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https://www.readbyqxmd.com/read/28821955/targeted-next-generation-sequencing-for-analyzing-the-genetic-alterations-in-atypical-adenomatous-hyperplasia-and-adenocarcinoma-in-situ
#1
Xuan Xu, Na Li, Ruiying Zhao, Lei Zhu, Jinchen Shao, Jie Zhang
PURPOSE: Atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS) have been defined as preinvasive pulmonary adenocarcinoma lesions according to the 2015 World Health Organization lung adenocarcinoma classification. We aimed to search for the most common gene mutations in patients with AAH and AIS and investigate the distinctions between the two groups at the molecular level. METHODS: We performed targeted next-generation sequencing on 18 cases with AAH and 28 cases with AIS to screen for mutations with the Ion Torrent Oncomine Solid Tumor DNA panel...
August 18, 2017: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/28811082/correlation-between-molecular-analysis-diagnosis-according-to-the-2015-who-classification-of-unresected-lung-tumours-and-ttf1-expression-in-small-biopsies-and-cytology-specimens-from-344-non-small-cell-lung-carcinoma-patients
#2
Prudence A Russell, Toni-Maree Rogers, Benjamin Solomon, Naveed Alam, Stephen A Barnett, Vivek Rathi, Richard A Williams, Gavin M Wright, Matthew Conron
We investigated correlations between diagnosis according to the 2015 World Health Organization (WHO) classification of unresected lung tumours, molecular analysis and TTF1 expression in small biopsy and cytology specimens from 344 non-small cell lung carcinoma (NSCLC) patients. One case failed testing for EGFR, KRAS and ALK abnormalities and six had insufficient tumour for ALK testing. Overall mutation rate in 343 cases was 48% for the genes tested, with 19% EGFR, 33% KRAS and 4% BRAF mutations, and 5% ALK rearrangements detected...
August 12, 2017: Pathology
https://www.readbyqxmd.com/read/28783725/a-braf-kinase-inactive-mutant-induces-lung-adenocarcinoma
#3
Patricia Nieto, Chiara Ambrogio, Laura Esteban-Burgos, Gonzalo Gómez-López, María Teresa Blasco, Zhan Yao, Richard Marais, Neal Rosen, Roberto Chiarle, David G Pisano, Mariano Barbacid, David Santamaría
The initiating oncogenic event in almost half of human lung adenocarcinomas is still unknown, a fact that complicates the development of selective targeted therapies. Yet these tumours harbour a number of alterations without obvious oncogenic function including BRAF-inactivating mutations. Inactivating BRAF mutants in lung predominate over the activating V600E mutant that is frequently observed in other tumour types. Here we demonstrate that the expression of an endogenous Braf(D631A) kinase-inactive isoform in mice (corresponding to the human BRAF(D594A) mutation) triggers lung adenocarcinoma in vivo, indicating that BRAF-inactivating mutations are initiating events in lung oncogenesis...
August 10, 2017: Nature
https://www.readbyqxmd.com/read/28783719/tumours-with-class-3-braf-mutants-are-sensitive-to-the-inhibition-of-activated-ras
#4
Zhan Yao, Rona Yaeger, Vanessa S Rodrik-Outmezguine, Anthony Tao, Neilawattie M Torres, Matthew T Chang, Matthias Drosten, Huiyong Zhao, Fabiola Cecchi, Todd Hembrough, Judith Michels, Hervé Baumert, Linde Miles, Naomi M Campbell, Elisa de Stanchina, David B Solit, Mariano Barbacid, Barry S Taylor, Neal Rosen
Approximately 200 BRAF mutant alleles have been identified in human tumours. Activating BRAF mutants cause feedback inhibition of GTP-bound RAS, are RAS-independent and signal either as active monomers (class 1) or constitutively active dimers (class 2). Here we characterize a third class of BRAF mutants-those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signalling is RAS-dependent. The mutants bind more tightly than wild-type BRAF to RAS-GTP, and their binding to and activation of wild-type CRAF is enhanced, leading to increased ERK signalling...
August 2, 2017: Nature
https://www.readbyqxmd.com/read/28782530/chemotherapeutics-resistance-arms-race-an-update-on-mechanisms-involved-in-resistance-limiting-egfr-inhibitors-in-lung-cancer
#5
REVIEW
Pankaj Kumar Singh, Om Silakari
Clinical reports suggest that EGFR-mutated lung cancer usually respond significantly towards small molecule tyrosine kinase inhibitors. Same studies also report the eventual development of acquired resistance within a median time interval of 9 to 14months. One of the major mechanisms involved in this acquired resistance was found to be a secondary point mutation at gate-keeper residue, EGFR T790M. However, there are other recent studies which disclose the role of few other novel key players such as, ZEB1, TOPK etc...
August 4, 2017: Life Sciences
https://www.readbyqxmd.com/read/28776576/gnas-mutations-in-primary-mucinous-and-non-mucinous-lung-adenocarcinomas
#6
Lauren L Ritterhouse, Marina Vivero, Mari Mino-Kenudson, Lynette M Sholl, A John Iafrate, Valentina Nardi, Fei Dong
GNAS mutations have been described in mucinous and non-mucinous epithelial neoplasms of the appendix, pancreas, and colon, with hotspot GNAS mutations found in up to two-thirds of pancreatic intraductal papillary mucinous neoplasms. Additionally, many GNAS-mutated tumors have concurrent mutations in the Ras/Raf pathway. The clinicopathologic features of GNAS-mutated lung carcinomas, however, have not yet been characterized. Primary lung carcinomas from Brigham and Women's Hospital (n=1282) or Massachusetts General Hospital (n=1070) were genotyped on a targeted massively parallel sequencing panel of oncogenes and tumor suppressor genes including GNAS...
August 4, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28762087/non-small-cell-lung-cancer-nsclc-harboring-alk-translocations-clinical-characteristics-and-management-in-a-real-life-setting-a-french-retrospective-analysis-gfpc-02-14-study
#7
Jean-Bernard Auliac, Isabelle Monnet, Catherine Dubos-Arvis, Anne Marie Chiappa, Nathalie Baize, Suzana Bota, Alain Vergnenegre, Helene Doubre, Chrystele Locher, Acya Bizieux, Gilles Robinet, Christos Chouaid
BACKGROUND: Chromosomal translocations involving the anaplastic lymphoma kinase gene (ALK) are rare oncogenic events found in 3-5% of non-small-cell lung cancers (NSCLC). Limited data have been published on the management of these patients outside clinical trials. OBJECTIVE: To investigate the clinical characteristics and management of patients with NSCLC harboring ALK translocations (ALK+) in a real-life setting in France. METHODS: This multicenter, observational, retrospective study included all NSCLC patients harboring ALK translocations diagnosed in participating centers between January 2012 and December 2014...
July 31, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28758104/liquid-biopsies-in-lung-cancer-time-to-implement-research-technologies-in-routine-care
#8
REVIEW
Linda Köhn, Mikael Johansson, Kjell Grankvist, Jonas Nilsson
Lung cancer is the leading cause of cancer mortality. A substantial progress in the understanding of lung cancer biology has resulted in several promising targeted therapies for advanced disease. Druggable targets today include point mutations such as EGFR, BRAF and re-arrangements in genes such as ALK and ROS1. Liquid biopsies collecting e.g., circulating tumor DNA (ctDNA) reflects overall tumor information and is not biased by analyzing of only a small fraction of the tumor and is always accessible in contrast to the lung cancer tissue...
July 2017: Annals of Translational Medicine
https://www.readbyqxmd.com/read/28756651/relationship-between-driver-gene-mutations-their-relative-protein-expressions-and-survival-in-non-small-cell-lung-carcinoma-in-macao
#9
Kin Iong Chan, Hong Ting Vong, Lai Fang Sin, Yuk Ching Yip, Xue Yun Zhong, Jian Ming Wen
Objectives We report the status of most common gene mutations in non-small cell lung carcinoma (NSCLC) in Macao, and explore the relationship between each gene mutation and clinicopathologic features and survival. Methods EGFR, KRAS and BRAF mutations were detected by PCR in 122 cases of NSCLC. ALK translocation and MET amplification were detected by fluorescence in situ hybridization (FISH). MET and thyroid transcription factor (TTF-1) were investigated by immunohistochemistry. Clinical data were collected for analyzing their correlation with the gene mutations...
July 29, 2017: Clinical Respiratory Journal
https://www.readbyqxmd.com/read/28753563/pathologic-subtype-defined-prognosis-is-dependent-on-both-tumor-stage-and-status-of-oncogenic-driver-mutations-in-lung-adenocarcinoma
#10
Yu Dong, Ying Li, Bo Jin, Jie Zhang, Jinchen Shao, Hong Peng, Shichun Tu, Baohui Han
Previous studies have shown that the prognosis of lung adenocarcinoma is associated with pathological characterization. In this study, we investigated whether pathology-based prognosis was further influenced by both tumor stage and oncogenic driver mutations. To this end, we recruited a cohort of 465 lung adenocarcinoma patients in China. These patients were classified into 6 pathology-defined subtypes i.e., lepidic-predominant adenocarcinoma (LPA), acinar-predominant adenocarcinoma (APA), papillary-predominant adenocarcinoma (PPA), micropapillary-predominant adenocarcinoma (MPA), solid-predominant adenocarcinoma (SPA), and invasive mucinous adenocarcinoma (IMA)...
July 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28745322/p53-loss-does-not-permit-escape-from-braf-v600e-induced-senescence-in-a-mouse-model-of-lung-cancer
#11
S Garnett, K L Dutchak, R V McDonough, D Dankort
Lung cancer arises through the acquisition of a number of genetic lesions, with a preponderance of activating mutations in the canonical mitogen-activated protein kinase (MAPK) cascade (RTK-RAS-RAF-MEK). Braf(V600E) expression induces benign lung adenomas that fail to progress to adenocarcinoma because of oncogene-induced senescence (OIS). Braf(V600E) expression, coupled with simultaneous p53 ablation, permits bypass of senescence and progression to lung adenocarcinoma. However, spontaneous human tumors sustain mutations in a temporally separated manner...
July 24, 2017: Oncogene
https://www.readbyqxmd.com/read/28721808/molecular-tests-for-the-choice-of-cancer-therapy
#12
Anna P Sokolenko, Evgeny N Imyanitov
There are over a dozen of approved cancer drugs, whose administration is tailored to predictive laboratory tests. The examples include estrogen and progesterone receptor status determination for the use of endocrine therapy, HER2 assessment for the administration of HER2-targeting agents, EGFR and ALK gene testing for lung cancer treatment, BRAF analysis in melanoma, etc. While first predictive tests relied on relatively easy laboratory procedures, more recent developments require rather sophisticated assays...
July 19, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28714990/an-approach-to-suppress-the-evolution-of-resistance-in-braf-v600e-mutant-cancer
#13
Yaohua Xue, Luciano Martelotto, Timour Baslan, Alberto Vides, Martha Solomon, Trang Thi Mai, Neelam Chaudhary, Greg J Riely, Bob T Li, Kerry Scott, Fabiola Cechhi, Ulrika Stierner, Kalyani Chadalavada, Elisa de Stanchina, Sarit Schwartz, Todd Hembrough, Gouri Nanjangud, Michael F Berger, Jonas Nilsson, Scott W Lowe, Jorge S Reis-Filho, Neal Rosen, Piro Lito
The principles that govern the evolution of tumors exposed to targeted therapy are poorly understood. Here we modeled the selection and propagation of an amplification in the BRAF oncogene (BRAF(amp)) in patient-derived tumor xenografts (PDXs) that were treated with a direct inhibitor of the kinase ERK, either alone or in combination with other ERK signaling inhibitors. Single-cell sequencing and multiplex fluorescence in situ hybridization analyses mapped the emergence of extra-chromosomal amplification in parallel evolutionary trajectories that arose in the same tumor shortly after treatment...
August 2017: Nature Medicine
https://www.readbyqxmd.com/read/28709170/-leptomeningeal-carcinomatosis-as-a-rare-metastatic-spreading-of-braf-mutated-microsatellite-stable-colon%C3%A2-cancer
#14
Aksana Höblinger, Stephanie Weber, Florian Tschirner, Stefan Kröber, Konrad Streetz
Leptomeningeal carcinomatosis is a rare but serious complication of solid tumors such as melanoma, breast and lung cancer, as well as gastrointestinal carcinomas. Its clinical manifestation is highly variable, presenting as radicular pain with or without neurological deficits, as well as with headaches and hallucinatory irritation symptoms. Leptomeningeal carcinomatosis is often misdiagnosed, which delays treatment. Here we report a rare case of a patient with BRAF-mutated microsatellite stable colon carcinoma with lymphatic and skeletal metastases, who developed neurological symptoms one month after the initial diagnosis of malignancy...
July 2017: Zeitschrift Für Gastroenterologie
https://www.readbyqxmd.com/read/28690524/erdheim-chester-disease-case-report-with-aggressive-multisystem-manifestations-and-review-of-the-literature
#15
Sultan Alotaibi, Osama Alhafi, Hatem Nasr, Khalid Eltayeb, Ghaleb Elyamany
Erdheim-Chester disease (ECD) is an extremely rare and aggressive form of non-Langerhans cell histiocytosis. ECD usually presents with bone pain in adults aged 40-60. Its etiology is unknown but it is thought to be either a reactive or neoplastic disorder. Recently, mutation of the proto-oncogene BRAF (BRAFV600E) has been found in more than 50% of cases. The multisystemic form of ECD is associated with significant morbidity, which may arise due to histiocytic infiltration of critical organ systems. The common sites of involvement are the skeleton, central nervous system, cardiovascular system, lungs, retroperitoneum, and skin...
May 2017: Case Reports in Oncology
https://www.readbyqxmd.com/read/28689173/current-understanding-and-management-of-pulmonary-langerhans-cell-histiocytosis
#16
Robert Vassallo, Sergio Harari, Abdellatif Tazi
Pulmonary Langerhans cell histiocytosis (PLCH) is a diffuse lung disease that usually affects young adult smokers. PLCH affects different lung compartments; bronchiolar, interstitial and pulmonary vascular dysfunction may coexist to varying extents, resulting in diverse phenotypes. Analyses of PLCH tissues have identified activating mutations of specific mitogen-activated protein kinases (BRAF(V600E) and others). The current consensus is that PLCH represents a myeloid neoplasm with inflammatory properties: the myeloid tumour cells exhibit surface CD1a expression and up to 50% of the cells harbour activating BRAF or other MAPK mutations...
July 8, 2017: Thorax
https://www.readbyqxmd.com/read/28675691/pd-1-inhibition-in-congenital-pigment-synthesizing-metastatic-melanoma
#17
Angela C Weyand, Rajen J Mody, Raja M Rabah, Valerie P Opipari
A newborn female child was born with a congenital pigment synthesizing melanoma of the scalp. Further workup revealed metastatic disease within the liver, lungs, and left tibia. Whole exome sequencing was performed on multiple samples that revealed one somatic mutation, lysine methyltransferase 2C (KMT2C), at low allelic frequency but no v-Raf murine sarcoma viral oncogene homolog B (BRAF), NF-1 mutation. Programmed death ligand 1 was moderately expressed. Treatment was initiated with the programmed cell death protein 1 inhibitor nivolumab...
July 4, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28671973/pd-l1-expression-in-pleomorphic-spindle-cell-and-giant-cell-carcinoma-of-the-lung-is-related-to-ttf-1-p40-expression-and-might-indicate-a-worse-prognosis
#18
Violaine Yvorel, Arnaud Patoir, François Casteillo, Claire Tissot, Pierre Fournel, Marie-Laure Stachowicz, Georgia Karpathiou, Olivier Tiffet, Michel Péoc'h, Fabien Forest
Lung sarcomatoid carcinoma of the lung is a rare tumor with a poor prognosis. More than 90% of them are pleomorphic, spindle cell and giant cell carcinoma (PSCGCC). This rare subtype of lung cancer is thought to be more resistant to chemotherapy, and a small subset of them seems to exhibit targetable mutations. Immunotherapy against PD1/PDL-1 is a new emerging treatment, and might be of interest in PSGSCC because they frequently express PD-L1. The aim of our work is to evaluate PD1 and PDL-1 expression in a surgical series of lung PSCGCC and their relationship with morphological and immunohistochemical parameters and prognosis...
2017: PloS One
https://www.readbyqxmd.com/read/28647671/use-of-oncogenic-driver-mutations-in-staging-of-multiple-primary-lung-carcinomas-a-single-center-experience
#19
Ramsey Asmar, Joshua R Sonett, Gopal Singh, Mahesh M Mansukhani, Alain C Borczuk
PURPOSE: The staging of multiple pulmonary adenocarcinomas requires the distinction of intrapulmonary metastasis (IPM) from multiple primary lung cancers (MPLC). This can be challenging in some patients, and the addition of data from oncogenic driver mutations in these tumors may be helpful in this determination. PROCEDURES: As a proof of principle, molecular driver results from primary tumors and their metastases in 45 patients were compared (cohort 1). Then, 69 patients with a total of 154 synchronous or metachronous lung carcinomas were identified, with pathologic findings compared to oncogenic driver mutation...
June 21, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28639239/significant-improvement-in-detecting-braf-kras-and-egfr-mutations-using-next-generation-sequencing-as-compared-with-fda-cleared-kits
#20
Wanlong Ma, Steven Brodie, Sally Agersborg, Vincent A Funari, Maher Albitar
INTRODUCTION: We compared mutations detected in EGFR, KRAS, and BRAF genes using next-generation sequencing (NGS) and confirmed by Sanger sequencing with mutations that could be detected by FDA-cleared testing kits. METHODS: Paraffin-embedded tissue from 822 patients was tested for mutations in EGFR, KRAS, and BRAF by NGS. Sanger sequencing of hot spots was used with locked nucleic acid to increase sensitivity for specific hot-spot mutations. This included 442 (54%) lung cancers, 168 (20%) colorectal cancers, 29 (4%) brain tumors, 33 (4%) melanomas, 14 (2%) thyroid cancers, and 16% others (pancreas, head and neck, and cancer of unknown origin)...
June 21, 2017: Molecular Diagnosis & Therapy
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