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TP53 and triple negative breast cancer

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
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
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...
September 12, 2016: International Journal of Cancer. Journal International du Cancer
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
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
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
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
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
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)
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
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
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
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
Vassiliki Kotoula, Vasilios Karavasilis, Flora Zagouri, George Kouvatseas, Eleni Giannoulatou, Helen Gogas, Sotiris Lakis, George Pentheroudakis, Mattheos Bobos, Kyriaki Papadopoulou, Eleftheria Tsolaki, Dimitrios Pectasides, Georgios Lazaridis, Angelos Koutras, Gerasimos Aravantinos, Christos Christodoulou, Pavlos Papakostas, Christos Markopoulos, George Zografos, Christos Papandreou, George Fountzilas
The purpose of this study is to investigate whether the outcome of breast cancer (BC) patients treated with adjuvant chemotherapy is affected by co-mutated TP53 and PIK3CA according to stromal tumor-infiltrating lymphocytes (TILs). Paraffin tumors of all clinical subtypes from 1661 patients with operable breast cancer who were treated within 4 adjuvant trials with anthracycline-taxanes chemotherapy were informative for TP53 and PIK3CA mutation status (semiconductor sequencing genotyping) and for stromal TILs density...
July 2016: Breast Cancer Research and Treatment
Dawid Walerych, Kamil Lisek, Roberta Sommaggio, Silvano Piazza, Yari Ciani, Emiliano Dalla, Katarzyna Rajkowska, Katarzyna Gaweda-Walerych, Eleonora Ingallina, Claudia Tonelli, Marco J Morelli, Angela Amato, Vincenzo Eterno, Alberto Zambelli, Antonio Rosato, Bruno Amati, Jacek R Wiśniewski, Giannino Del Sal
In cancer, the tumour suppressor gene TP53 undergoes frequent missense mutations that endow mutant p53 proteins with oncogenic properties. Until now, a universal mutant p53 gain-of-function program has not been defined. By means of multi-omics: proteome, DNA interactome (chromatin immunoprecipitation followed by sequencing) and transcriptome (RNA sequencing/microarray) analyses, we identified the proteasome machinery as a common target of p53 missense mutants. The mutant p53-proteasome axis globally affects protein homeostasis, inhibiting multiple tumour-suppressive pathways, including the anti-oncogenic KSRP-microRNA pathway...
August 2016: Nature Cell Biology
Carey K Anders, Vandana Abramson, Tira Tan, Rebecca Dent
Triple-negative breast cancer (TNBC) is clinically defined as lacking expression of the estrogen receptor (ER), progesterone receptor (ER), and HER2. Historically, TNBC has been characterized by an aggressive natural history and worse disease-specific outcomes compared with other breast cancer subtypes. The advent of next-generation sequencing (NGS) has allowed for the dissection of TNBC into molecular subtypes (i.e., basal-like, claudin-low). Within TNBC, several subtypes have emerged as "immune-activated," consistently illustrating better disease outcome...
2016: American Society of Clinical Oncology Educational Book
Adam D Pfefferle, Yash N Agrawal, Daniel C Koboldt, Krishna L Kanchi, Jason I Herschkowitz, Elaine R Mardis, Jeffrey M Rosen, Charles M Perou
Targeted therapies against basal-like breast tumors, which are typically 'triple-negative breast cancers (TNBCs)', remain an important unmet clinical need. Somatic TP53 mutations are the most common genetic event in basal-like breast tumors and TNBC. To identify additional drivers and possible drug targets of this subtype, a comparative study between human and murine tumors was performed by utilizing a murine Trp53-null mammary transplant tumor model. We show that two subsets of murine Trp53-null mammary transplant tumors resemble aspects of the human basal-like subtype...
July 1, 2016: Disease Models & Mechanisms
George Fountzilas, Eleni Giannoulatou, Zoi Alexopoulou, Flora Zagouri, Eleni Timotheadou, Kyriaki Papadopoulou, Sotiris Lakis, Mattheos Bobos, Christos Poulios, Maria Sotiropoulou, Aggeliki Lyberopoulou, Helen Gogas, George Pentheroudakis, Dimitrios Pectasides, Angelos Koutras, Christos Christodoulou, Christos Papandreou, Epaminontas Samantas, Pavlos Papakostas, Paris Kosmidis, Dimitrios Bafaloukos, Charisios Karanikiotis, Meletios-Athanassios Dimopoulos, Vassiliki Kotoula
BACKGROUND: We investigated the impact of PIK3CA and TP53 mutations and p53 protein status on the outcome of patients who had been treated with adjuvant anthracycline-taxane chemotherapy within clinical trials in the pre- and post-trastuzumab era. RESULTS: TP53 and PIK3CA mutations were found in 380 (21.5%) and 458 (25.9%) cases, respectively, including 104 (5.9%) co-mutated tumors; p53 immunopositivity was observed in 848 tumors (53.5%). TP53 mutations (p < 0...
May 31, 2016: Oncotarget
Benjamin A Katchman, Rodrigo Barderas, Rizwan Alam, Diego Chowell, Matthew S Field, Laura J Esserman, Garrick Wallstrom, Joshua LaBaer, Daniel W Cramer, Michael A Hollingsworth, Karen S Anderson
PURPOSE: Mutations in TP53 induce autoantibody immune responses in a subset of cancer patients, which have been proposed as biomarkers for early detection. Here, we investigate the association of p53-specific autoantibodies with multiple tumor subtypes and determine the association with p53 mutation status and epitope specificity. EXPERIMENTAL DESIGN: IgG p53 autoantibodies (p53-AAb), were quantified in 412 serum samples using a programmable ELISA assay from patients with serous ovarian, pancreatic adenocarcinoma, and breast cancer...
July 2016: Proteomics. Clinical Applications
Francesca Menghi, Koichiro Inaki, XingYi Woo, Pooja A Kumar, Krzysztof R Grzeda, Ankit Malhotra, Vinod Yadav, Hyunsoo Kim, Eladio J Marquez, Duygu Ucar, Phung T Shreckengast, Joel P Wagner, George MacIntyre, Krishna R Murthy Karuturi, Ralph Scully, James Keck, Jeffrey H Chuang, Edison T Liu
Next-generation sequencing studies have revealed genome-wide structural variation patterns in cancer, such as chromothripsis and chromoplexy, that do not engage a single discernable driver mutation, and whose clinical relevance is unclear. We devised a robust genomic metric able to identify cancers with a chromotype called tandem duplicator phenotype (TDP) characterized by frequent and distributed tandem duplications (TDs). Enriched only in triple-negative breast cancer (TNBC) and in ovarian, endometrial, and liver cancers, TDP tumors conjointly exhibit tumor protein p53 (TP53) mutations, disruption of breast cancer 1 (BRCA1), and increased expression of DNA replication genes pointing at rereplication in a defective checkpoint environment as a plausible causal mechanism...
April 26, 2016: Proceedings of the National Academy of Sciences of the United States of America
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