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TP53 and triple negative breast cancer

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https://www.readbyqxmd.com/read/27923045/tumor-evolution-in-two-patients-with-basal-like-breast-cancer-a-retrospective-genomics-study-of-multiple-metastases
#1
Katherine A Hoadley, Marni B Siegel, Krishna L Kanchi, Christopher A Miller, Li Ding, Wei Zhao, Xiaping He, Joel S Parker, Michael C Wendl, Robert S Fulton, Ryan T Demeter, Richard K Wilson, Lisa A Carey, Charles M Perou, Elaine R Mardis
BACKGROUND: Metastasis is the main cause of cancer patient deaths and remains a poorly characterized process. It is still unclear when in tumor progression the ability to metastasize arises and whether this ability is inherent to the primary tumor or is acquired well after primary tumor formation. Next-generation sequencing and analytical methods to define clonal heterogeneity provide a means for identifying genetic events and the temporal relationships between these events in the primary and metastatic tumors within an individual...
December 2016: PLoS Medicine
https://www.readbyqxmd.com/read/27915434/differences-in-the-mutational-landscape-of-triple-negative-breast-cancer-in-african-americans-and-caucasians
#2
Foluso O Ademuyiwa, Yu Tao, Jingqin Luo, Katherine Weilbaecher, Cynthia X Ma
BACKGROUND: Triple-negative breast cancer (TNBC) occurs at higher frequency in African Americans compared with Caucasians. It is unclear if the biology of TNBC is different in African American versus Caucasians. In this study, we sought to evaluate racial differences in the molecular pathology of TNBC. METHODS: Using data from The Cancer Genome Atlas, we identified TNBC patients with information on race. We analyzed differences in clinical characteristics, tumor somatic mutations, and gene expression patterns by race from whole exome and microarray data...
December 3, 2016: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/27900363/integration-of-genomics-and-histology-revises-diagnosis-and-enables-effective-therapy-of-refractory-cancer-of-unknown-primary-with-pdl1-amplification
#3
Stefan Gröschel, Martin Bommer, Barbara Hutter, Jan Budczies, David Bonekamp, Christoph Heining, Peter Horak, Martina Fröhlich, Sebastian Uhrig, Daniel Hübschmann, Christina Geörg, Daniela Richter, Nicole Pfarr, Katrin Pfütze, Stephan Wolf, Peter Schirmacher, Dirk Jäger, Christof von Kalle, Benedikt Brors, Hanno Glimm, Wilko Weichert, Albrecht Stenzinger, Stefan Fröhling
Identification of the tissue of origin in cancer of unknown primary (CUP) poses a diagnostic challenge and is critical for directing site-specific therapy. Currently, clinical decision-making in patients with CUP primarily relies on histopathology and clinical features. Comprehensive molecular profiling has the potential to contribute to diagnostic categorization and, most importantly, guide CUP therapy through identification of actionable lesions. We here report the case of an advanced-stage malignancy initially mimicking poorly differentiated soft-tissue sarcoma that did not respond to multiagent chemotherapy...
November 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27846853/dgca-a-comprehensive-r-package-for-differential-gene-correlation-analysis
#4
Andrew T McKenzie, Igor Katsyv, Won-Min Song, Minghui Wang, Bin Zhang
BACKGROUND: Dissecting the regulatory relationships between genes is a critical step towards building accurate predictive models of biological systems. A powerful approach towards this end is to systematically study the differences in correlation between gene pairs in more than one distinct condition. RESULTS: In this study we develop an R package, DGCA (for Differential Gene Correlation Analysis), which offers a suite of tools for computing and analyzing differential correlations between gene pairs across multiple conditions...
November 15, 2016: BMC Systems Biology
https://www.readbyqxmd.com/read/27815358/phase-i-study-of-gdc-0425-a-checkpoint-kinase-1-inhibitor-in-combination-with-gemcitabine-in-patients-with-refractory-solid-tumors
#5
Jeffrey R Infante, Antoine Hollebecque, Sophie Postel-Vinay, Todd M Bauer, Elizabeth Blackwood, Marie Evangelista, Sami Mahrus, Franklin Peale, Xuyang Lu, Srikumar Sahasranaman, Rui Zhu, Yuan Chen, Xiao Ding, Elaine Murray, Jennifer Schutzman, Jennifer O Lauchle, Jean-Charles Soria, Patricia M LoRusso
PURPOSE: Chk1 inhibition potentiates DNA-damaging chemotherapy by overriding cell cycle arrest and genome repair. This Phase I study evaluated the Chk1 inhibitor GDC-0425 given in combination with gemcitabine to patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients received GDC-0425 alone for a 1-week lead-in followed by 21-day cycles of gemcitabine plus GDC-0425. Gemcitabine was initially administered at 750 mg/m2 (Arm A), then increased to 1000 mg/m2 (Arm B), on Days 1 and 8 in a 3+3+3 dose escalation to establish maximum tolerated dose (MTD)...
November 4, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27806348/clinical-outcomes-based-on-multigene-profiling-in-metastatic-breast-cancer-patients
#6
Reva K Basho, Debora de Melo Gagliato, Naoto T Ueno, Chetna Wathoo, Huiqin Chen, Maryam Shariati, Caimiao Wei, Ricardo H Alvarez, Stacy L Moulder, Aysegul A Sahin, Sinchita Roy-Chowdhuri, Mariana Chavez-MacGregor, Jennifer K Litton, Vincent Valero, Raja Luthra, Jia Zeng, Kenna R Shaw, John Mendelsohn, Gordon B Mills, Debu Tripathy, Funda Meric-Bernstam
BACKGROUND: Identifying the clinical impact of recurrent mutations can help define their role in cancer. Here, we identify frequent hotspot mutations in metastatic breast cancer (MBC) patients and associate them with clinical outcomes. PATIENTS AND METHODS: Hotspot mutation testing was conducted in 500 MBC patients using an 11 gene (N = 126) and/or 46 or 50 gene (N = 391) panel. Patients were stratified by hormone receptor (HR) and human epidermal growth factor 2 (HER2) status...
October 28, 2016: Oncotarget
https://www.readbyqxmd.com/read/27785100/current-advances-in-biomarkers-for-targeted-therapy-in-triple-negative-breast-cancer
#7
REVIEW
Brett Fleisher, Charlotte Clarke, Sihem Ait-Oudhia
Triple-negative breast cancer (TNBC) is a complex heterogeneous disease characterized by the absence of three hallmark receptors: human epidermal growth factor receptor 2, estrogen receptor, and progesterone receptor. Compared to other breast cancer subtypes, TNBC is more aggressive, has a higher prevalence in African-Americans, and more frequently affects younger patients. Currently, TNBC lacks clinically accepted targets for tailored therapy, warranting the need for candidate biomarkers. BiomarkerBase, an online platform used to find biomarkers reported in clinical trials, was utilized to screen all potential biomarkers for TNBC and select only the ones registered in completed TNBC trials through clinicaltrials...
2016: Breast Cancer: Targets and Therapy
https://www.readbyqxmd.com/read/27713419/genetic-analysis-of-microglandular-adenosis-and-acinic-cell-carcinomas-of-the-breast-provides-evidence-for-the-existence-of-a-low-grade-triple-negative-breast-neoplasia-family
#8
Felipe C Geyer, Samuel H Berman, Caterina Marchiò, Kathleen A Burke, Elena Guerini-Rocco, Salvatore Piscuoglio, Charlotte Ky Ng, Fresia Pareja, Hannah Y Wen, Zoltan Hodi, Stuart J Schnitt, Emad A Rakha, Ian O Ellis, Larry Norton, Britta Weigelt, Jorge S Reis-Filho
Acinic cell carcinoma is an indolent form of invasive breast cancer, whereas microglandular adenosis has been shown to be a neoplastic proliferation. Both entities display a triple-negative phenotype, and may give rise to and display somatic genomic alterations typical of high-grade triple-negative breast cancers. Here we report on a comparison of previously published data on eight carcinoma-associated microglandular adenosis and eight acinic cell carcinomas subjected to targeted massively parallel sequencing targeting all exons of 236 genes recurrently mutated in breast cancer and/or DNA repair-related...
October 7, 2016: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/27685159/tumor-infiltrating-lymphocytes-affect-the-outcome-of-patients-with-operable-triple-negative-breast-cancer-in-combination-with-mutated-amino-acid-classes
#9
Vassiliki Kotoula, Sotiris Lakis, Ioannis S Vlachos, Eleni Giannoulatou, Flora Zagouri, Zoi Alexopoulou, Helen Gogas, Dimitrios Pectasides, Gerasimos Aravantinos, Ioannis Efstratiou, George Pentheroudakis, Kyriaki Papadopoulou, Kyriakos Chatzopoulos, Pavlos Papakostas, Maria Sotiropoulou, Irene Nicolaou, Evangelia Razis, Amanda Psyrri, Paris Kosmidis, Christos Papadimitriou, George Fountzilas
BACKGROUND: Stromal tumor infiltrating lymphocytes (TILs) density is an outcome predictor in triple-negative breast cancer (TNBC). Herein we asked whether TILs are related to coding mutation load and to the chemical class of the resulting mutated amino acids, i.e., charged, polar, and hydrophobic mutations. METHODS: We examined paraffin tumors from TNBC patients who had been treated with adjuvant chemotherapy mostly within clinical trials (training cohort, N = 133; validation, N = 190) for phenotype concordance; TILs density; mutation load and types...
2016: PloS One
https://www.readbyqxmd.com/read/27616075/gene-panel-sequencing-in-familial-breast-ovarian-cancer-patients-identifies-multiple-novel-mutations-also-in-genes-others-than-brca1-2
#10
Cornelia Kraus, Juliane Hoyer, Georgia Vasileiou, Marius Wunderle, Michael P Lux, Peter A Fasching, Mandy Krumbiegel, Steffen Uebe, Miriam Reuter, Matthias W Beckmann, André Reis
Breast and ovarian cancer (BC/OC) predisposition has been attributed to a number of high- and moderate to low-penetrance susceptibility genes. With the advent of next generation sequencing (NGS) simultaneous testing of these genes has become feasible. In this monocentric study, we report results of panel-based screening of 14 BC/OC susceptibility genes (BRCA1, BRCA2, RAD51C, RAD51D, CHEK2, PALB2, ATM, NBN, CDH1, TP53, MLH1, MSH2, MSH6 and PMS2) in a group of 581 consecutive individuals from a German population with BC and/or OC fulfilling diagnostic criteria for BRCA1 and BRCA2 testing including 179 with a triple-negative tumor...
January 1, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27611952/role-of-tp53-mutations-in-triple-negative-and-her2-positive-breast-cancer-treated-with-neoadjuvant-anthracycline-taxane-based-chemotherapy
#11
Silvia Darb-Esfahani, Carsten Denkert, Albrecht Stenzinger, Christoph Salat, Bruno Sinn, Christian Schem, Volker Endris, Peter Klare, Wolfgang Schmitt, Jens-Uwe Blohmer, Wilko Weichert, Markus Möbs, Hans Tesch, Sherko Kümmel, Peter Sinn, Christian Jackisch, Manfred Dietel, Toralf Reimer, Sherene Loi, Michael Untch, Gunter von Minckwitz, Valentina Nekljudova, Sibylle Loibl
BACKGROUND: TP53 mutations are frequent in breast cancer, however their clinical relevance in terms of response to chemotherapy is controversial. METHODS: 450 pre-therapeutic, formalin-fixed, paraffin-embedded core biopsies from the phase II neoadjuvant GeparSixto trial that included HER2-positive and triple negative breast cancer (TNBC) were subjected to Sanger sequencing of exons 5-8 of the TP53 gene. TP53 status was correlated to response to neoadjuvant anthracycline/taxane-based chemotherapy with or without carboplatin and trastuzumab/lapatinib in HER2-positive and bevacizumab in TNBC...
September 7, 2016: Oncotarget
https://www.readbyqxmd.com/read/27571409/rb1-deficiency-in-triple-negative-breast-cancer-induces-mitochondrial-protein-translation
#12
Robert A Jones, Tyler J Robinson, Jeff C Liu, Mariusz Shrestha, Veronique Voisin, YoungJun Ju, Philip E D Chung, Giovanna Pellecchia, Victoria L Fell, SooIn Bae, Lakshmi Muthuswamy, Alessandro Datti, Sean E Egan, Zhe Jiang, Gustavo Leone, Gary D Bader, Aaron Schimmer, Eldad Zacksenhaus
Triple-negative breast cancer (TNBC) includes basal-like and claudin-low subtypes for which no specific treatment is currently available. Although the retinoblastoma tumor-suppressor gene (RB1) is frequently lost together with TP53 in TNBC, it is not directly targetable. There is thus great interest in identifying vulnerabilities downstream of RB1 that can be therapeutically exploited. Here, we determined that combined inactivation of murine Rb and p53 in diverse mammary epithelial cells induced claudin-low-like TNBC with Met, Birc2/3-Mmp13-Yap1, and Pvt1-Myc amplifications...
October 3, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27545642/the-relationship-between-nuclear-factor-nf-%C3%AE%C2%BAb-family-gene-expression-and-prognosis-in-triple-negative-breast-cancer-tnbc-patients-receiving-adjuvant-doxorubicin-treatment
#13
Ji-Yeon Kim, Hae Hyun Jung, Soomin Ahn, SooYoun Bae, Se Kyung Lee, Seok Won Kim, Jeong Eon Lee, Seok Jin Nam, Jin Seok Ahn, Young-Hyuck Im, Yeon Hee Park
We investigated gene expression profiles of the NF-κB pathway in patients with triple-negative breast cancer (TNBC) receiving adjuvant chemotherapy to determine the prognostic value of NF-κB pathway genes according to chemotherapeutic regimen. We used the nCounter expression assay to measure expression of 11 genes (NFKB1, NFKB2, RELA, RELB, REL, TP53, FOXC1, TBP, SP1, STAT3 and IRF1 genes) belonging to the NF-κB pathway using mRNA extracted from paraffin-embedded tumor tissues from 203 patients diagnosed with TNBC...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27531819/comprehensive-profiling-of-metaplastic-breast-carcinomas-reveals-frequent-overexpression-of-programmed-death-ligand-1
#14
Upasana Joneja, Semir Vranic, Jeffrey Swensen, Rebecca Feldman, Wangjuh Chen, Jeffrey Kimbrough, Nianqing Xiao, Sandeep Reddy, Juan Palazzo, Zoran Gatalica
AIMS: Metaplastic breast carcinoma (MBC) is a rare subtype of breast carcinoma less responsive to conventional chemotherapy than ductal carcinoma. In molecular terms, MBCs usually cluster with triple-negative breast cancers (TNBCs), but have a worse prognosis than TNBCs. Studies investigating MBCs for specific biomarkers of therapy response are rare and limited by the methodological approaches. The aim of the present study was to characterise MBCs on a molecular level and test programmed death-ligand 1 (PD-L1) biomarker expression in MBCs for future therapeutic interventions...
August 16, 2016: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/27527855/genetic-polymorphisms-and-response-to-5-fluorouracil-doxorubicin-and-cyclophosphamide-chemotherapy-in-breast-cancer-patients
#15
Karolina Tecza, Jolanta Pamula-Pilat, Joanna Lanuszewska, Ewa Grzybowska
Clinical resistance to chemotherapy is one of the major problems in breast cancer treatment. In this study we analyzed possible impact of 22 polymorphic variants on the treatment response in 324 breast cancer patients. Selected genes were involved in FAC chemotherapy drugs transport (ABCB1, ABCC2, ABCG2, SLC22A16), metabolism (CYP1B1, CYP2C19, GSTT1, GSTM1, GSTP1, TYMS, MTHFR, DPYD), drug-induced damage repair (ERCC1, ERCC2, XRCC1) and involved in regulation of DNA damage response and cell cycle control (ATM, TP53)...
August 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27472710/integrative-exploration-of-genomic-profiles-for-triple-negative-breast-cancer-identifies-potential-drug-targets
#16
Xiaosheng Wang, Chittibabu Guda
BACKGROUND: Triple negative breast cancer (TNBC) is high-risk due to its rapid drug resistance and recurrence, metastasis, and lack of targeted therapy. So far, no molecularly targeted therapeutic agents have been clinically approved for TNBC. It is imperative that we discover new targets for TNBC therapy. OBJECTIVES: A large volume of cancer genomics data are emerging and advancing breast cancer research. We may integrate different types of TNBC genomic data to discover molecular targets for TNBC therapy...
July 2016: Medicine (Baltimore)
https://www.readbyqxmd.com/read/27454576/prognostic-factor-analysis-for-breast-cancer-using-gene-expression-profiles
#17
Soobok Joe, Hojung Nam
BACKGROUND: The survival of patients with breast cancer is highly sporadic, from a few months to more than 15 years. In recent studies, the gene expression profiling of tumors has been used as a promising means of predicting prognosis factors. METHODS: In this study, we used gene expression datasets of tumors to identify prognostic factors in breast cancer. We conducted log-rank tests and used unsupervised clustering methods to find reciprocally expressed gene sets associated with worse survival rates...
2016: BMC Medical Informatics and Decision Making
https://www.readbyqxmd.com/read/27402769/phosphoinositide-3-kinase-inhibitors-induce-dna-damage-through-nucleoside-depletion
#18
Ashish Juvekar, Hai Hu, Sina Yadegarynia, Costas A Lyssiotis, Soumya Ullas, Evan C Lien, Gary Bellinger, Jaekyoung Son, Rosanna C Hok, Pankaj Seth, Michele B Daly, Baek Kim, Ralph Scully, John M Asara, Lewis C Cantley, Gerburg M Wulf
We previously reported that combining a phosphoinositide 3-kinase (PI3K) inhibitor with a poly-ADP Rib polymerase (PARP)-inhibitor enhanced DNA damage and cell death in breast cancers that have genetic aberrations in BRCA1 and TP53. Here, we show that enhanced DNA damage induced by PI3K inhibitors in this mutational background is a consequence of impaired production of nucleotides needed for DNA synthesis and DNA repair. Inhibition of PI3K causes a reduction in all four nucleotide triphosphates, whereas inhibition of the protein kinase AKT is less effective than inhibition of PI3K in suppressing nucleotide synthesis and inducing DNA damage...
July 26, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27397723/somatic-gene-mutation-analysis-of-triple-negative-breast-cancers
#19
J L Dillon, S M Mockus, G Ananda, V Spotlow, W A Wells, G J Tsongalis, J D Marotti
OBJECTIVES: The aims of this study were to analyze triple negative breast cancer (TNBC) using an expanded next generation sequencing (NGS) assay, assess the clinical relevance using a recently described database, and correlate tumor morphology with detected genetic alterations. METHODS: DNA was isolated from twenty primary TNBCs and genes of interest were enriched and sequenced with hybrid capture, followed by variant detection and functional and clinical annotation...
October 2016: Breast: Official Journal of the European Society of Mastology
https://www.readbyqxmd.com/read/27384237/deciphering-and-targeting-oncogenic-mutations-and-pathways-in-breast-cancer
#20
REVIEW
Libero Santarpia, Giulia Bottai, Catherine M Kelly, Balázs Győrffy, Borbala Székely, Lajos Pusztai
UNLABELLED: : Advances in DNA and RNA sequencing revealed substantially greater genomic complexity in breast cancer than simple models of a few driver mutations would suggest. Only very few, recurrent mutations or copy-number variations in cancer-causing genes have been identified. The two most common alterations in breast cancer are TP53 (affecting the majority of triple-negative breast cancers) and PIK3CA (affecting almost half of estrogen receptor-positive cancers) mutations, followed by a long tail of individually rare mutations affecting <1%-20% of cases...
September 2016: Oncologist
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