scholarly journals An Investigation of Point Mutations Discovers Novel Genes and Their Corresponding Motifs in Pancreatic Cancer

2021 ◽  
Author(s):  
Amin Ghareyazi ◽  
Amir Mohseni ◽  
Hamed Dashti ◽  
Abdollah Dehzangi ◽  
Hamid R. Rabiee ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Point Mutations ◽  
Growth Factor Receptor ◽  
Causative Mutation ◽  
Cancer Subtypes ◽  
P53 Signaling ◽  
Pancreatic Cancers

It has now known that at least 10% of samples with pancreatic cancers (PC) contain a causative mutation in the known susceptibility genes, suggesting the importance of identifying cancer-associated genes that carry the causative mutations in high-risk individuals for early detection of PC. In this study, we develop a statistical pipeline using a new concept, called gene-motif, that utilizes both mutated genes and mutational processes to identify 4,211 3-nucleotide PC-associated gene-motifs within 203 significantly mutated genes in PC. Using these gene-motifs as distinguishable features for pancreatic cancer subtyping results in identifying five PC subtypes with distinguishable phenotypes and genotypes. Our comprehensive biological characterization reveals that these PC subtypes are associated with different molecular mechanisms including unique cancer related signaling pathways, in which for most of the subtypes targeted treatment options are currently available. Some of the pathways we identified in all five PC subtypes, including cell cycle and the Axon guidance pathway are frequently seen and mutated in cancer. We also identified Protein kinase C, EGFR (epidermal growth factor receptor) signaling pathway and P53 signaling pathways as potential targets for treatment of the PC subtypes. Altogether, our results uncover the importance of considering both the mutation type and mutated genes in the identification of cancer subtypes and biomarkers.

scholarly journals Whole-Genome Analysis of De Novo Somatic Point Mutations Reveals Novel Mutational Biomarkers in Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4376
Author(s):  
Amin Ghareyazi ◽  
Amir Mohseni ◽  
Hamed Dashti ◽  
Amin Beheshti ◽  
Abdollah Dehzangi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Treatment Options ◽  
Point Mutations ◽  
Growth Factor Receptor ◽  
Causative Mutation ◽  
Whole Genome Analysis ◽  
Cancer Subtypes

It is now known that at least 10% of samples with pancreatic cancers (PC) contain a causative mutation in the known susceptibility genes, suggesting the importance of identifying cancer-associated genes that carry the causative mutations in high-risk individuals for early detection of PC. In this study, we develop a statistical pipeline using a new concept, called gene-motif, that utilizes both mutated genes and mutational processes to identify 4211 3-nucleotide PC-associated gene-motifs within 203 significantly mutated genes in PC. Using these gene-motifs as distinguishable features for pancreatic cancer subtyping results in identifying five PC subtypes with distinguishable phenotypes and genotypes. Our comprehensive biological characterization reveals that these PC subtypes are associated with different molecular mechanisms including unique cancer related signaling pathways, in which for most of the subtypes targeted treatment options are currently available. Some of the pathways we identified in all five PC subtypes, including cell cycle and the Axon guidance pathway are frequently seen and mutated in cancer. We also identified Protein kinase C, EGFR (epidermal growth factor receptor) signaling pathway and P53 signaling pathways as potential targets for treatment of the PC subtypes. Altogether, our results uncover the importance of considering both the mutation type and mutated genes in the identification of cancer subtypes and biomarkers.

scholarly journals Multi-omic tumor data reveal diversity of molecular mechanisms that correlate with survival

2018 ◽  
Author(s):  
Daniele Ramazzotti ◽  
Avantika Lal ◽  
Bo Wang ◽  
Serafim Batzoglou ◽  
Arend Sidow
Keyword(s):  
Molecular Mechanisms ◽  
Molecular Subtypes ◽  
Point Mutations ◽  
Integrated Analysis ◽  
Tumor Type ◽  
Cancer Subtypes ◽  
Cancer Types ◽  
Copy Number Changes ◽  
Omic Data

Outcomes for cancer patients vary greatly even within the same tumor type, and characterization of molecular subtypes of cancer holds important promise for improving prognosis and personalized treatment. This promise has motivated recent efforts to produce large amounts of multidimensional genomic (‘multi-omic’) data, but current algorithms still face challenges in the integrated analysis of such data. Here we present Cancer Integration via Multikernel Learning (CIMLR), a new cancer subtyping method that integrates multi-omic data to reveal molecular subtypes of cancer. We apply CIMLR to multi-omic data from 36 cancer types and show significant improvements in both computational efficiency and ability to extract biologically meaningful cancer subtypes. The discovered subtypes exhibit significant differences in patient survival for 27 of 36 cancer types. Our analysis reveals integrated patterns of gene expression, methylation, point mutations and copy number changes in multiple cancers and highlights patterns specifically associated with poor patient outcomes.

scholarly journals PRMT1 regulates EGFR and Wnt signaling pathways and is a promising target for combinatorial treatment of breast cancer

2021 ◽  
Author(s):  
Samyuktha Suresh ◽  
Solène Huard ◽  
Amélie Brisson ◽  
Fariba Némati ◽  
Coralie Poulard ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Wnt Signaling ◽  
Signaling Pathways ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Xenograft Model ◽  
Growth Factor Receptor ◽  
Breast Cancer Cell Lines ◽  
Type I ◽  
Cancer Subtypes

Identifying new therapeutic strategies for triple-negative breast cancer (TNBC) patients is a priority as these patients are highly prone to relapse after chemotherapy. Here, we found that protein arginine methyltransferase 1 (PRMT1) is highly expressed in all breast cancer subtypes. Its depletion decreases cell survival by inducing DNA damage and apoptosis in various breast cancer cell lines. Transcriptomic analysis and chromatin immunoprecipitation revealed that PRMT1 regulates the epidermal growth factor receptor (EGFR) and the Wnt signaling pathways, reported to be activated in TNBC. The enzymatic activity of PRMT1 is also required to stimulate the canonical Wnt pathway. Recently developed type I PRMT inhibitors decrease breast cancer cell proliferation and show anti-tumor activity in a TNBC xenograft model. These inhibitors display synergistic interactions with some chemotherapies used to treat TNBC patients, as well as the EGFR inhibitor, erlotinib. Therefore, targeting PRMT1 in combination with drugs used in the clinic may improve current treatments for TNBC patients.

scholarly journals Molecular Mechanisms of Trastuzumab Resistance in HER2 Overexpressing Breast Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Gabriel L. Fiszman ◽  
María A. Jasnis
Keyword(s):  
Breast Cancer ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Breast Cancers ◽  
Trastuzumab Resistance ◽  
Alternative Pathways ◽  
Downstream Signaling ◽  
Therapeutic Modalities

The epidermal growth factor receptor 2 (HER2) is a tyrosine kinase overexpressed in nearly 20% to 25% of invasive breast cancers. Trastuzumab is a humanized monoclonal antibody that targets HER2. The majority of patients with metastatic breast cancer initially respond to trastuzumab, however, within 1 year of treatment disease progresses. Several molecular mechanisms have been described as contributing to the development of trastuzumab resistance. They could be grouped as impaired access of trastuzumab to HER2, upregulation of HER2 downstream signaling pathways, signaling of alternative pathways, and impaired immune antitumor mechanisms. However, since many of them have overlapping effects, it would be of great clinical impact to identify the principal signaling pathways involved in drug resistance. Significant efforts are being applied to find other therapeutic modalities besides trastuzumab treatment to be used alone or in combination with current modalities.

scholarly journals Biomarkers and Targeted Therapy in Pancreatic Cancer

2016 ◽  
Vol 8s1 ◽  
pp. BIC.S34414 ◽  
Author(s):  
Fataneh Karandish ◽  
Sanku Mallik
Keyword(s):  
Drug Delivery ◽  
Pancreatic Cancer ◽  
Signaling Pathways ◽  
Targeted Drug Delivery ◽  
Ductal Adenocarcinoma ◽  
Invasion And Metastasis ◽  
Critical Research ◽  
Cell Behaviors ◽  
Second Stage ◽  
Pancreatic Cancers

Pancreatic ductal adenocarcinoma (PDAC) constitutes 90% of pancreatic cancers. PDAC is a complex and devastating disease with only 1%–3% survival rate in five years after the second stage. Treatment of PDAC is complicated due to the tumor microenvironment, changing cell behaviors to the mesenchymal type, altered drug delivery, and drug resistance. Considering that pancreatic cancer shows early invasion and metastasis, critical research is needed to explore different aspects of the disease, such as elaboration of biomarkers, specific signaling pathways, and gene aberration. In this review, we highlight the biomarkers, the fundamental signaling pathways, and their importance in targeted drug delivery for pancreatic cancers.

scholarly journals Nanomedicine to Overcome Multidrug Resistance Mechanisms in Colon and Pancreatic Cancer: Recent Progress

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2058
Author(s):  
Raúl Ortíz ◽  
Francisco Quiñonero ◽  
Beatriz García-Pinel ◽  
Marco Fuel ◽  
Cristina Mesas ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Treatment ◽  
Recent Progress ◽  
Molecular Mechanisms ◽  
Resistance Mechanisms ◽  
New Horizons ◽  
Dna Repair Mechanisms ◽  
Pancreatic Cancers ◽  
Different Types ◽  
Repair Mechanisms

The development of drug resistance is one of the main causes of cancer treatment failure. This phenomenon occurs very frequently in different types of cancer, including colon and pancreatic cancers. However, the underlying molecular mechanisms are not fully understood. In recent years, nanomedicine has improved the delivery and efficacy of drugs, and has decreased their side effects. In addition, it has allowed to design drugs capable of avoiding certain resistance mechanisms of tumors. In this article, we review the main resistance mechanisms in colon and pancreatic cancers, along with the most relevant strategies offered by nanodrugs to overcome this obstacle. These strategies include the inhibition of efflux pumps, the use of specific targets, the development of nanomedicines affecting the environment of cancer-specific tissues, the modulation of DNA repair mechanisms or RNA (miRNA), and specific approaches to damage cancer stem cells, among others. This review aims to illustrate how advanced nanoformulations, including polymeric conjugates, micelles, dendrimers, liposomes, metallic and carbon-based nanoparticles, are allowing to overcome one of the main limitations in the treatment of colon and pancreatic cancers. The future development of nanomedicine opens new horizons for cancer treatment.

scholarly journals Loss of p53 tumor suppression function drives invasion and genomic instability in models of murine pancreatic cancer

2022 ◽  
Author(s):  
Claudia Tonelli ◽  
Astrid Deschênes ◽  
Melissa A. Yao ◽  
Youngkyu Park ◽  
David A. Tuveson
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Morphological Changes ◽  
Treatment Options ◽  
Intraepithelial Neoplasia ◽  
Ductal Adenocarcinoma ◽  
Wild Type

Pancreatic ductal adenocarcinoma (PDA) is a deadly disease with few treatment options. There is an urgent need to better understand the molecular mechanisms that drive disease progression, with the ultimate aim of identifying early detection markers and clinically actionable targets. To investigate the transcriptional and morphological changes associated with pancreatic cancer progression, we analyzed the KrasLSLG12D/+; Trp53LSLR172H/+; Pdx1-Cre (KPC) mouse model. We have identified an intermediate cellular event during pancreatic carcinogenesis in the KPC mouse model of PDA that is represented by a subpopulation of tumor cells that express KrasG12D, p53R172H and one allele of wild-type Trp53. In vivo, these cells represent a histological spectrum of pancreatic intraepithelial neoplasia (PanIN) and acinar-to-ductal metaplasia (ADM) and rarely proliferate. Following loss of wild-type p53, these precursor lesions undergo malignant de-differentiation and acquire invasive features. We have established matched organoid cultures of pre-invasive and invasive cells from murine PDA. Expression profiling of the organoids led to the identification of markers of the pre-invasive cancer cells in vivo and mechanisms of disease aggressiveness.

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