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Endocrine tumors, next generation sequencing

Moritz Jesinghaus, Björn Konukiewitz, Gisela Keller, Matthias Kloor, Katja Steiger, Magdalena Reiche, Roland Penzel, Volker Endris, Ruza Arsenic, Gratiana Hermann, Albrecht Stenzinger, Wilko Weichert, Nicole Pfarr, Günter Klöppel
Colorectal mixed adenoneuroendocrine carcinomas are rare and clinically aggressive neoplasms with considerable morphological heterogeneity. Data on their genomic characteristics and molecular associations to either conventional colorectal adenocarcinomas or poorly differentiated neuroendocrine neoplasms is still scarce, hampering optimized patient treatment and care. Tissue from 19 colorectal mixed adenoneuroendocrine carcinomas and eight colorectal poorly differentiated neuroendocrine neoplasms (neuroendocrine carcinomas) was microdissected and subjected to next-generation sequencing using a colorectal adenocarcinoma-specific panel comprising 196 amplicons covering 32 genes linked to colorectal adenocarcinoma, and poorly differentiated neuroendocrine neoplasm tumorigenesis...
April 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Karen Page, David S Guttery, Daniel Fernandez-Garcia, Allison Hills, Robert K Hastings, Jinli Luo, Kate Goddard, Vedia Shahin, Laura Woodley-Barker, Brenda M Rosales, R Charles Coombes, Justin Stebbing, Jacqueline A Shaw
BACKGROUND: Breast cancer tissues are heterogeneous and show diverse somatic mutations and somatic copy number alterations (CNAs). We used a novel targeted next generation sequencing (NGS) panel to examine cell-free DNA (cfDNA) to detect somatic mutations and gene amplification in women with metastatic breast cancer (MBC). METHODS: cfDNA from pretreated patients (n = 42) and 9 healthy controls were compared with matched lymphocyte DNA by NGS, using a custom 158 amplicon panel covering hot-spot mutations and CNAs in 16 genes, with further validation of results by droplet digital PCR...
February 2017: Clinical Chemistry
Na Zhou, Congmin Liu, Helei Hou, Chuantao Zhang, Dong Liu, Guanqun Wang, Kewei Liu, Jingjuan Zhu, Hongying Lv, Tianjun Li, Xiaochun Zhang
Spindle cell carcinoma of the breast is a rare subtype of metaplastic carcinoma, and no effective chemotherapy special for metaplastic carcinoma exists until now. As spindle cell carcinomas of the breast are typically "Triple Negative", endocrine therapy and molecular therapy targeted to Her2 might not be favorable, resulting in poor prognosis. Apatinib is currently being tested in patients with breast or lung cancers. Here we report a successful case using Apatinib to treat spindle cell carcinoma of breast...
November 1, 2016: Oncotarget
Cristina L Ronchi, Guido Di Dalmazi, Simon Faillot, Silviu Sbiera, Guillaume Assié, Isabel Weigand, Davide Calebiro, Thomas Schwarzmayr, Silke Appenzeller, Beatrice Rubin, Jens Waldmann, Carla Scaroni, Detlef K Bartsch, Franco Mantero, Massimo Mannelli, Darko Kastelan, Iacopo Chiodini, Jerome Bertherat, Martin Reincke, Tim M Strom, Martin Fassnacht, Felix Beuschlein
CONTEXT: Adrenocortical adenomas (ACAs) are among the most frequent human neoplasias. Genetic alterations affecting the cAMP/protein kinase A signaling pathway are common in cortisol-producing ACAs, whereas activating mutations in the gene encoding β-catenin (CTNNB1) have been reported in a subset of both benign and malignant adrenocortical tumors. However, the molecular pathogenesis of most ACAs is still largely unclear. OBJECTIVE: The aim of the study was to define the genetic landscape of sporadic unilateral ACAs...
September 2016: Journal of Clinical Endocrinology and Metabolism
Ingrid A Mayer, Vandana G Abramson, Luigi Formisano, Justin M Balko, Mónica V Estrada, Melinda E Sanders, Dejan Juric, David Solit, Michael F Berger, Helen H Won, Yisheng Li, Lewis C Cantley, Eric Winer, Carlos L Arteaga
PURPOSE: Alpelisib, a selective oral inhibitor of the class I PI3K catalytic subunit p110α, has shown synergistic antitumor activity with endocrine therapy against ER(+)/PIK3CA-mutated breast cancer cells. This phase Ib study evaluated alpelisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER(+) breast cancer refractory to endocrine therapy. EXPERIMENTAL DESIGN: Twenty-six patients received letrozole and alpelisib daily...
January 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Hamdy A Azim, Loay Kassem, Isabelle Treilleux, Qing Wang, Mona Abu El Enein, Shady E Anis, Thomas Bachelot
BACKGROUND: The PI3K/AKT/mTOR pathway alterations have been shown to play significant roles in the development, progression, and metastatic spread of breast cancer. Furthermore, they have been implicated in the process of drug resistance, especially endocrinal therapies. In this study, we aimed to define the correlation between the PI3K mutations and the expression of the phosphorylated forms of different downstream molecules in women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2-negative (luminal) early breast cancer treated at Cairo university hospitals...
April 2016: Translational Oncology
Parnian Ahmadi Moghaddam, Renu Virk, Ali Sakhdari, Manju L Prasad, Ediz F Cosar, Ashraf Khan
CONTEXT: Thyroid carcinoma is the most common malignant tumor of endocrine organs, yet it only accounts for approximately 1% of all cancers in the United States with more than 35,000 new cases diagnosed each year and more than 450,000 people living with this disease. While most tumors can be diagnosed without much difficulty, a few tumor types, especially tumors with follicular pattern, sometimes pose a diagnostic challenge. OBJECTIVE: To discuss morphologic, immunohistochemical, and molecular features of thyroid tumors...
February 2016: Archives of Pathology & Laboratory Medicine
Nicole Maison, Esther Korpershoek, Graeme Eisenhofer, Mercedes Robledo, Ronald de Krijger, Felix Beuschlein
UNLABELLED: Pheochromocytomas (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors arising from chromaffin cells of the neural crest. Mutations in the RET-proto-oncogene are associated with sporadic pheochromocytoma, familial or sporadic medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia type 2. In the past, only few cases of pigmented PCCs, PGLs, and one case of pigmented MTC have been reported in the literature. Herein, we present the case of a 77-year old woman with a history of Tako-tsubo-cardiomyopathy and laboratory, as well as radiological, high suspicion of pheochromocytoma, who underwent left-sided adrenalectomy...
2016: Endocrinology, Diabetes & Metabolism Case Reports
Cristina L Ronchi, Erika Peverelli, Sabine Herterich, Isabel Weigand, Giovanna Mantovani, Thomas Schwarzmayr, Silviu Sbiera, Bruno Allolio, Jürgen Honegger, Silke Appenzeller, Andrea G Lania, Martin Reincke, Davide Calebiro, Anna Spada, Michael Buchfelder, Joerg Flitsch, Tim M Strom, Martin Fassnacht
CONTEXT: Alterations in the cAMP signaling pathway are common in hormonally active endocrine tumors. Somatic mutations at GNAS are causative in 30-40% of GH-secreting adenomas. Recently, mutations affecting the USP8 and PRKACA gene have been reported in ACTH-secreting pituitary adenomas and cortisol-secreting adrenocortical adenomas respectively. However, the pathogenesis of many GH-secreting adenomas remains unclear. AIM: Comprehensive genetic characterization of sporadic GH-secreting adenomas and identification of new driver mutations...
March 2016: European Journal of Endocrinology
Jiaxin Niu, Grant Andres, Kim Kramer, Madappa N Kundranda, Ricardo H Alvarez, Eiko Klimant, Ankur R Parikh, Bradford Tan, Edgar D Staren, Maurie Markman
BACKGROUND: ESR1 mutation has recently emerged as one of the important mechanisms involved in endocrine resistance. The incidence and clinical implication of ESR1 mutation has not been well evaluated in heavily pretreated breast cancer patients. METHODS: We conducted a retrospective review of advanced breast cancer patients with tumors who underwent next-generation sequencing genomic profiling using Foundation One test at Cancer Treatment Centers of America(®) regional hospitals between November 2012 and November 2014...
2015: OncoTargets and Therapy
Caren Weinhouse, Ingrid L Bergin, Craig Harris, Dana C Dolinoy
Bisphenol A (BPA) is an endocrine disrupting chemical (EDC) that has been implicated as a potential carcinogen and epigenotoxicant. We have previously reported dose-dependent incidence of hepatic tumors in 10-month-old isogenic mice perinatally exposed to BPA. Here, we evaluated DNA methylation at 3 candidate genes (Esr1, Il-6st, and Stat3) in liver tissue of BPA-exposed mice euthanized at 2 time points: post-natal day 22 (PND22; n = 147) or 10-months of age (n = 78, including n = 18 with hepatic tumors). Additionally, DNA methylation profiles were analyzed at human homologs of murine candidate genes in human fetal liver samples (n = 50) with known liver tissue BPA levels...
2015: Epigenetics: Official Journal of the DNA Methylation Society
Irene Esposito, Angela Segler, Katja Steiger, Günter Klöppel
Over the past decade, there have been substantial improvements in our knowledge of pancreatic neoplasms and their precursor lesions. Extensive genetic analyses, recently using high-throughput molecular techniques and next-generation sequencing methodologies, and the development of sophisticated genetically engineered mouse models closely recapitulating human disease, have improved our understanding of the genetic basis of pancreatic neoplasms. These advances are paving the way for refined, molecular-based classifications of pancreatic neoplasms with the potential to better predict prognosis and, possibly, response to therapy...
November 2015: Pancreatology: Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]
David Chu, Costanza Paoletti, Christina Gersch, Dustin A VanDenBerg, Daniel J Zabransky, Rory L Cochran, Hong Yuen Wong, Patricia Valda Toro, Justin Cidado, Sarah Croessmann, Bracha Erlanger, Karen Cravero, Kelly Kyker-Snowman, Berry Button, Heather A Parsons, W Brian Dalton, Riaz Gillani, Arielle Medford, Kimberly Aung, Nahomi Tokudome, Arul M Chinnaiyan, Anne Schott, Dan Robinson, Karen S Jacks, Josh Lauring, Paula J Hurley, Daniel F Hayes, James M Rae, Ben Ho Park
PURPOSE: Mutations in the estrogen receptor (ER)α gene, ESR1, have been identified in breast cancer metastases after progression on endocrine therapies. Because of limitations of metastatic biopsies, the reported frequency of ESR1 mutations may be underestimated. Here, we show a high frequency of ESR1 mutations using circulating plasma tumor DNA (ptDNA) from patients with metastatic breast cancer. EXPERIMENTAL DESIGN: We retrospectively obtained plasma samples from eight patients with known ESR1 mutations and three patients with wild-type ESR1 identified by next-generation sequencing (NGS) of biopsied metastatic tissues...
February 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
David S Guttery, Karen Page, Allison Hills, Laura Woodley, Stephanie D Marchese, Basma Rghebi, Robert K Hastings, Jinli Luo, J Howard Pringle, Justin Stebbing, R Charles Coombes, Simak Ali, Jacqueline A Shaw
BACKGROUND: Activating mutations in the estrogen receptor 1 (ESR1) gene are acquired on treatment and can drive resistance to endocrine therapy. Because of the spatial and temporal limitations of needle core biopsies, our goal was to develop a highly sensitive, less invasive method of detecting activating ESR1 mutations via circulating cell-free DNA (cfDNA) and tumor cells as a "liquid biopsy." METHODS: We developed a targeted 23-amplicon next-generation sequencing (NGS) panel for detection of hot-spot mutations in ESR1, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), tumor protein p53 (TP53), fibroblast growth factor receptor 1 (FGFR1), and fibroblast growth factor receptor 2 (FGFR2) in 48 patients with estrogen receptor-α-positive metastatic breast cancer who were receiving systemic therapy...
July 2015: Clinical Chemistry
Maren K Levin, Kai Wang, Roman Yelensky, Ying Cao, Corinne Ramos, Nicholas Hoke, John Pippen, Joanne L Blum, Barry Brooks, Gary Palmer, Norma Palma, Sohail Balasubramanian, Jeffrey S Ross, Joyce O'Shaughnessy
We analyzed the genomic and phosphoproteomic profiles of breast cancer tissue obtained from six patients with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer who had highly durable (≥ 5 years) and, in some cases, ongoing clinical responses with capecitabine. Formalin-fixed, paraffin-embedded tissue samples from patients' primary (n = 4) or metastatic (n = 2) breast cancers were utilized for targeted next-generation sequencing and reversed phase protein microarray. Two patients received capecitabine monotherapy...
August 2015: Cancer Medicine
Urs D Lichtenauer, Guido Di Dalmazi, Emily P Slater, Thomas Wieland, Anne Kuebart, Anett Schmittfull, Thomas Schwarzmayr, Susanne Diener, Dominik Wiese, Wolfgang E Thasler, Martin Reincke, Thomas Meitinger, Matthias Schott, Martin Fassnacht, Detlef K Bartsch, Tim M Strom, Felix Beuschlein
CONTEXT: Insulinomas represent pancreatic neuroendocrine neoplasms that cause severe morbidity attributed to their often pronounced endocrine activity. Apart from hereditary forms such as multiple endocrine neoplasia type 1 (MEN-1), genetic causes for sporadic insulinoma development had remained obscure until recently. Applying next-generation sequencing methods, disease-causing genetic alterations have been identified in various endocrine tumors. OBJECTIVE AND DESIGN: Paired tumor and blood DNA from eight patients with sporadic insulinomas (five females and two malignant tumors) were analyzed by whole-exome sequencing...
May 2015: Journal of Clinical Endocrinology and Metabolism
Thomas G Papathomas, Lindsey Oudijk, Alexandre Persu, Anthony J Gill, Francien van Nederveen, Arthur S Tischler, Frédérique Tissier, Marco Volante, Xavier Matias-Guiu, Marcel Smid, Judith Favier, Elena Rapizzi, Rosella Libe, Maria Currás-Freixes, Selda Aydin, Thanh Huynh, Urs Lichtenauer, Anouk van Berkel, Letizia Canu, Rita Domingues, Roderick J Clifton-Bligh, Magdalena Bialas, Miikka Vikkula, Gustavo Baretton, Mauro Papotti, Gabriella Nesi, Cécile Badoual, Karel Pacak, Graeme Eisenhofer, Henri J Timmers, Felix Beuschlein, Jérôme Bertherat, Massimo Mannelli, Mercedes Robledo, Anne-Paule Gimenez-Roqueplo, Winand Nm Dinjens, Esther Korpershoek, Ronald R de Krijger
Despite the established role of SDHB/SDHA immunohistochemistry as a valuable tool to identify patients at risk for familial succinate dehydrogenase-related pheochromocytoma/paraganglioma syndromes, the reproducibility of the assessment methods has not as yet been determined. The aim of this study was to investigate interobserver variability among seven expert endocrine pathologists using a web-based virtual microscopy approach in a large multicenter pheochromocytoma/paraganglioma cohort (n=351): (1) 73 SDH mutated, (2) 105 non-SDH mutated, (3) 128 samples without identified SDH-x mutations, and (4) 45 with incomplete SDH molecular genetic analysis...
June 2015: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Bence Sipos, Jan Sperveslage, Martin Anlauf, Maike Hoffmeister, Tobias Henopp, Stephan Buch, Jochen Hampe, Achim Weber, Pascal Hammel, Anne Couvelard, Walter Höbling, Wolfgang Lieb, Bernhard O Boehm, Günter Klöppel
CONTEXT: Glucagon cell adenomatosis (GCA) was recently recognized as a multifocal hyperplastic and neoplastic disease of the glucagon cells unrelated to multiple endocrine neoplasia type 1 and von-Hippel-Lindau disease. OBJECTIVE: The study focused on the molecular analysis of the glucagon receptor (GCGR) gene in GCA and a description of the clinicopathological features of GCA with and without GCGR mutations. DESIGN: Pancreatic tissues from patients showing multiple glucagon cell tumors were morphologically characterized and macro- or microdissected...
May 2015: Journal of Clinical Endocrinology and Metabolism
Wenchu Lin, Hideo Watanabe, Shouyong Peng, Joshua M Francis, Nathan Kaplan, Chandra Sekhar Pedamallu, Aruna Ramachandran, Agoston Agoston, Adam J Bass, Matthew Meyerson
UNLABELLED: The tumor suppressor gene MEN1 is frequently mutated in sporadic pancreatic neuroendocrine tumors (PanNET) and is responsible for the familial multiple endocrine neoplasia type 1 (MEN-1) cancer syndrome. Menin, the protein product of MEN1, associates with the histone methyltransferases (HMT) MLL1 (KMT2A) and MLL4 (KMT2B) to form menin-HMT complexes in both human and mouse model systems. To elucidate the role of methylation of histone H3 at lysine 4 (H3K4) mediated by menin-HMT complexes during PanNET formation, genome-wide histone H3 lysine 4 trimethylation (H3K4me3) signals were mapped in pancreatic islets using unbiased chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq)...
April 2015: Molecular Cancer Research: MCR
Nicole Pinto, Morgan Black, Krupal Patel, John Yoo, Joe S Mymryk, John W Barrett, Anthony C Nichols
Thyroid cancer is an endocrine malignancy with an incidence rate that has been increasing steadily over the past 30 years. While well-differentiated subtypes have a favorable prognosis when treated with surgical resection and radioiodine, undifferentiated subtypes, such as anaplastic thyroid cancer (ATC), are far more aggressive and have a poor prognosis. Conventional therapies (surgical resection, radiation, chemotherapy, and radioiodine) have been utilized for treatment of ATC, yet these treatments have not significantly improved the overall mortality rate...
2014: Journal of Oncology
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