with low CD4T and NKT cell infiltration but high Th2 and MDSC infiltration, inversely correlated with antigen-presenting molecules and positively correlated with a variety of immune negative regulatory molecules. Notably, patients with melanoma, lung, and kidney cancer with high NUSAP1 expression levels have shorter survival times and lower immunotherapy response rates. Using Cmap analysis, we identify Entinostat and AACOCF3 as potential inhibitors of NUSAP1-mediated pro-oncogenic effects. and experiments further confirm that NUSAP1 knockdown significantly reduces the proliferation ability of A549 and MCF-7 cells. Overall, our study highlights the potential of NUSAP1 expression as a novel biomarker for predicting prognosis and immuno-therapeutic efficacy across different human cancers and suggests its potential for developing novel antitumor drugs or improving immunotherapy.
Topics: Humans; Cell Line, Tumor; Microtubule-Associated Proteins; Cell Proliferation; Kidney Neoplasms; Biomarkers, Tumor; Immunotherapy; Tumor Microenvironment
PubMed: 37781040
DOI: 10.7150/ijbs.80017 -
GeroScience Jun 2023Progress in ovarian cancer treatment lags behind other tumor types. With diagnosis usually at an advanced stage, there is a high demand for reliable prognostic...
Progress in ovarian cancer treatment lags behind other tumor types. With diagnosis usually at an advanced stage, there is a high demand for reliable prognostic biomarkers capable of the selection of effective chemo- and targeted therapies. Our goal was to establish a large-scale transcriptomic database and use it to uncover and rank survival-associated genes. Ovarian cancer cohorts with transcriptome-level gene expression data and clinical follow-up were identified from public repositories. All samples were normalized and entered into an integrated database. Cox univariate survival analysis was performed for all genes and was followed by multivariate analysis for selected genes involving clinical and pathological variables. False discovery rate was computed for multiple hypothesis testing and a 1% cutoff was used to determine statistical significance. The complete integrated database comprises 1816 samples from 17 datasets. Altogether, 2468 genes were correlated to progression-free survival (PFS), and 704 genes were correlated with overall survival (OS). The most significant genes were WBP1L, ASAP3, CNNM2, and NCAPH2 for progression-free survival and CSE1L, NUAK1, ALPK2, and SHKBP1 for overall survival. Genes significant for PFS were also preferentially significant for predicting OS as well. All data including HR and p values as well as the used cutoff values for all genes for both PFS and OS are provided to enable the ranking of future biomarker candidates across all genes. Our results help to prioritize genes and to neglect those which are most likely to fail in studies aiming to establish new clinically useful biomarkers and therapeutic targets in serous ovarian cancer.
Topics: Humans; Female; Prognosis; Biomarkers, Tumor; Ovarian Neoplasms; Cystadenocarcinoma, Serous; Transcription Factors; Protein Kinases; Repressor Proteins
PubMed: 36856946
DOI: 10.1007/s11357-023-00742-4 -
Tumour Biology : the Journal of the... 2024Circulating tumor DNA (ctDNA), i.e., DNA shed from tumor cells into the bloodstream, is emerging as one of the most useful plasma biomarkers in patients with multiple... (Review)
Review
Circulating tumor DNA (ctDNA), i.e., DNA shed from tumor cells into the bloodstream, is emerging as one of the most useful plasma biomarkers in patients with multiple types of cancer, including patients with non-small cell lung cancer (NSCLC). Indeed, NSCLC was the first malignancy in which measurement of ctDNA was approved for clinical use, i.e., mutational testing of EGFR for predicting response to EGFR tyrosine kinase inhibitors in patients with advanced disease. Although historically the gold standard method for EGFR mutational analysis required tumor tissue, the use of ctDNA is more convenient and safer for patients, results in a faster turn-around-time for return of results, provides a more complete representation of genetic alteration in heterogeneous tumors and is less costly to perform. Emerging uses of ctDNA in patients with lung or suspected lung cancer include screening for early disease, surveillance following initial treatment and monitoring response to therapy in metastatic disease. For evaluating therapy response, ctDNA appears to be especially useful in patients receiving targeted therapies against driver oncogenes or immunotherapy. Further work should not only validate these emerging findings but also aim to optimize and standardize ctDNA assays.
Topics: Humans; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Circulating Tumor DNA; ErbB Receptors; Mutation; Biomarkers, Tumor
PubMed: 37270828
DOI: 10.3233/TUB-220044 -
The Journal of Clinical Investigation Jan 2024Several poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved by FDA to treat cancer with BRCA mutations. BRCA mutations are considered to fuel a PARPi...
Several poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved by FDA to treat cancer with BRCA mutations. BRCA mutations are considered to fuel a PARPi killing effect by inducing apoptosis. However, resistance to PARPi is frequently observed in the clinic due to an incomplete understanding on the molecular basis of PARPi function and a lack of good markers, beyond BRCA mutations, to predict response. Here, we show that gasdermin C (GSDMC) sensitized tumor cells to PARPi in vitro and in immunocompetent mice and caused durable tumor regression in an immune-dependent manner. A high expression level of GSDMC predicted better response to PARPi treatment in patients with triple-negative breast cancer (TNBC). PARPi treatment triggered GSDMC/caspase-8-mediated cancer cell pyroptosis (CCP) that enhanced PARPi killing of tumor cells. GSDMC-mediated CCP increased memory CD8+ T cell population in lymph node (LN), spleen, and tumor and, thus, promoted cytotoxic CD8+ T cell infiltration in the tumor microenvironment. T cell-derived granzyme B (GZMB) activated caspase-6, which subsequently cleaved GSDMC to induce pyroptosis. Interestingly, IFN-γ induced GSDMC expression, which, in turn, enhanced the cytotoxicity of PARPi and T cells. Importantly, GSDMC promoted tumor clearance independent of BRCA deficiency in multiple cancer types with PARPi treatment. This study identifies a general marker and target for PARPi therapy and offers insights into the mechanism of PARPi function.
Topics: Humans; Animals; Mice; Poly(ADP-ribose) Polymerase Inhibitors; Gasdermins; Neoplasms; Apoptosis; Pyroptosis; Tumor Microenvironment; Biomarkers, Tumor
PubMed: 37883181
DOI: 10.1172/JCI166841 -
Nature Communications Dec 2023Single-cell and spatial technologies that profile gene expression across a whole tissue are revolutionizing the resolution of molecular states in clinical samples....
Single-cell and spatial technologies that profile gene expression across a whole tissue are revolutionizing the resolution of molecular states in clinical samples. Current commercially available technologies provide whole transcriptome single-cell, whole transcriptome spatial, or targeted in situ gene expression analysis. Here, we combine these technologies to explore tissue heterogeneity in large, FFPE human breast cancer sections. This integrative approach allowed us to explore molecular differences that exist between distinct tumor regions and to identify biomarkers involved in the progression towards invasive carcinoma. Further, we study cell neighborhoods and identify rare boundary cells that sit at the critical myoepithelial border confining the spread of malignant cells. Here, we demonstrate that each technology alone provides information about molecular signatures relevant to understanding cancer heterogeneity; however, it is the integration of these technologies that leads to deeper insights, ushering in discoveries that will progress oncology research and the development of diagnostics and therapeutics.
Topics: Humans; Female; Tumor Microenvironment; Biomarkers, Tumor; Breast Neoplasms; Gene Expression Profiling; Transcriptome; Single-Cell Analysis
PubMed: 38114474
DOI: 10.1038/s41467-023-43458-x -
Journal of Clinical Pathology Dec 2023GATA binding protein 3 (GATA3) is a zinc-finger pioneer transcription factor involved in diverse processes. GATA3 regulates gene expression through binding nucleosomal... (Review)
Review
GATA binding protein 3 (GATA3) is a zinc-finger pioneer transcription factor involved in diverse processes. GATA3 regulates gene expression through binding nucleosomal DNA and facilitating chromatin remodelling. Post-translational modifications modulate its activity. During development, GATA3 plays a key role in cell differentiation. Mutations in are linked to breast and bladder cancer. GATA3 expression is a feature of the luminal subtype of bladder cancer and has implications for immune status and therapeutic response. It also has clinical relevance in squamous cell carcinomas and soft tissue sarcomas. This paper reviews the structure and function of GATA3, its role in cancer and its use and pitfalls as an immunohistochemical marker.
Topics: Humans; Female; Breast; Urinary Bladder Neoplasms; Mutation; GATA3 Transcription Factor; Breast Neoplasms; Biomarkers, Tumor
PubMed: 37726118
DOI: 10.1136/jcp-2023-209017 -
Trends in Molecular Medicine Jul 2023Cancer cells accumulate many genetic alterations throughout their lifetime, but only a few of them drive cancer progression, termed driver mutations. Driver mutations... (Review)
Review
Cancer cells accumulate many genetic alterations throughout their lifetime, but only a few of them drive cancer progression, termed driver mutations. Driver mutations may vary between cancer types and patients, can remain latent for a long time and become drivers at particular cancer stages, or may drive oncogenesis only in conjunction with other mutations. The high mutational, biochemical, and histological tumor heterogeneity makes driver mutation identification very challenging. In this review we summarize recent efforts to identify driver mutations in cancer and annotate their effects. We underline the success of computational methods to predict driver mutations in finding novel cancer biomarkers, including in circulating tumor DNA (ctDNA). We also report on the boundaries of their applicability in clinical research.
Topics: Humans; Neoplasms; Mutation; Carcinogenesis; Biomarkers, Tumor
PubMed: 37076339
DOI: 10.1016/j.molmed.2023.03.007