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Radiology and Oncology Sep 2019Background Colorectal cancer is a successful model of genetic biomarker development in oncology. Currently, several predictive or prognostic genetic alterations have... (Review)
Review
Background Colorectal cancer is a successful model of genetic biomarker development in oncology. Currently, several predictive or prognostic genetic alterations have been identified and are used in clinical practice. The RAS gene family, which includes KRAS and NRAS act as predictors for anti-epithelial growth factor receptor treatment (anti-EGFR), and it has been suggested that NRAS mutations also play a role in prognosis: patients harboring NRAS alterations have a significantly shorter survival compared to those with wild type tumours. BRAF V600E mutations are rare and occur mostly in tumors located in the ascending colon in elderly female patients. BRAF is instrumental in establishing prognosis: survival is shorter by 10-16 months in BRAF-mutant patients, and BRAF may be a negative prognostic factor for patients who undergo hepatic or pulmonary metastasectomy. Moreover, this mutation is used as a negative predictive factor for anti-EGFR therapies. Two new biomarkers have recently been added to the metastatic colorectal cancer panel: HER2 and microsatellite instability. While HER2 is still being investigated in different prospective studies in order to validate its prognostic role, microsatellite instability already guides clinical decisions in substituted with advanced colorectal cancer. Conclusions There are current evidences that support using above mentioned genetic biomarkers to better identify the right medicine that is supposed to be used in the right patient. This approach contributes to a more individualized patient-oriented treatment in daily clinical practice.
Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; ErbB Receptors; Female; Genes, erbB-2; Genes, ras; Genetic Markers; Humans; Ipilimumab; Male; Microsatellite Instability; Mutation; Panitumumab; Prognosis; Proto-Oncogene Proteins B-raf; Sex Factors; Trastuzumab
PubMed: 31553708
DOI: 10.2478/raon-2019-0033 -
Nature Communications May 2022c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with...
c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Analyses of clinical specimens reveal that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with ChIP-seq uncover an increase in RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.
Topics: Cell Line, Tumor; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Genes, myc; Humans; Male; Prostate; Prostatic Neoplasms; Proto-Oncogene Proteins c-myc; Receptors, Androgen
PubMed: 35562350
DOI: 10.1038/s41467-022-30257-z -
Cancer Cell Mar 2024KRAS inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRAS-mutated lung cancers; however, most patients eventually develop resistance. In...
KRAS inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRAS-mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRAS and STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRAS and Kras lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives AST and modulates response to KRAS inhibition. We identify an intermediate high-plastic cell state marked by expression of an AST plasticity signature and Krt6a. Notably, expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.
Topics: Animals; Mice; Humans; Proto-Oncogene Proteins p21(ras); Lung Neoplasms; Genes, ras; Carcinoma, Squamous Cell; Mutation; Acetonitriles; Piperazines; Pyrimidines
PubMed: 38402609
DOI: 10.1016/j.ccell.2024.01.012 -
Gastroenterology Dec 2020The pattern of genetic alterations in cancer driver genes in patients with hepatocellular carcinoma (HCC) is highly diverse, which partially explains the low efficacy of...
BACKGROUND AND AIMS
The pattern of genetic alterations in cancer driver genes in patients with hepatocellular carcinoma (HCC) is highly diverse, which partially explains the low efficacy of available therapies. In spite of this, the existing mouse models only recapitulate a small portion of HCC inter-tumor heterogeneity, limiting the understanding of the disease and the nomination of personalized therapies. Here, we aimed at establishing a novel collection of HCC mouse models that captured human HCC diversity.
METHODS
By performing hydrodynamic tail-vein injections, we tested the impact of altering a well-established HCC oncogene (either MYC or β-catenin) in combination with an additional alteration in one of eleven other genes frequently mutated in HCC. Of the 23 unique pairs of genetic alterations that we interrogated, 9 were able to induce HCC. The established HCC mouse models were characterized at histopathological, immune, and transcriptomic level to identify the unique features of each model. Murine HCC cell lines were generated from each tumor model, characterized transcriptionally, and used to identify specific therapies that were validated in vivo.
RESULTS
Cooperation between pairs of driver genes produced HCCs with diverse histopathology, immune microenvironments, transcriptomes, and drug responses. Interestingly, MYC expression levels strongly influenced β-catenin activity, indicating that inter-tumor heterogeneity emerges not only from specific combinations of genetic alterations but also from the acquisition of expression-dependent phenotypes.
CONCLUSIONS
This novel collection of murine HCC models and corresponding cell lines establishes the role of driver genes in diverse contexts and enables mechanistic and translational studies.
Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Computational Biology; Disease Models, Animal; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Genetic Heterogeneity; Humans; Liver Neoplasms; Male; Mice; Mice, Transgenic; Proto-Oncogenes; Tumor Escape; Tumor Microenvironment
PubMed: 32814112
DOI: 10.1053/j.gastro.2020.08.015 -
International Journal of Molecular... Dec 2023Neuroblastoma (NB), a childhood cancer arising from the neural crest, poses significant clinical challenges, particularly in cases featuring amplification of the... (Review)
Review
Neuroblastoma (NB), a childhood cancer arising from the neural crest, poses significant clinical challenges, particularly in cases featuring amplification of the oncogene. Epigenetic factors play a pivotal role in normal neural crest and NB development, influencing gene expression patterns critical for tumorigenesis. This review delves into the multifaceted interplay between MYCN and known epigenetic modifications during NB genesis, shedding light on the intricate regulatory networks underlying the disease. We provide an extensive survey of known epigenetic mechanisms, encompassing DNA methylation, histone modifications, non-coding RNAs, super-enhancers (SEs), bromodomains (BET), and chromatin modifiers in -amplified (MNA) NB. These epigenetic changes collectively contribute to the dysregulated gene expression landscape observed in MNA NB. Furthermore, we review emerging therapeutic strategies targeting epigenetic regulators, including histone deacetylase inhibitors (HDACi), histone methyltransferase inhibitors (HMTi), and DNA methyltransferase inhibitors (DNMTi). We also discuss and summarize current drugs in preclinical and clinical trials, offering insights into their potential for improving outcomes for MNA NB patients.
Topics: Humans; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Genes, myc; N-Myc Proto-Oncogene Protein; Neuroblastoma
PubMed: 38069407
DOI: 10.3390/ijms242317085 -
Cancer Medicine Apr 2021This study aimed to explore the novel biomarkers for immune checkpoint inhibitor (ICI) responses in non-small cell lung cancer (NSCLC) by integrating genomic profiling,...
OBJECTIVES
This study aimed to explore the novel biomarkers for immune checkpoint inhibitor (ICI) responses in non-small cell lung cancer (NSCLC) by integrating genomic profiling, tumor mutational burden (TMB), and expression of programmed death receptor 1 ligand (PD-L1).
MATERIALS AND METHODS
Tumor and blood samples from 637 Chinese patients with NSCLC were collected for targeted panel sequencing. Genomic alterations, including single nucleotide variations, insertions/deletions, copy number variations, and gene rearrangements, were assessed and TMB was computed. TMB-high (TMB-H) was defined as ≥10 mutations/Mb. PD-L1 positivity was defined as ≥1% tumor cells with membranous staining. Genomic data and ICI outcomes of 240 patients with NSCLC were derived from cBioPortal.
RESULTS
EGFR-sensitizing mutations, ALK, RET, and ROS1 rearrangements were associated with lower TMB and PD-L1+/TMB-H proportions, whereas KRAS, ALK, RET, and ROS1 substitutions/indels correlated with higher TMB and PD-L1+/TMB-H proportions than wild-type genotypes. Histone-lysine N-methyltransferase 2 (KMT2) family members (KMT2A, KMT2C, and KMT2D) were frequently mutated in NSCLC tumors, and these mutations were associated with higher TMB and PD-L1 expression, as well as higher PD-L1+/TMB-H proportions. Specifically, patients with KMT2C mutations had higher TMB and PD-L1+/TMB-H proportions than wild-type patients. The median progression-free survival (PFS) was 5.47 months (95% CI 2.5-NA) in patients with KMT2C mutations versus 3.17 months (95% CI 2.6-4.27) in wild-type patients (p = 0.058). Furthermore, in patients with NSCLC who underwent ICI treatment, patients with TP53/KMT2C co-mutations had significantly longer PFS and greater durable clinical benefit (HR: 0.48, 95% CI: 0.24-0.94, p = 0.033). TP53 mutation combined with KMT2C or KRAS mutation was a better biomarker with expanded population benefit from ICIs therapy and increased the predictive power (HR: 0.46, 95% CI: 0.26-0.81, p = 0.007).
CONCLUSION
We found that tumors with different alterations in actionable target genes had variable expression of PD-L1 and TMB in NSCLC. TP53/KMT2C co-mutation might serve as a predictive biomarker for ICI responses in NSCLC.
IMPLICATIONS FOR PRACTICE
Cancer immunotherapies, especially immune checkpoint inhibitors (ICIs), have revolutionized the treatment of non-small cell lung cancer (NSCLC); however, only a proportion of patients derive durable responses to this treatment. Biomarkers with greater accuracy are highly needed. In total, 637 Chinese patients with NSCLC were analyzed using next-generation sequencing and IHC to characterize the unique features of genomic alterations and TMB and PD-L1 expression. Our study demonstrated that KMT2C/TP53 co-mutation might be an accurate, cost-effective, and reliable biomarker to predict responses to PD-1 blockade therapy in NSCLC patients and that adding KRAS to the biomarker combination creates a more robust parameter to identify the best responders to ICI therapy.
Topics: Aged; Anaplastic Lymphoma Kinase; B7-H1 Antigen; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; China; Female; Gene Rearrangement; Genes, erbB-1; Genes, p53; Genes, ras; Genetic Markers; Genetic Profile; High-Throughput Nucleotide Sequencing; Histone-Lysine N-Methyltransferase; Humans; Immune Checkpoint Inhibitors; Immunotherapy, Adoptive; Lung Neoplasms; Male; Middle Aged; Mutation; Progression-Free Survival; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ret; Retrospective Studies
PubMed: 33655698
DOI: 10.1002/cam4.3649 -
ELife May 2021What level of Ras genes activity leads to the development of cancer?
What level of Ras genes activity leads to the development of cancer?
Topics: Codon; Genes, ras
PubMed: 33998996
DOI: 10.7554/eLife.69192 -
Blood Mar 2023Upregulation of the proto-oncogene T-cell leukemia/lymphoma 1A (TCL1A) is causally implicated in various B-cell and T-cell malignancies. High-level TCL1A correlates with...
Upregulation of the proto-oncogene T-cell leukemia/lymphoma 1A (TCL1A) is causally implicated in various B-cell and T-cell malignancies. High-level TCL1A correlates with aggressive disease features and inferior clinical outcomes. However, the molecular and cell biological consequences of, particularly nuclear, TCL1A are not fully elucidated. We observed here in mouse models of subcellular site-specific TCL1A-induced lymphomagenesis that TCL1A exerts a strong transforming impact via nuclear topography. In proteomic screens of TCL1A-bound molecules in chronic lymphocytic leukemia (CLL) cells and B-cell lymphoma lines, we identified regulators of cell cycle and DNA repair pathways as novel TCL1A interactors, particularly enriched under induced DNA damage and mitosis. By functional mapping and in silico modeling, we specifically identified the mitotic checkpoint protein, cell division cycle 20 (CDC20), as a direct TCL1A interactor. According to the regulatory impact of TCL1A on the activity of the CDC20-containing mitotic checkpoint and anaphase-promoting complexes during mitotic progression, TCL1A overexpression accelerated cell cycle transition in B-cell lymphoma lines, impaired apoptotic damage responses in association with pronounced chromosome missegregation, and caused cellular aneuploidy in Eμ-TCL1A mice. Among hematopoietic cancers, CDC20 levels seem particularly low in CLL. CDC20 expression negatively correlated with TCL1A and lower expression marked more aggressive and genomically instable disease and cellular phenotypes. Knockdown of Cdc20 in TCL1A-initiated murine CLL promoted aneuploidy and leukemic acceleration. Taken together, we discovered a novel cell cycle-associated effect of TCL1A abrogating controlled cell cycle transition. This adds to our concept of oncogenic TCL1A by targeting genome stability. Overall, we propose that TCL1A acts as a pleiotropic adapter molecule with a synergistic net effect of multiple hijacked pathways.
Topics: Mice; Animals; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins; Proteomics; Lymphoma, B-Cell; Cell Cycle; Proto-Oncogenes; Cell Cycle Proteins; Mitosis
PubMed: 36179280
DOI: 10.1182/blood.2022015494 -
Cancer Metastasis Reviews Dec 2020One of the mechanisms potentially explaining the discrepancy between the number of human genes and the functional complexity of organisms is generating alternative... (Review)
Review
One of the mechanisms potentially explaining the discrepancy between the number of human genes and the functional complexity of organisms is generating alternative splice variants, an attribute of the vast majority of multi-exon genes. Members of the RAS family, such as NRAS, KRAS and HRAS, all of which are of significant importance in cancer biology, are no exception. The structural and functional differences of these splice variants, particularly if they contain the canonical (and therefore routinely targeted for diagnostic purposes) hot spot mutations, pose a significant challenge for targeted therapies. We must therefore consider whether these alternative splice variants constitute a minor component as originally thought and how therapies targeting the canonical isoforms affect these alternative splice variants and their overall functions.
Topics: Alternative Splicing; Amino Acid Sequence; Animals; Base Sequence; Genes, ras; Humans; Mutation; Neoplasms; Protein Processing, Post-Translational; Proto-Oncogene Proteins p21(ras); RNA, Messenger
PubMed: 32772213
DOI: 10.1007/s10555-020-09920-8 -
Oncogene May 2023KRAS, HRAS and NRAS proto-oncogenes belong to a family of 40 highly homologous genes, which in turn are a subset of a superfamily of >160 genes encoding small GTPases....
KRAS, HRAS and NRAS proto-oncogenes belong to a family of 40 highly homologous genes, which in turn are a subset of a superfamily of >160 genes encoding small GTPases. RAS proteins consist of a globular G-domain (aa1-166) and a 22-23 aa unstructured hypervariable region (HVR) that mediates membrane targeting. The evolutionary origins of the RAS isoforms, their HVRs and alternative splicing of the KRAS locus has not been explored. We found that KRAS is basal to the RAS proto-oncogene family and its duplication generated HRAS in the common ancestor of vertebrates. In a second round of duplication HRAS generated NRAS and KRAS generated an additional RAS gene we have designated KRASBL, absent in mammals and birds. KRAS4A arose through a duplication and insertion of the 4 exon of NRAS into the 3 intron of KRAS. We found evolutionary conservation of a short polybasic region (PBR1) in HRAS, NRAS and KRAS4A, a second polybasic region (PBR2) in KRAS4A, two neutralized basic residues (NB) and a serine in KRAS4B and KRASBL, and a modification of the CaaX motif in vertebrates with farnesyl rather than geranylgeranyl polyisoprene lipids, suggesting that a less hydrophobic membrane anchor is critical to RAS protein function. The persistence of four RAS isoforms through >400 million years of evolution argues strongly for differential function.
Topics: Animals; Humans; Proto-Oncogene Proteins p21(ras); Protein Isoforms; ras Proteins; Genes, ras; Mammals
PubMed: 37031342
DOI: 10.1038/s41388-023-02672-z