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Molecular Oncology

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https://www.readbyqxmd.com/read/28719033/identification-of-driver-copy-number-alterations-in-diverse-cancer-types-and-application-in-drug-repositioning
#1
Wenbin Zhou, Zhangxiang Zhao, Ruiping Wang, Yue Han, Chengyu Wang, Fan Yang, Ya Han, Haihai Liang, Lishuang Qi, Chenguang Wang, Zheng Guo, Yunyan Gu
Results from numerous studies suggest an important role for somatic copy number alterations (SCNAs) in cancer progression. Our work aimed to identify the drivers (oncogenes or tumor suppressor genes) that reside in recurrently aberrant genomic regions, including a large number of genes or non-coding genes, which remain a challenge for decoding the SCNAs involved in carcinogenesis. Here, we propose a new approach to comprehensively identify drivers, using 8740 cancer samples involving 18 cancer types from The Cancer Genome Atlas (TCGA)...
July 18, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28700115/lkb1-pro-oncogenic-activity-triggers-cell-survival-in-circulating-tumor-cells
#2
Elisabeth Katharina Trapp, Leonie Majunke, Beate Zill, Harald Sommer, Ulrich Andergassen, Julian Koch, Nadia Harbeck, Sven Mahner, Thomas Wolfram Paul Friedl, Wolfgang Janni, Brigitte Rack, Marianna Alunni-Fabbroni
During intravasation, circulating tumor cells (CTCs) detach from the epithelium of origin and begin the Epithelial-to Mesenchymal-Transition (EMT) process, where they lose epithelial features and pass through the endothelium to enter circulation. Although detachment from the extracellular matrix is a strong source of metabolic stress, which induces anoikis, CTCs can survive. Recently, the tumor suppressor liver kinase B1 (LKB1) has gained attention for its role as a proto-oncogene in restoring the correct ATP/AMP ratio during metabolic stress...
July 12, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28691390/an-improved-digital-polymerase-chain-reaction-protocol-to-capture-low-copy-kras-mutations-in-plasma-cell-free-dna-by-resolving-subsampling-issues
#3
REVIEW
Yusuke Ono, Ayumu Sugitani, Hidenori Karasaki, Munehiko Ogata, Reo Nozaki, Junpei Sasajima, Tomoki Yokochi, Shingo Asahara, Kazuya Koizumi, Kiyohiro Ando, Katsunori Hironaka, Tsutomu Daito, Yusuke Mizukami
Genetic alterations responsible for the initiation of cancer may serve as immediate biomarkers for early diagnosis. Plasma levels of cell-free DNA (cfDNA) in cancer patients are higher than those in healthy individuals, however, the major technical challenge for the widespread implementation of cfDNA genotyping as a diagnostic tool is the insufficient sensitivity and specificity of detecting early-stage tumors that shed low amounts of cfDNA. To establish a protocol for ultrasensitive droplet digital polymerase chain reaction (ddPCR) for quantification of low-frequency alleles within a limited cfDNA pool, two-step multiplex ddPCR targeting eight clinically relevant mutant KRAS variants was examined...
July 10, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28675785/gas6-expressing-and-self-sustaining-cancer-cells-in-3d-spheroids-activate-the-pdk-rsk-mtor-pathway-for-survival-and-drug-resistance
#4
Christine Baumann, Axel Ullrich, Robert Torka
AXL Receptor Tyrosine Kinase (RTK) inhibition presents a promising therapeutic strategy for aggressive tumor subtypes, as AXL signaling is upregulated in many cancers resistant to first line treatments. Furthermore, the AXL ligand Growth Arrest-Specific gene 6 (GAS6) has recently been linked to cancer drug resistance. Here, we established that challenging conditions, such as serum deprivation, divide AXL overexpressing tumor cell lines into non-self-sustaining and self-sustaining subtypes in 3D spheroid culture...
July 4, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28675654/bioinformatory-assisted-analysis-of-next-generation-sequencing-data-for-precision-medicine-in-pancreatic-cancer
#5
Linnéa Malgerud, Johan Lindberg, Valtteri Wirta, Maria Gustafsson-Liljefors, Masoud Karimi, Carlos Fernández Moro, Katrin Stecker, Alexander Picker, Carolin Huelsewig, Martin Stein, Regina Bohnert, Marco Del Chiaro, Stephan L Haas, Rainer L Heuchel, Johan Permert, Markus J Maeurer, Stephan Brock, Caroline S Verbeke, Lars Engstrand, David B Jackson, Henrik Grönberg, J-Matthias Löhr
Pancreatic ductal adenocarcinoma (PDAC) is a tumor with an extremely poor prognosis, predominantly due to chemotherapy resistance and numerous somatic mutations. Consequently, PDAC is a prime candidate for the use of sequencing to identify causative mutations, facilitating subsequent administration of targeted therapy. In a feasibility study, we retrospectively assessed the therapeutic recommendations of a novel, evidence-based software that analyzes Next-generation sequencing (NGS) data using a large panel of pharmacogenomic biomarkers for efficacy and toxicity...
July 4, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28672103/shingosine-1-phosphate-suppresses-chondrosarcoma-metastasis-by-up-regulation-of-tissue-inhibitor-of-metalloproteinase-3-through-suppressing-mir-101-expression
#6
Chun-Hao Tsai, Dong-Ying Yang, Chih-Yang Lin, Tsung-Ming Chen, Chih-Hsin Tang, Yuan-Li Huang
Chondrosarcoma is the second most common primary malignancy form of bone cancer, exhibiting resistance to chemotherapy and radiation therapy as well as developing high metastasis ability in late stage tumors. Thus, understanding the metastatic processes of chondrosarcoma is considered a strategy for treatment of this disease. Sphingosine 1-phosphate (S1P), a bioactive sphingolipid, is produced intracellularly by sphingosine kinase (SphK) and is regarded as a second signaling molecule that regulates inflammation, proliferation, angiogenesis, and metastasis...
July 3, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28672102/prognostic-and-functional-role-of-subtype-specific-tumor-stroma-interaction-in-breast-cancer
#7
Giuseppe Merlino, Patrizia Miodini, Maurizio Callari, Francesca D'Aiuto, Vera Cappelletti, Maria Grazia Daidone
None of the clinically relevant gene expression signatures available for breast cancer were specifically developed to capture the influence of the microenvironment on tumor cells. Here, we attempted to build subtype-specific signatures derived from an in vitro model reproducing tumor cell modifications after interaction with activated or normal stromal cells. Gene expression signatures derived from HER2+, luminal and basal breast cancer cell lines (treated by normal fibroblasts or cancer-associated fibroblasts conditioned media) were evaluated in clinical tumors by in silico analysis on published gene expression profiles (GEPs)...
July 3, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28657165/serum-n-glycome-alterations-in-breast-cancer-during-multi-modal-treatment-and-follow-up
#8
Radka Saldova, Vilde D Haakensen, Einar Rødland, Ian Walsh, Henning Stöckmann, Olav Engebraaten, Anne-Lise Børresen-Dale, Pauline M Rudd
Using our recently developed high-throughput automated platform, N-glycans from all serum glycoproteins from breast cancer patients were analysed at diagnosis, after neoadjuvant chemotherapy, surgery, radiotherapy, and up to 3 years after surgery. Surprisingly, alterations in the serum N-glycome after chemotherapy were pro-inflammatory with an increase in glycan structures associated with cancer. Surgery, on the other hand, induced anti-inflammatory changes in the serum N-glycome, towards a non-cancerous phenotype...
June 28, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28649742/genotranscriptomic-meta-analysis-of-the-chd-family-chromatin-remodelers-in-human-cancers-initial-evidence-of-an-oncogenic-role-for-chd7
#9
Xiaofang Chu, Xuhui Guo, Yuanyuan Jiang, Huimei Yu, Lanxin Liu, Wenqi Shan, Zeng-Quan Yang
Chromodomain helicase DNA binding proteins (CHD) are characterized by N-terminal tandem chromodomains and a central ATP-dependent helicase domain. CHDs govern the cellular machinery's access to DNA, thereby playing critical roles in various cellular processes including transcription, proliferation, and DNA damage repair. Accumulating evidence demonstrates that mutation and dysregulation of CHDs are implicated in the pathogenesis of developmental disorders and cancer. However, we know little about genomic and transcriptomic alterations and the clinical significance of most CHDs in human cancer...
June 26, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28636767/aberrant-expression-of-kallikrein-related-peptidase-7-is-correlated-to-human-melanoma-aggressiveness-by-stimulating-cell-migration-and-invasion
#10
Tiphaine Delaunay, Lydia Deschamps, Meriem Haddada, Francine Walker, Antoninus Soosaipillai, Feryel Soualmia, Chahrazade El Amri, Eleftherios P Diamandis, Maria Brattsand, Viktor Magdolen, Dalila Darmoul
Members of the tissue kallikrein-related peptidase (KLK) family not only regulate several important physiological functions, but aberrant expression has also been associated with various malignancies. Clinically, KLKs have been suggested as promising biomarkers for diagnosis and prognosis in many types of cancer. As of yet, expression of KLKs and their role in skin cancers are, however, poorly addressed. Malignant melanoma is an aggressive disease associated with poor prognosis. Hence, diagnostic biomarkers to monitor melanoma progression are needed...
June 21, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28632938/mek-inhibitors-induce-akt-activation-and-drug-resistance-by-suppressing-negative-feedback-erk-mediated-her2-phosphorylation-at-thr701
#11
Chia-Hung Chen, Te-Chun Hsia, Ming-Hsin Yeh, Tsung-Wei Chen, Yun-Ju Chen, Jung-Tsu Chen, Ya-Ling Wei, Chih-Yen Tu, Wei-Chien Huang
Targeting the MEK/ERK pathway has been viewed as a promising strategy for cancer therapy. However, MEK inhibition leads to the compensatory PI3K/AKT activation and thus contributes to the desensitization of cancer cells to MEK inhibitors. The underlying molecular mechanism of this event is not yet understood. In this study, our data showed that the induction of Akt activity by MEK inhibitors was specifically observed in HER2-positive breast cancer cells. Silence of HER2, or overexpression of HER2 kinase-dead mutant, prevents the induction of Akt activation in response to MEK inhibition, indicating HER2 as a critical regulator for this event...
June 20, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28627792/%C3%AE-catenin-in-desmoid-type-fibromatosis-deep-insights-on-the-role-of-t41a-and-s45f-mutations-on-protein-structure-and-gene-expression
#12
C Colombo, A Belfiore, N Paielli, L De Cecco, S Canevari, E Laurini, M Fermeglia, S Pricl, P Verderio, S Bottelli, M Fiore, S Stacchiotti, E Palassini, A Gronchi, S Pilotti, F Perrone
Desmoid- type fibromatosis (DF) is a rare mesenchymal lesion with high risk of local recurrence. Specific β-catenin mutations (S45F) appeared to be related to this higher risk compared to T41A mutated or wild type (WT). We explored the influence of both mutations and WT on structure stability and affinity of β-catenin for α-catenin and the pattern of gene expression that may influence DF behavior. Using 33 surgically resected primary DFs harboring T41A (n=14), S45F (n=10) or WT (n=9), we performed a comparative molecular analysis by protein/protein interaction modeling, gene expression by DASL microarrays, human inflammation gene panel and assessment of immune system-based biomarkers by immunohistochemistry...
June 19, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28618197/analysis-of-mutant-allele-fractions-in-driver-genes-in-colorectal-cancer-biological-and-clinical-insights
#13
Rodrigo Dienstmann, Elena Elez, Guillem Argiles, Ignacio Matos, Enrique Sanz-Garcia, Carolina Ortiz, Teresa Macarulla, Jaume Capdevila, Maria Alsina, Tamara Sauri, Helena Verdaguer, Marta Vilaro, Fiorella Ruiz-Pace, Cristina Viaplana, Ariadna Garcia, Stefania Landolfi, Hector G Palmer, Paolo Nuciforo, Jordi Rodon, Ana Vivancos, Josep Tabernero
Sequencing of tumors is now routine and guides personalized cancer therapy. Mutant allele fractions (MAFs, or the 'mutation dose') of a driver gene may reveal the genomic structure of tumors and influence response to targeted therapies. We performed a comprehensive analysis of MAFs of driver alterations in unpaired primary and metastatic colorectal cancer (CRC) at our institution from 2010 to 2015 and studied their potential clinical relevance. Out of 763 CRC samples, 622 had detailed annotation on overall survival in the metastatic setting (OSmet) and 89 received targeted agents matched to KRAS (MEK inhibitors), BRAF (BRAF inhibitors) or PIK3CA mutations (PI3K pathway inhibitors)...
June 15, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28618162/zeb1-regulated-inflammatory-phenotype-in-breast-cancer-cells
#14
Akihiro Katsura, Yusuke Tamura, Satoshi Hokari, Mayumi Harada, Masato Morikawa, Tsubasa Sakurai, Kei Takahashi, Anna Mizutani, Jun Nishida, Yuichiro Yokoyama, Yasuyuki Morishita, Takashi Murakami, Shogo Ehata, Kohei Miyazono, Daizo Koinuma
Zinc finger E-box binding protein 1 (ZEB1) and ZEB2 induce epithelial-mesenchymal transition (EMT) and enhance cancer progression. However, the global view of transcriptional regulation by ZEB1 and ZEB2 is yet to be elucidated. Here, we identified a ZEB1-regulated inflammatory phenotype in breast cancer cells using chromatin immunoprecipitation-sequencing and RNA sequencing, followed by gene set enrichment analysis (GSEA) of ZEB1-bound genes. Knockdown of ZEB1 and/or ZEB2 resulted in the down-regulation of genes encoding inflammatory cytokines related to poor prognosis in cancer patients, including IL6 and IL8, therefore suggesting that ZEB1 and ZEB2 have similar functions in terms of the regulation of production of inflammatory cytokines...
June 15, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28614631/trpm4-regulates-akt-gsk3-%C3%AE-activity-and-enhances-%C3%AE-catenin-signaling-and-cell-proliferation-in-prostate-cancer-cells
#15
Alfredo I Sagredo, Eduardo A Sagredo, Claudio Cappelli, Pablo Báez, Andaur M Rodrigo, Constanza Blanco, Julio C Tapia, César Echeverría, Oscar Cerda, Andrés Stutzin, Felipe Simon, Katherine Marcelain, Ricardo Armisén
Increased expression of the TRPM4 channel has been reported to be associated with the progression of prostate cancer. However, the molecular mechanism underlying its effect remains unknown. This work found that decreasing TRPM4 levels leads to the reduced proliferation of PC3 cells. This effect was associated with a decrease in total β-catenin protein levels and its nuclear localization, and a significant reduction in Tcf/Lef transcriptional activity. Moreover, TRPM4 silencing increases the Ser33/Ser37/Thr41 β-catenin phosphorylated population and reduces the phosphorylation of GSK-3β at Ser9, suggesting an increase in β-catenin degradation as the underlying mechanism...
June 14, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28580773/hbx-mediated-decrease-of-aim2-contributes-to-hepatocellular-carcinoma-metastasis
#16
Shi-Lu Chen, Li-Li Liu, Shi-Xun Lu, Rong-Zhen Luo, Chun-Hua Wang, Hong Wang, Shao-Hang Cai, Xia Yang, Dan Xie, Chris Zhiyi Zhang, Jing-Ping Yun
Tumor metastasis is responsible for the high mortality rates in patients with hepatocellular carcinoma (HCC). Absent in Melanoma 2 (AIM2) has been implicated in inflammation and carcinogenesis, but its role in HCC metastasis remains unknown. Here, we show that AIM2 protein expression was noticeably reduced in HCC cell lines and clinical samples. A reduction in AIM2 was closely associated with higher serum AFP levels, vascular invasion, poor tumor differentiation, an incomplete tumor capsule and unfavorable postsurgical survival odds...
June 5, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28580735/ddah1-mediates-gastric-cancer-cell-invasion-and-metastasis-via-wnt-%C3%AE-catenin-signaling-pathway
#17
Jianxin Ye, Jie Xu, Yun Li, Qiang Huang, Jinsheng Huang, Jinzhou Wang, Wenjing Zhong, Xinjian Lin, Wannan Chen, Xu Lin
Gastric cancer (GC) represents the fourth most common malignant neoplasm and the second leading cause of cancer death. Despite therapeutic advances in recent decades, the clinical outcome remains dismal owing to the fact that most patients with GC show advanced disease at diagnosis and current chemotherapy only confers a modest survival advantage. Identification of key molecular signaling pathways involved in gastric carcinogenesis and progression would aid in early diagnosis and provide a rational design for targeted therapies in selected patients with advanced GC, to improve their outcome...
June 5, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28557340/trka-is-a-binding-partner-of-npm-alk-that-promotes-the-survival-of-alk-t-cell-lymphoma
#18
Wenyu Shi, Suraj Konnath George, Bhawana George, Choladda V Curry, Albina Murzabdillaeva, Serhan Alkan, Hesham M Amin
Nucleophosmin-anaplastic lymphoma kinase-expressing (NPM-ALK(+) ) T-cell lymphoma is an aggressive neoplasm that is more commonly seen in children and young adults. The pathogenesis of NPM-ALK(+) T-cell lymphoma is not completely understood. It is characterized by the expression of the chimeric tyrosine kinase NPM-ALK. Wild-type ALK is a receptor tyrosine kinase that is physiologically expressed in neural tissues during early stages of human development, which suggests that ALK may interact with neurotrophic factors...
May 30, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28557306/sk4-channels-modulate-ca-2-signalling-and-cell-cycle-progression-in-murine-breast-cancer
#19
Friederike A Steudel, Corinna J Mohr, Benjamin Stegen, Hoang Y Nguyen, Andrea Barnert, Marc Steinle, Sandra Beer-Hammer, Pierre Koch, Wing-Yee Lo, Werner Schroth, Reiner Hoppe, Hiltrud Brauch, Peter Ruth, Stephan M Huber, Robert Lukowski
Oncogenic signalling via Ca(2+) -activated K(+) channels of intermediate conductance (SK4, also known as KCa 3.1 or IK) has been implicated in different cancer entities including breast cancer. Yet, the role of endogenous SK4 channels for tumourigenesis is unclear. Herein, we generated SK4-negative tumours by crossing SK4-deficient (SK4 KO) mice to the polyoma middle T-antigen (PyMT) and epidermal growth factor receptor 2 (cNeu) breast cancer models in which oncogene expression is driven by the retroviral promotor MMTV...
May 30, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28556483/drug-sensitivity-and-resistance-testing-identifies-plk1-inhibitors-and-gemcitabine-as-potent-drugs-for-malignant-peripheral-nerve-sheath-tumors-mpnst
#20
Matthias Kolberg, Jarle Bruun, Astrid Murumägi, John P Mpindi, Christian H Bergsland, Maren Høland, Ina A Eilertsen, Stine A Danielsen, Olli Kallioniemi, Ragnhild A Lothe
Patients with malignant peripheral nerve sheath tumor (MPNST), a rare soft tissue cancer associated with loss of the tumor suppressor neurofibromin (NF1), have poor prognosis and typically respond poorly to adjuvant therapy. We evaluated the effect of 299 clinical and investigational compounds on seven MPNST cell lines, two primary cultures of human Schwann cells, and five normal bone marrow aspirates, to identify potent drugs for MPNST treatment with few side effects. Top hits included Polo-like kinase 1 (PLK1) inhibitors (volasertib and BI2536) and the fluoronucleoside gemcitabine, which were validated in orthogonal assays measuring viability, cytotoxicity and apoptosis...
May 29, 2017: Molecular Oncology
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