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Mutation analysis biomarkers cancer

Takaki Akamine, Kazuki Takada, Gouji Toyokawa, Fumihiko Kinoshita, Taichi Matsubara, Yuka Kozuma, Naoki Haratake, Shinkichi Takamori, Fumihiko Hirai, Tetsuzo Tagawa, Tatsuro Okamoto, Yasuto Yoneshima, Isamu Okamoto, Mototsugu Shimokawa, Yoshinao Oda, Yoichi Nakanishi, Yoshihiko Maehara
OBJECTIVES: Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have been approved as a standard therapy for metastatic non-small cell lung cancer (NSCLC). Although PD-L1 expression serves as a predictive biomarker for the efficacy of immunotherapy, there are no established biomarkers to predict the expression of PD-L1. The inflammatory markers C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) were recently shown to predict the efficacy of nivolumab for NSCLC patients...
March 2018: Surgical Oncology
Nirmesh Patel, Daniel Weekes, Konstantinos Drosopoulos, Patrycja Gazinska, Elodie Noel, Mamun Rashid, Hasan Mirza, Jelmar Quist, Fara Brasó-Maristany, Sumi Mathew, Riccardo Ferro, Ana Mendes Pereira, Cynthia Prince, Farzana Noor, Erika Francesch-Domenech, Rebecca Marlow, Emanuele de Rinaldis, Anita Grigoriadis, Spiros Linardopoulos, Pierfrancesco Marra, Andrew N J Tutt
Triple negative breast cancers (TNBCs) lack recurrent targetable driver mutations but demonstrate frequent copy number aberrations (CNAs). Here, we describe an integrative genomic and RNAi-based approach that identifies and validates gene addictions in TNBCs. CNAs and gene expression alterations are integrated and genes scored for pre-specified target features revealing 130 candidate genes. We test functional dependence on each of these genes using RNAi in breast cancer and non-malignant cells, validating malignant cell selective dependence upon 37 of 130 genes...
March 13, 2018: Nature Communications
Masood Abu-Halima, Mustafa Kahraman, Dominic Henn, Tanja Rädle-Hurst, Andreas Keller, Hashim Abdul-Khaliq, Eckart Meese
BACKGROUND: MicroRNAs (miRNAs) are small RNAs regulating gene expression post-transcriptionally. While acquired changes of miRNA and mRNA profiles in cancer have been extensively studied, little is known about expression changes of circulating miRNAs and messenger RNAs (mRNA) in monogenic constitutional anomalies affecting several organ systems, like Marfan syndrome (MFS). We performed integrated miRNA and mRNA expression profiling in blood samples of Marfan patients in order to investigate deregulated miRNA and mRNA networks in these patients which could serve as potential diagnostic and prognostic tools for MFS therapy...
March 12, 2018: Journal of Translational Medicine
Marcel Wiesweg, Henning Reis, Tobias Köster, Moritz Goetz, Karl Worm, Thomas Herold, Andreas Paul, Alexander Dechêne, Brigitte Schumacher, Peter Markus, Isabel Virchow, Karina Kostbade, Nathalie Wolf, Gregor Zaun, Martin Metzenmacher, Kurt W Schmid, Martin Schuler, Stefan Kasper
BACKGROUND: Deregulation of signal transduction pathways plays a critical role in oncogenesis of colorectal cancer (CRC) and directly affects sensitivity to targeted therapies. Against this background we developed a comprehensive biomarker profiling program including markers of downstream signaling to study their association with clinical outcomes. PATIENTS AND METHODS: A prospectively studied cohort of 160 patients with metastatic CRC was included. Standard diagnostic workup included mutational analyses of Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS), and v-Raf murine sarcoma viral oncogene homolog B (BRAF)...
February 17, 2018: Clinical Colorectal Cancer
Alex Root, Peter Allen, Paul Tempst, Kenneth Yu
Approximately 75% of patients with pancreatic ductal adenocarcinoma are diagnosed with advanced cancer, which cannot be safely resected. The most commonly used biomarker CA19-9 has inadequate sensitivity and specificity for early detection, which we define as Stage I/II cancers. Therefore, progress in next-generation biomarkers is greatly needed. Recent reports have validated a number of biomarkers, including combination assays of proteins and DNA mutations; however, the history of translating promising biomarkers to clinical utility suggests that several major hurdles require careful consideration by the medical community...
March 7, 2018: Cancers
J Smeby, A Sveen, M A Merok, S A Danielsen, I A Eilertsen, M G Guren, R Dienstmann, A Nesbakken, R A Lothe
BACKGROUND: The prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer (CRC) varies with microsatellite instability (MSI) status. The gene expression-based consensus molecular subtypes (CMS) of CRC define molecularly and clinically distinct subgroups, and represent a novel stratification framework in biomarker analysis. We investigated the prognostic value of these mutations within the CMS groups. PATIENTS AND METHODS: Totally 1197 primary tumors from a Norwegian series of CRC stage I-IV were analyzed for MSI and mutation status in hotspots in KRAS (codons 12, 13 and 61) and BRAF (codon 600)...
March 5, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Klaus Højgaard Jensen, Jose M G Izarzugaza, Agnieszka Sierakowska Juncker, Rasmus Borup Hansen, Torben Frøstrup Hansen, Pascal Timshel, Thorarinn Blondal, Thomas Skøt Jensen, Eske Rygaard-Hjalsted, Peter Mouritzen, Michael Thorsen, Rasmus Wernersson, Henrik Bjørn Nielsen, Anders Jakobsen, Søren Brunak, Flemming Brandt Sørensen
Colorectal cancer (CRC) is a leading cause of death worldwide. Surgical intervention is a successful treatment for stage I patients, whereas other more advanced cases may require adjuvant chemotherapy. The selection of effective adjuvant treatments remains, however, challenging. Accurate patient stratification is necessary for the identification of the subset of patients likely responding to treatment, while sparing others from pernicious treatment. Targeted sequencing approaches may help in this regard, enabling rapid genetic investigation, and at the same time easily applicable in routine diagnosis...
February 6, 2018: Oncotarget
Andrew Graham Hill, Michael Findlay, Matthew Burge, Christopher Jackson, Pilar García Alfonso, Leslie Samuel, Vinod Ganju, Meinolf Karthaus, Alessio Amatu, Mark Jeffery, Maria Di Bartolomeo, John Bridgewater, Andrew L Coveler, Manuel Hidalgo, Amy V Kapp, Roxana Sufan, Bruce McCall, William Hanley, Elicia Penuel, Andrea Pirzkall, Josep Tabernero
PURPOSE: Duligotuzumab is a dual-action antibody directed against EGFR and HER3. EXPERIMENTAL DESIGN: mCRC patients with KRAS ex2 wild-type received duligotuzumab or cetuximab and FOLFIRI until progression or intolerable toxicity. Mandatory tumor samples underwent mutation and biomarker analysis. Efficacy analysis was conducted in patients with RAS exon 2/3 wild-type tumors. RESULTS: Of 134 randomized patients, 98 were RAS ex2/3 wild-type...
March 5, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Mark Lupo, Richard Guttler, Zsofia Geck, Theresa R Tonozzi, Anja Kammesheidt, Glenn D Braunstein
OBJECTIVE: Circulating tumor DNA (ctDNA), a subset of circulating free DNA (cfDNA), measurement is a potential biomarker for thyroid cancer. We determined the performance of a ctDNA panel for detection of thyroid malignancy in patients with thyroid nodules. METHODS: Sixty-six patients with thyroid nodules without a prior history of cancer enrolled in a prospective, one-year study in which blood was drawn for ctDNA analysis prior to undergoing fine-needle aspiration biopsy (FNAB) of thyroid nodules...
March 2, 2018: Endocrine Practice
Jo Ishizawa, Kenji Nakamaru, Takahiko Seki, Koichi Tazaki, Kensuke Kojima, Dhruv Chachad, Ran Zhao, Lauren E Heese, Wencai Ma, Man Chun John Ma, Courtney D DiNardo, Sherry A Pierce, Keyur P Patel, Archie Tse, R Eric Davis, Arvind Rao, Michael Andreeff
Early clinical trials using murine double minute 2 (MDM2) inhibitors demonstrated proof-of-concept of p53-induced apoptosis by MDM2 inhibition in cancer cells, however, not all wild-type TP53 tumors are sensitive to MDM2 inhibition. Therefore, more potent inhibitors and biomarkers predictive of tumor sensitivity are needed. The novel MDM2 inhibitor DS-3032b is 10-fold more potent than the first-generation inhibitor nutlin-3a. TP53 mutations were predictive of resistance to DS-3032b, and allele frequencies of TP53 mutations were negatively correlated with sensitivity to DS-3032b...
February 28, 2018: Cancer Research
Min Yuen Teo, Kenneth Seier, Irina Ostrovnaya, Ashley M Regazzi, Brooke E Kania, Meredith M Moran, Catharine K Cipolla, Mark J Bluth, Joshua Chaim, Hikmat Al-Ahmadie, Alexandra Snyder, Maria I Carlo, David B Solit, Michael F Berger, Samuel Funt, Jedd D Wolchok, Gopa Iyer, Dean F Bajorin, Margaret K Callahan, Jonathan E Rosenberg
Purpose Alterations in DNA damage response and repair (DDR) genes are associated with increased mutation load and improved clinical outcomes in platinum-treated metastatic urothelial carcinoma. We examined the relationship between DDR alterations and response to PD-1/PD-L1 blockade. Methods Detailed demographic, treatment response, and long-term outcome data were collected on patients with metastatic urothelial carcinoma treated with atezolizumab or nivolumab who had targeted exon sequencing performed on pre-immunotherapy tumor specimens...
February 28, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Ewelina Perdas, Robert Stawski, Dariusz Nowak, Maria Zubrzycka
Liquid biopsy is a minimally invasive detection method for molecular biomarkers such as miRNA and cell free DNA in body fluids. Deregulations of miRNA are involved in papillary thyroid carcinoma (PTC), one the most common endocrine malignancy. The most widespread common mutations detected in papillary thyroid cancers are BRAF mutations. Many studies indicate that the BRAF mutation is related to deregulation of miRNA. p53 has an important role in cell cycle control, DNA repair and apoptosis. Moreover, the p53 can regulate the expression of miRNAs and thus participate in thyroid oncogenesis...
February 26, 2018: Current Drug Targets
Takahiro Yoshioka, Kazuhiko Shien, Kei Namba, Hidejiro Torigoe, Hiroki Sato, Shuta Tomida, Hiromasa Yamamoto, Hiroaki Asano, Junichi Soh, Kazunori Tsukuda, Takeshi Nagasaka, Toshiyoshi Fujiwara, Shinichi Toyooka
Molecularly targeted therapy has enabled outstanding advances in cancer treatment. Whereas various anti-HER2 drugs have been developed, trastuzumab is still the only anti-HER2 drug presently available for gastric cancer. In this study, we propose novel treatment options for patients with HER2-positive gastric cancer. At first, we determined the molecular profiles of 12 gastric cancer cell lines, and examined the antitumor effect of the pan-HER inhibitors afatinib and neratinib in those cell lines. Additionally, we analyzed HER2 alteration in 123 primary gastric cancers resected from Japanese patients to clarify possible candidates with the potential to respond to these drugs...
February 21, 2018: Cancer Science
Elisabetta Marangoni, Cécile Laurent, Florence Coussy, Rania El Botty, Sophie Chateau-Joubert, Jean-Luc Servely, Ludmilla de Plater, Franck Assayag, Ahmed Dahmani, Elodie Montaudon, Fariba Némati, Justine Fleury, Sophie Vacher, David Gentien, Audrey Rapinat, Pierre Foidart, Nor Eddine Sounni, Agnès Noël, Anne Salomon, Marick Lae, Didier Decaudin, Sergio Roman-Roman, Ivan Bièche, Martine Piccard, Fabien Reyal
PURPOSE: triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy have a poor outcome. We developed patient-derived xenografts (PDX) from residual tumors to identify efficient chemotherapies and predictive biomarkers in a context of resistance to anthracyclines and taxanes-based treatments. EXPERIMENTAL DESIGN: PDX were established from residual tumors of primary breast cancer patients treated in neoadjuvant setting. TNBC PDX were treated by anthracyclines, taxanes, platins and capecitabine...
February 20, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Venkatesh Kancherla, Samir Abdullazade, Matthias S Matter, Manuela Lanzafame, Luca Quagliata, Guglielmo Roma, Yujin Hoshida, Luigi M Terracciano, Charlotte K Y Ng, Salvatore Piscuoglio
The TP53 gene is the most commonly mutated gene in human cancers and mutations in TP53 have been shown to have either gain-of-function or loss-of-function effects. Using the data generated by The Cancer Genome Atlas, we sought to define the spectrum of TP53 mutations in hepatocellular carcinomas (HCCs) and their association with clinicopathologic features, and to determine the oncogenic and mutational signatures in TP53 -mutant HCCs. Compared to other cancer types, HCCs harbored distinctive mutation hotspots at V157 and R249, whereas common mutation hotspots in other cancer types, R175 and R273, were extremely rare in HCCs...
2018: Frontiers in Genetics
Houliang Deng, Jianming Zeng, Ting Zhang, Longcai Gong, Hongjie Zhang, Edwin Cheung, Chris Jones, Gang Li
Lysine to Methionine mutations at position 27 (K27M) in the histone H3 (H3.3 and H3.1) are highly prevalent in pediatric high-grade gliomas (HGG) that arise in the midline of the central nervous system. H3K27M perturbs the activity of polycomb repressor complex 2 (PRC2) and correlates with DNA hypomethylation; however, the pathways whereby H3K27M drive the development of pediatric HGG remain poorly understood. To understand the mechanism of pediatric HGG development driven by H3.3K27M and discover potential therapeutic targets or biomarkers, we established pediatric glioma cell model systems harboring H3...
February 16, 2018: Molecular Cancer Research: MCR
J B Bachet, O Bouché, J Taieb, O Dubreuil, M L Garcia, A Meurisse, C Normand, J M Gornet, P Artru, S Louafi, F Bonnetain, A Thirot-Bidault, I Baumgaertner, R Coriat, D Tougeron, T Lecomte, F Mary, T Aparicio, L Marthey, V Taly, H Blons, D Vernerey, P Laurent-Puig
Background: RAS mutations are currently sought for in tumor samples, which takes a median of almost 3 weeks in western European countries. This creates problems in clinical situations that require urgent treatment and for inclusion in therapeutic trials that need RAS status for randomization. Analysis of circulating tumor DNA might help to shorten the time required to determine RAS mutational status prior to anti-EGFR antibody therapy for metastatic colorectal cancer. Here we compared plasma versus tissue RAS analysis in a large prospective multicenter cohort...
February 9, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Andrea Cacciato Insilla, Agnese Proietti, Nicla Borrelli, Elisabetta Macerola, Cristina Niccoli, Paolo Vitti, Paolo Miccoli, Fulvio Basolo
Papillary thyroid carcinoma (PTC) is the most common type of endocrine malignancy and accounts for ~80% of thyroid carcinomas in adults and 90% in children. Risk stratification is important for identifying patients at higher risk and, for this reason, recent advances in molecular genetics of thyroid cancer can be applied to provide novel biomarkers useful in understanding tumor behavior. B-Raf proto-oncogene, serine/threonine kinase (BRAF) and rat sarcoma (RAS) mutations have been widely studied and appear to have an important role in thyroid tumorigenesis...
March 2018: Oncology Letters
Takumi Yamaura, Junji Ezaki, Naoyuki Okabe, Hironori Takagi, Yuki Ozaki, Takuya Inoue, Yuzuru Watanabe, Mitsuro Fukuhara, Satoshi Muto, Yuki Matsumura, Takeo Hasegawa, Mika Hoshino, Jun Osugi, Yutaka Shio, Satoshi Waguri, Hirosumi Tamura, Jun-Ichi Imai, Emi Ito, Yuka Yanagisawa, Reiko Honma, Shinya Watanabe, Hiroyuki Suzuki
Lung adenocarcinoma (ADC) patients with tumors that harbor no targetable driver gene mutation, such as epidermal growth factor receptor (EGFR) gene mutations, have unfavorable prognosis, and thus, novel therapeutic targets are required. Family with sequence similarity 83, member B (FAM83B) is a biomarker for squamous cell lung cancer. FAM83B has also recently been shown to serve an important role in the EGFR signaling pathway. In the present study, the molecular and clinical impact of FAM83B in lung ADC was investigated...
February 2018: Oncology Letters
Clara Montagut, Guillem Argilés, Fortunato Ciardiello, Thomas T Poulsen, Rodrigo Dienstmann, Michael Kragh, Scott Kopetz, Trine Lindsted, Cliff Ding, Joana Vidal, Jenifer Clausell-Tormos, Giulia Siravegna, Francisco J Sánchez-Martín, Klaus Koefoed, Mikkel W Pedersen, Michael M Grandal, Mikhail Dvorkin, Lucjan Wyrwicz, Ana Rovira, Antonio Cubillo, Ramon Salazar, Françoise Desseigne, Cristina Nadal, Joan Albanell, Vittorina Zagonel, Salvatore Siena, Guglielmo Fumi, Giuseppe Rospo, Paul Nadler, Ivan D Horak, Alberto Bardelli, Josep Tabernero
Importance: Acquired resistance to anti-EGFR therapy (epidermal growth factor receptor) is frequently due to RAS and EGFR extracellular domain (ECD) mutations in metastatic colorectal cancer (mCRC). Some anti-EGFR-refractory patients retain tumor EGFR dependency potentially targetable by agents such as Sym004, which is a mixture of 2 nonoverlapping monoclonal antibodies targeting EGFR. Objective: To determine if continuous blockade of EGFR by Sym004 has survival benefit...
February 8, 2018: JAMA Oncology
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