المؤلفون: Deepak Salem, Manoj Chelvanambi, Walter J. Storkus, Ronald J. Fecek

المصدر: Frontiers in Immunology, Vol 12 (2021)

مصطلحات موضوعية: tertiary lymphoid structures, cutaneous melanoma, tumor mutational burden, driver mutations, DNA repair proteins, Immunologic diseases. Allergy, RC581-607

الوصف: Recent advances in immunotherapy have enabled rapid evolution of novel interventional approaches designed to reinvigorate and expand patient immune responses against cancer. An emerging approach in cancer immunology involves the conditional induction of tertiary lymphoid structures (TLS), which are non-encapsulated ectopic lymphoid structures forming at sites of chronic, pathologic inflammation. Cutaneous melanoma (CM), a highly-immunogenic form of solid cancer, continues to rise in both incidence and mortality rate, with recent reports supporting a positive correlation between the presence of TLS in melanoma and beneficial treatment outcomes amongst advanced-stage patients. In this context, TLS in CM are postulated to serve as dynamic centers for the initiation of robust anti-tumor responses within affected regions of active disease. Given their potential importance to patient outcome, significant effort has been recently devoted to gaining a better understanding of TLS neogenesis and the influence these lymphoid organs exert within the tumor microenvironment. Here, we briefly review TLS structure, function, and response to treatment in the setting of CM. To uncover potential tumor-intrinsic mechanisms that regulate TLS formation, we have taken the novel perspective of evaluating TLS induction in melanomas impacted by common driver mutations in BRAF, PTEN, NRAS, KIT, PRDM1, and MITF. Through analysis of The Cancer Genome Atlas (TCGA), we show expression of DNA repair proteins (DRPs) including BRCA1, PAXIP, ERCC1, ERCC2, ERCC3, MSH2, and PMS2 to be negatively correlated with expression of pro-TLS genes, suggesting DRP loss may favor TLS development in support of improved patient outcome and patient response to interventional immunotherapy.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fimmu.2021.629519/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/245c69b300d04599a8c681624d491c58Test

مرشدي الرسالة: González Izarzugaza, José María (tutor), Peso Ovalle, Luis del (ponente), UAM. Departamento de Bioquímica

مصطلحات موضوعية: Breast cancer, Driver mutations, 3D protein claster, Biología y Biomedicina / Biología, Informática

الوصول الحر: http://hdl.handle.net/10486/682666Test

المؤلفون: Lui, Vivian Wai Yan, Peyser, Noah D, Ng, Patrick Kwok-Shing, Hritz, Jozef, Zeng, Yan, Lu, Yiling, Li, Hua, Wang, Lin, Gilbert, Breean R, General, Ignacio J, Bahar, Ivet, Ju, Zhenlin, Wang, Zhenghe, Pendleton, Kelsey P, Xiao, Xiao, Du, Yu, Vries, John K, Hammerman, Peter S, Garraway, Levi A, Mills, Gordon B, Johnson, Daniel E, Grandis, Jennifer R

المصدر: Proceedings of the National Academy of Sciences of the United States of America. 111(3)

مصطلحات موضوعية: Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Biological Sciences, Oncology and Carcinogenesis, Cancer, Dental/Oral and Craniofacial Disease, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Amino Acid Sequence, Cell Line, Tumor, Cell Survival, Computer Simulation, Gene Expression Regulation, Neoplastic, HEK293 Cells, Head and Neck Neoplasms, Humans, Immunohistochemistry, Models, Molecular, Molecular Sequence Data, Mutation, Phosphorylation, Protein Structure, Tertiary, Proteome, Receptor-Like Protein Tyrosine Phosphatases, Class 2, STAT3 Transcription Factor, Transfection, STAT3 activation, driver mutations, phosphatase mutations

الوصف: The underpinnings of STAT3 hyperphosphorylation resulting in enhanced signaling and cancer progression are incompletely understood. Loss-of-function mutations of enzymes that dephosphorylate STAT3, such as receptor protein tyrosine phosphatases, which are encoded by the PTPR gene family, represent a plausible mechanism of STAT3 hyperactivation. We analyzed whole exome sequencing (n = 374) and reverse-phase protein array data (n = 212) from head and neck squamous cell carcinomas (HNSCCs). PTPR mutations are most common and are associated with significantly increased phospho-STAT3 expression in HNSCC tumors. Expression of receptor-like protein tyrosine phosphatase T (PTPRT) mutant proteins induces STAT3 phosphorylation and cell survival, consistent with a "driver" phenotype. Computational modeling reveals functional consequences of PTPRT mutations on phospho-tyrosine-substrate interactions. A high mutation rate (30%) of PTPRs was found in HNSCC and 14 other solid tumors, suggesting that PTPR alterations, in particular PTPRT mutations, may define a subset of patients where STAT3 pathway inhibitors hold particular promise as effective therapeutic agents.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/7ng6p7wrTest

المؤلفون: Gianluca Ascolani, Pietro Liò

المصدر: BMC Medical Genomics, Vol 12, Iss S6, Pp 1-19 (2019)

مصطلحات موضوعية: Driver mutations, Metabolic mutations, Mutation order, Breast cancer, Subordinated processes, Non-commuting operators, Internal medicine, RC31-1245, Genetics, QH426-470

الوصف: Abstract Background Not all the mutations are equally important for the development of metastasis. What about their order? The survival of cancer cells from the primary tumour site to the secondary seeding sites depends on the occurrence of very few driver mutations promoting oncogenic cell behaviours. Usually these driver mutations are among the most effective clinically actionable target markers. The quantitative evaluation of the effects of a mutation across primary and secondary sites is an important challenging problem that can lead to better predictability of cancer progression trajectory. Results We introduce a quantitative model in the framework of Cellular Automata to investigate the effects of metabolic mutations and mutation order on cancer stemness and tumour cell migration from breast, blood to bone metastasised sites. Our approach models three types of mutations: driver, the order of which is relevant for the dynamics, metabolic which support cancer growth and are estimated from existing databases, and non–driver mutations. We integrate the model with bioinformatics analysis on a cancer mutation database that shows metabolism-modifying alterations constitute an important class of key cancer mutations. Conclusions Our work provides a quantitative basis of how the order of driver mutations and the number of mutations altering metabolic processis matter for different cancer clones through their progression in breast, blood and bone compartments. This work is innovative because of multi compartment analysis and could impact proliferation of therapy-resistant clonal populations and patient survival. Mathematical modelling of the order of mutations is presented in terms of operators in an accessible way to the broad community of researchers in cancer models so to inspire further developments of this useful (and underused in biomedical models) methodology. We believe our results and the theoretical framework could also suggest experiments to measure the overall personalised cancer mutational signature.

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s12920-019-0541-4Test; https://doaj.org/toc/1755-8794Test

الوصول الحر: https://doaj.org/article/ce1e1117a17f4dc297722f2b2c189e39Test

المؤلفون: Wang F, Lu JB, Wu XY, Feng YF, Shao Q, An X, Wang HY

المصدر: Cancer Management and Research, Vol Volume 11, Pp 5489-5499 (2019)

مصطلحات موضوعية: large cell lung cancer, driver mutations, PD-L1, KRAS, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Fang Wang,1,2 Jia-Bin Lu,3 Xiao-Yan Wu,2 Yan-Fen Feng,1,3 Qiong Shao,2 Xin An,4 Hai-Yun Wang1,21State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of China; 2Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of China; 3Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of China; 4Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of ChinaBackground: Large-cell lung carcinomas (LCLCs) were reclassified by the World Health Organization 2015 criteria. and remain fairly unknown at the molecular level and targeted-therapeutic options.Methods: Data of 184 lung cancer patients were retrieved from clinical records, of which 54 were found to be pathologically diagnosed as LCLC. The genetic alterations EGFR/KRAS/BRAF mutations, MET copy number, and exon 14 mutation, ALK and ROS1 rearrangements, and PDL1 expression were investigated using clinical technologies. The relationship between clinicopathologic and genetic features was analyzed, and the Kaplan–Meier method with log-rank test was used for analyzing patient survival.Results: Major events, including EGFR, KRAS, and BRAF mutations and MET copy-number gain, were found in 5.6%, 16.7%, 1.9%, and 18.5% in LCLC, respectively. No ALK or ROS1 translocation was detected. PDL1 expression in tumor cells and in tumor-infiltrating lymphocytes was observed in 24 (44.4%) and 16 (29.6%) patients. Kaplan–Meier analysis showed that patients with a KRAS mutation had ower 5-year overall survival than those with wild-type KRAS (25.4% vs 47.8%, P=0.028) and that patients with negative PDL1 stained in tumor cells but positive for tumor-infiltrating lymphocytes had significantly favorable overall survival compared to those with solitary and positive PDL1 stained in tumor cells (62.5% vs 20.6%, P=0.044).Conclusion: KRAS mutations and PDL1 expression can predict patient survival and be potential target options in LCLC.Keywords: large-cell lung cancer, driver mutations, PD-L1, KRAS

وصف الملف: electronic resource

العلاقة: https://www.dovepress.com/clinical-genetic-features-and-related-survival-implications-in-patient-peer-reviewed-article-CMARTest; https://doaj.org/toc/1179-1322Test

الوصول الحر: https://doaj.org/article/9cbf6562cae54b608179aaad7d48df95Test

المؤلفون: Kumar Prabhash

المصدر: South Asian Journal of Cancer, Vol 8, Iss 1, Pp 1-17 (2019)

مصطلحات موضوعية: Consensus statement, driver mutations, nonsmall cell lung cancer, targeted therapies, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: The management of advanced nonsmall cell lung cancer (NSCLC) patients is becoming increasingly complex with the identification of driver mutations/rearrangements and development/availability of appropriate targeted therapies. In 2017, an expert group of medical oncologists with expertise in treating lung cancer used data from published literature and experience to arrive at practical consensus recommendations on treatment of advanced NSCLC for use by the community oncologists. This was published subsequently in the Indian Journal of Cancer with a plan to be updated annually. The present document is an update to the 2017 document.

وصف الملف: electronic resource

العلاقة: http://journal.sajc.org/article.asp?issn=2278-330X;year=2019;volume=8;issue=1;spage=1;epage=17;aulast=PrabhashTest; https://doaj.org/toc/2278-330XTest

الوصول الحر: https://doaj.org/article/93ce43adf0be4729b24fe9f7e7498decTest

المؤلفون: Iranzo, Jaime, Martincorena, Iñigo, Koonin, Eugene V.

المصدر: Proceedings of the National Academy of Sciences of the United States of America, 2018 Jun . 115(26), E6010-E6019.

الوصول الحر: https://www.jstor.org/stable/26510851Test

المؤلفون: Palmer, Sam, Albergante, Luca, Blackburn, Clare C., Newman, T. J.

المصدر: Proceedings of the National Academy of Sciences of the United States of America, 2018 Feb . 115(8), 1883-1888.

الوصول الحر: https://www.jstor.org/stable/26507575Test

المؤلفون: Hosgood, H Dean, Pao, William, Rothman, Nathaniel, Hu, Wei, Pan, Yumei Helen, Kuchinsky, Kyle, Jones, Kirk D, Xu, Jun, Vermeulen, Roel, Simko, Jeff, Lan, Qing

المصدر: Respiratory Medicine. 107(11)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Tobacco, Clinical Research, Lung, Health Effects of Indoor Air Pollution, Cancer, Genetics, Tobacco Smoke and Health, Lung Cancer, Prevention, 2.2 Factors relating to the physical environment, Aetiology, Respiratory, Good Health and Well Being, Adenocarcinoma, Adult, Air Pollution, Indoor, Carcinoma, Squamous Cell, Cell Differentiation, Coal, ErbB Receptors, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Humans, Lung Neoplasms, Middle Aged, Mutation, Neoplasm Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), Smoke, Smoking, Young Adult, ras Proteins, EGFR, KRAS, Lung cancer, Never smoking, China, Driver mutations, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Respiratory System, Cardiovascular medicine and haematology

الوصف: Lung cancer in never smokers, which has been partially attributed to household solid fuel use (i.e., coal), is etiologically and clinically different from lung cancer attributed to tobacco smoking. To explore the spectrum of driver mutations among lung cancer tissues from never smokers, specifically in a population where high lung cancer rates have been attributed to indoor air pollution from domestic coal use, multiplexed assays were used to detect >40 point mutations, insertions, and deletions (EGFR, KRAS, BRAF, HER2, NRAS, PIK3CA, MEK1, AKT1, and PTEN) among the lung tumors of confirmed never smoking females from Xuanwei, China [32 adenocarcinomas (ADCs), 7 squamous cell carcinomas (SCCs), 1 adenosquamous carcinoma (ADSC)]. EGFR mutations were detected in 35% of tumors. 46% of these involved EGFR exon 18 G719X, while 14% were exon 21 L858R mutations. KRAS mutations, all of which were G12C_34G>T, were observed in 15% of tumors. EGFR and KRAS mutations were mutually exclusive, and no mutations were observed in the other tested genes. Most point mutations were transversions and were also found in tumors from patients who used coal in their homes. Our high mutation frequencies in EGFR exon 18 and KRAS and low mutation frequency in EGFR exon 21 are strikingly divergent from those in other smoking and never smoking populations from Asia. Given that our subjects live in a region where coal is typically burned indoors, our findings provide new insights into the pathogenesis of lung cancer among never smoking females exposed to indoor air pollution from coal.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/4641z29nTest

المؤلفون: H. Robert Frost, Christopher I. Amos

المصدر: BMC Bioinformatics, Vol 19, Iss 1, Pp 1-14 (2018)

مصطلحات موضوعية: Gene set testing, Pathway analysis, Cancer genomics, Driver mutations, Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5

الوصف: Abstract Background Cancer develops when pathways controlling cell survival, cell fate or genome maintenance are disrupted by the somatic alteration of key driver genes. Understanding how pathway disruption is driven by somatic alterations is thus essential for an accurate characterization of cancer biology and identification of therapeutic targets. Unfortunately, current cancer pathway analysis methods fail to fully model the relationship between somatic alterations and pathway activity. Results To address these limitations, we developed a multi-omics method for identifying biologically important pathways and genes in human cancer. Our approach combines single-sample pathway analysis with multi-stage, lasso-penalized regression to find pathways whose gene expression can be explained largely in terms of gene-level somatic alterations in the tumor. Importantly, this method can analyze case-only data sets, does not require information regarding pathway topology and supports personalized pathway analysis using just somatic alteration data for a limited number of cancer-associated genes. The practical effectiveness of this technique is illustrated through an analysis of data from The Cancer Genome Atlas using gene sets from the Molecular Signatures Database. Conclusions Novel insights into the pathophysiology of human cancer can be obtained from statistical models that predict expression-based pathway activity in terms of non-silent somatic mutations and copy number variation. These models enable the identification of biologically important pathways and genes and support personalized pathway analysis in cases where gene expression data is unavailable.

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s12859-018-2476-8Test; https://doaj.org/toc/1471-2105Test

الوصول الحر: https://doaj.org/article/d6c9e571e93d4e0eacbde64ea5e45282Test