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Katarzyna Modzelewska, Elena F Boer, Timothy L Mosbruger, Daniel Picard, Daniela Anderson, Rodney R Miles, Mitchell Kroll, William Oslund, Theodore J Pysher, Joshua D Schiffman, Randy Jensen, Cicely A Jette, Annie Huang, Rodney A Stewart
Malignant brain tumors are the leading cause of cancer-related deaths in children. Primitive neuroectodermal tumors of the CNS (CNS-PNETs) are particularly aggressive embryonal tumors of unknown cellular origin. Recent genomic studies have classified CNS-PNETs into molecularly distinct subgroups that promise to improve diagnosis and treatment; however, the lack of cell- or animal-based models for these subgroups prevents testing of rationally designed therapies. Here, we show that a subset of CNS-PNETs co-express oligoneural precursor cell (OPC) markers OLIG2 and SOX10 with coincident activation of the RAS/MAPK (mitogen-activated protein kinase) pathway...
October 25, 2016: Cell Reports
Filippo Pietrantonio, Claudio Vernieri, Giulia Siravegna, Alessia Mennitto, Rosa Berenato, Federica Perrone, Annunziata Gloghini, Elena Tamborini, Sara Lonardi, Federica Morano, Benedetta Picciani, Adele Busico, Chiara C Volpi, Antonia Martinetti, Francesca Battaglin, Ilaria Bossi, Alessio Pellegrinelli, Massimo Milione, Chiara Cremolini, Maria Di Bartolomeo, Alberto Bardelli, Filippo de Braud
Purpose Even if RAS-BRAF wild-type and HER2/MET negative mCRC patients frequently respond to anti-EGFR monoclonal antibodies, acquired resistance almost invariably occurs. Mechanisms of resistance to EGFR blockade include the emergence of KRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations. However, these findings derive from retrospective studies that analyzed one single resistance mechanism at a time; moreover, it is still unclear how molecular heterogeneity affects clonal evolution in patients...
October 25, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Simona De Summa, Michele Guida, Stefania Tommasi, Sabino Strippoli, Cristina Pellegrini, Maria Concetta Fargnoli, Brunella Pilato, Iole Natalicchio, Gabriella Guida, Rosamaria Pinto
Multiple primary melanoma (MPM) is a rare condition, whose genetic basis has not yet been clarified. Only 8-12% of MPM are due to germline mutations of CDKN2A. However, other genes (POT1, BRCA1/2, MC1R, MGMT) have been demonstrated to be involved in predisposition to this pathology.To our knowledge, this is the first family study based on two siblings with the rare coexistence of MPM and oculocutaneous albinism (OCA), an autosomal recessive disease characterized by the absence or decrease in pigmentation in the skin, hair, and eyes...
October 20, 2016: Oncotarget
Yongcheng Pan, Lusi Zhang, Qiong Liu, Ying Li, Hui Guo, Yu Peng, Hexiang Peng, Beisha Tang, Zhengmao Hu, Jingping Zhao, Kun Xia, Jia-Da Li
AMPD1 is an adenosine monophosphate deaminase that catalyzes the deamination of AMP to IMP. To understand the physiological function of AMPD1, we obtained a strain of Ampd1 mutant mice from KOMP repository, which was generated by a knockout-first strategy. An elevated AMP level and almost complete lack of IMP was detected in the skeletal muscle of E18.5 Ampd1(tm1a/tm1a) mice. However, Ampd1(tm1a/tm1a) mice died in 2 days postnatally, which was contradicting to previous reports. After removal of the knockout-first cassette and critical exon, mice homozygous for the Ampd1(tm1c/tm1c) and Ampd1(tm1d/tm1d) alleles survived to adulthood...
October 24, 2016: Scientific Reports
Hojabr Kakavand, Trina Lum, James S Wilmott, Elizabeth Smith, Sandra O'Toole, Georgina V Long, Richard A Scolyer
No abstract text is available yet for this article.
February 2016: Pathology
Tatsuya Kaji, Osamu Yamasaki, Minoru Takata, Masaki Otsuka, Toshihisa Hamada, Shin Morizane, Kenji Asagoe, Hiroyuki Yanai, Yoji Hirai, Hiroshi Umemura, Keiji Iwatsuki
BACKGROUND: Searching for driver mutations in melanoma is critical to understanding melanoma genesis, progression and response to therapy. OBJECTIVES: We aimed to investigate the frequency and pattern of driver mutations in Japanese primary and metastatic melanomas including cases of unknown primary origin, in relation to their clinicopathologic manifestations. METHODS: Seventy-seven samples from 60 patients with melanoma were screened for 70 driver mutations of 20 oncogenes by Sequenom MelaCarta MassARRAY, and the results for primary and metastatic melanomas were compared...
October 13, 2016: Journal of Dermatological Science
Meinolf Karthaus, Ralf-Dieter Hofheinz, Laurent Mineur, Henry Letocha, Richard Greil, Josef Thaler, Eva Fernebro, Kelly S Oliner, Michael Boedigheimer, Brian Twomey, Ying Zhang, Gaston Demonty, Claus-Henning Köhne
BACKGROUND: To investigate tumour biomarker status and efficacy of first-line panitumumab+FOLFIRI for metastatic colorectal carcinoma (mCRC). METHODS: 154 patients received first-line panitumumab + FOLFIRI every 14 days. Primary end point was objective response rate (ORR). Data were analysed by tumour RAS (KRAS/NRAS) and BRAF status, and baseline amphiregulin (AREG) expression. RESULTS: Objective responses occurred more frequently in RAS wild type (WT) (59%) vs RAS mutant (MT) (41%) mCRC and in RAS WT/BRAF WT (68%) vs RAS or BRAF MT (37%) disease...
October 20, 2016: British Journal of Cancer
Min Wu, Jinyan Huang, Jianming Zhang, Cyril Benes, Bo Jiao, Ruibao Ren
RAS oncogenic mutations are common in human cancers, but RAS proteins have been difficult to target. We sought to identify pharmacological agents to block the RAS oncogenic signaling by a distinct mechanism. Since the biological activity of RAS proteins rely upon lipid modifications and RAS regulates lipid metabolisms in cancer cells, we screened a bioactive lipid library using a RAS specific cell viability assay. We report the discovery of a new class of inhibitors for RAS transformation. Compounds in the class represented by endocannabinoid N-arachidonoyl dopamine (NADA) can induce cell oncosis, independent of its ability to engage cannabinoid receptors...
October 19, 2016: Molecular Cancer Therapeutics
Wayne O Miles, Antonio Lembo, Angela Volorio, Elena Brachtel, Bin Tian, Dennis Sgroi, Paolo Provero, Nicholas Dyson
Alternative polyadenylation (APA) is a process that changes the post-transcriptional regulation and translation potential of mRNAs via addition or deletion of 3'UTR sequences. To identify post-transcriptional regulatory events affected by APA in breast tumors, tumor datasets were analyzed for recurrent APA events. Motif mapping of the changed 3'UTR region found that APA-mediated removal of Pumilio Regulatory Elements (PRE) was unusually common. Breast tumor sub-type specific APA profiling identified triple-negative breast tumors as having the highest levels of APA...
October 10, 2016: Cancer Research
Valentina Kovaleva, Anna-Lena Geissler, Lisa Lutz, Ralph Fritsch, Frank Makowiec, Sebastian Wiesemann, Ulrich T Hopt, Bernward Passlick, Martin Werner, Silke Lassmann
BACKGROUND: Targeted next generation sequencing (tNGS) has become part of molecular pathology diagnostics for determining RAS mutation status in colorectal cancer (CRC) patients as predictive tool for decision on EGFR-targeted therapy. Here, we investigated mutation profiles of case-matched tissue specimens throughout the disease course of CRC, to further specify RAS-status dynamics and to identify de novo mutations associated with distant metastases. METHODS: Case-matched formalin-fixed and paraffin-embedded (FFPE) resection specimens (n = 70; primary tumours, synchronous and/or metachronous liver and/or lung metastases) of 14 CRC cases were subjected to microdissection of normal colonic epithelial, primary and metastatic tumour cells, their DNA extraction and an adapted library protocol for limited DNA using the 48 gene TruSeq Amplicon Cancer Panel(TM), MiSeq sequencing and data analyses (Illumina)...
October 18, 2016: Molecular Cancer
Siavash Rahimi, Iolia Akaev, Costa Repanos, Peter A Brennan, Jean Daniel Dubois
Primary lingual intestinal-type adenocarcinomas are extremely rare with only a few cases described. A case with immunohistochemical expression of Androgen Receptor (AR) which was treated solely by chemo-radiotherapy is reported herein. A 54-year-old male was referred with symptoms of fullness in his tongue. Clinical examination showed an asymmetry of the tongue with a hard mass palpable within the middle of the tongue. Biopsy showed intestinal-type adenocarcinoma. The tumour showed positive staining with cytokeratin 7, cytokeratin 20, CDX2, AR, β-catenin and was mismatch repair proteins (MMR) proficient...
October 17, 2016: Head and Neck Pathology
Kento Kurata, Naoyoshi Onoda, Satoru Noda, Shinichiro Kashiwagi, Yuka Asano, Kosei Hirakawa, Masaichi Ohira
Anaplastic thyroid cancer (ATC) is a rare malignancy that progresses extremely aggressively and often results in dismal prognosis. We investigated the efficacy of inhibiting the activated RAS/RAF/MEK pathway in ATC cells aiming to clarify the mechanism of effect and resistance. Four human ATC cell lines (ACT-1, OCUT-2, OCUT-4 and OCUT-6) were used. OCUT-4 had a BRAF mutation. OCUT-2 had both BRAF and PI3KCA mutations. ACT-1 and OCUT-6 had wild-type BRAF and NRAS mutations. The effects of dabrafenib, a selective inhibitor of the BRAFV600E kinase, and trametinib, a reversible inhibitor of MEK activity, were investigated...
October 7, 2016: International Journal of Oncology
Manojkumar Bupathi, Christina Wu
Colorectal cancer (CRC) is a heterogeneous disease for which the treatment backbone has primarily been cytotoxic chemotherapy. With better understanding of the involved molecular mechanisms, it is now known that there are a number of epigenetic and genetic events, which are involved in CRC pathogenesis. Specific biomarkers have been identified which can be used to determine the clinical outcome of patients beyond tumor staging and predict for treatment efficacy. Molecular testing is now routinely performed to select for patients that will benefit the most from targeted agents and immunotherapy...
October 2016: Journal of Gastrointestinal Oncology
Joanna D Nowacka, Christian Baumgartner, Cristiana Pelorosso, Mareike Roth, Johannes Zuber, Manuela Baccarini
The dual-specificity kinases MEK1 and MEK2 act downstream of RAS/RAF to induce ERK activation, which is generally considered protumorigenic. Activating MEK mutations have not been discovered in leukemia, in which pathway activation is caused by mutations in upstream components such as RAS or Flt3. The anti-leukemic potential of MEK inhibitors is being tested in clinical trials; however, downregulation of MEK1 promotes Eμ-Myc-driven lymphomagenesis and MEK1 ablation induces myeloproliferative disease in mice, raising the concern that MEK inhibitors may be inefficient or counterproductive in this context...
October 10, 2016: Oncotarget
Kyuichi Kadota, Camelia S Sima, Maria E Arcila, Cyrus Hedvat, Mark G Kris, David R Jones, Prasad S Adusumilli, William D Travis
The potential clinical impact of KRAS and epidermal growth factor receptor (EGFR) mutations has been investigated in lung adenocarcinomas; however, their prognostic value remains controversial. In our study, we sought to investigate the prognostic significance of driver mutations using a large cohort of early-stage lung adenocarcinomas. We reviewed patients with pathologic early-stage, lymph node-negative, solitary lung adenocarcinoma who had undergone surgical resection (1995 to 2005; stage I/II=463/19). Tumors were classified according to the IASLC/ATS/ERS classification and genotyped by Sequenom MassARRAY system and polymerase chain reaction-based assays...
October 12, 2016: American Journal of Surgical Pathology
Grazia Palomba, Valentina Doneddu, Antonio Cossu, Panagiotis Paliogiannis, Antonella Manca, Milena Casula, Maria Colombino, Annamaria Lanzillo, Efisio Defraia, Antonio Pazzola, Giovanni Sanna, Carlo Putzu, Salvatore Ortu, Mario Scartozzi, Maria Teresa Ionta, Giovanni Baldino, Giuseppina Sarobba, Francesca Capelli, Tito Sedda, Luciano Virdis, Michela Barca, Giulia Gramignano, Mario Budroni, Francesco Tanda, Giuseppe Palmieri
BACKGROUND: Activation of oncogenes downstream the EGFR gene contributes to colorectal tumorigenesis and determines the sensitivity to anti-EGFR treatments. The aim of this study was to evaluate the prognostic value of KRAS, BRAF, NRAS and PIK3CA mutations in a large collection of CRC patients from genetically-homogeneous Sardinian population. METHODS: A total of 1284 Sardinian patients with histologically-proven diagnosis of colorectal carcinoma (CRC) and presenting with metastatic disease were included into the study...
October 13, 2016: Journal of Translational Medicine
Timothy L Frankel, Efsevia Vakiani, Hari Nathan, Ronald P DeMatteo, T Peter Kingham, Peter J Allen, William R Jarnagin, Nancy E Kemeny, David B Solit, Michael I D'Angelica
BACKGROUND: In the past 3 decades, a better understanding of gene mutations and their role in carcinogenesis has led to improvement in our ability to treat patients with metastatic disease. The objective of the current study was to determine whether the location of a driver mutation within an affected gene impacts the biology of metastatic colorectal cancer. METHODS: DNA was collected from 165 randomly selected specimens of patients who underwent margin-negative resection of colorectal liver metastases with curative intent...
October 13, 2016: Cancer
Tae Won Kim, Anneli Elme, Zvonko Kusic, Joon Oh Park, Anghel Adrian Udrea, Sun Young Kim, Joong Bae Ahn, Ricardo Villalobos Valencia, Srinivasan Krishnan, Ante Bilic, Nebojsa Manojlovic, Jun Dong, Xuesong Guan, Catherine Lofton-Day, A Scott Jung, Eduard Vrdoljak
BACKGROUND: We assessed the treatment effect of panitumumab plus best supportive care (BSC) vs BSC on overall survival (OS) in patients with chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer (mCRC) and report the first prospective extended RAS analysis in a phase 3 trial. METHODS: Patients with wild-type KRAS exon 2 mCRC were randomised 1 : 1 to panitumumab (6 mg kg(-1) Q2W) plus BSC or BSC. On-study crossover was prohibited. RAS mutation status was determined by central laboratory testing...
October 13, 2016: British Journal of Cancer
Evert van den Broek, Oscar Krijgsman, Daoud Sie, Marianne Tijssen, Sandra Mongera, Mark A van de Wiel, Eric J. Belt, Sjoerd H den Uil, Herman Bril, Hein B A C Stockmann, Bauke Ylstra, Beatriz Carvalho, Gerrit A Meijer, Remond J A Fijneman
Tumor profiling of DNA alterations, i.e. gene point mutations, somatic copy number aberrations (CNAs) and structural variants (SVs), improves insight into the molecular pathology of cancer and clinical outcome. Here, associations between genomic aberrations and disease recurrence in stage II and III colon cancers were investigated. A series of 114 stage II and III microsatellite stable colon cancer samples were analyzed by high-resolution array-comparative genomic hybridization (array-CGH) to detect CNAs and CNA-associated chromosomal breakpoints (SVs)...
October 6, 2016: Oncotarget
Claudio Bellevicine, Roberta Sgariglia, Umberto Malapelle, Elena Vigliar, Mariantonia Nacchio, Giuseppe Ciancia, Markus Eszlinger, Ralf Paschke, Giancarlo Troncone
BACKGROUND: Fine-needle aspiration (FNA) cytology is accurate and cost-effective in the evaluation of thyroid nodules. Molecular techniques may contribute to risk stratification in indeterminate cases. Although next-generation sequencing (NGS) is a promising technique for the molecular testing of thyroid FNA specimens, thyroid-specific cancer gene panels are not commercially available. Conversely, the Ion AmpliSeq Cancer Hotspot Panel v2 (CHPv2), which includes the genes most frequently mutated in thyroid neoplasms, is commercially available and may represent an alternative to thyroid-specific panels...
September 26, 2016: Cancer
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