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Eleonora Sementino, Craig W Menges, Yuwaraj Kadariya, Suraj Peri, Jinfei Xu, Zemin Liu, Richard G Wilkes, Kathy Q Cai, Frank J Rauscher, Andres J Klein-Szanto, Joseph R Testa
Malignant mesothelioma (MM) is a therapy-resistant cancer arising primarily from the lining of the pleural and peritoneal cavities. The most frequently altered genes in human MM are cyclin-dependent kinase inhibitor 2A (CDKN2A), which encodes components of the p53 (p14ARF) and RB (p16INK4A) pathways, BRCA1-associated protein 1 (BAP1), and neurofibromatosis 2 (NF2). Furthermore, the p53 gene (TP53) itself is mutated in ~15% of MMs. In many MMs, the PI3K-PTEN-AKT-mTOR signaling node is hyperactivated, which contributes to tumor cell survival and therapeutic resistance...
June 15, 2018: Journal of Cellular Physiology
Klaus Griewank, Christian Koelsche, Johannes A P van de Nes, Daniel Schrimpf, Marco Gessi, Inga Möller, Antje Sucker, Richard A Scolyer, Michael E Buckland, Rajmohan Murali, Torsten Pietsch, Andreas von Deimling, Dirk Schadendorf
PURPOSE: In the central nervous system, distinguishing primary leptomeningeal melanocytic tumors from melanoma metastases and predicting their biological behavior solely using histopathologic criteria can be challenging. We aimed to assess the diagnostic and prognostic value of integrated molecular analysis. EXPERIMENTAL DESIGN: Targeted next-generation-sequencing, array-based genome-wide methylation analysis and BAP1 immunohistochemistry was performed on the largest cohort of central nervous system melanocytic tumors analyzed to date, incl...
June 11, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Tilmann Bochtler, Volker Endris, Anna Reiling, Jonas Leichsenring, Michal R Schweiger, Sebastian Klein, Fabian Stögbauer, Benjamin Goeppert, Peter Schirmacher, Alwin Krämer, Albrecht Stenzinger
This case report presents a male patient with epithelioid mesothelioma that was initially misdiagnosed as cancer of unknown primary (CUP) and correctly identified using molecular panel sequencing. The patient had a prior history of colon and breast cancer. To assess the enlarged mediastinal lymph nodes, retrosternal lymphadenectomy was performed in 2016. The lymph nodes were histologically deemed unrelated to the known breast cancer by the reference pathologist, thus leading to the diagnosis of a CUP syndrome...
June 2018: Journal of the National Comprehensive Cancer Network: JNCCN
Tao Wang, Rong Lu, Payal Kapur, Bijay S Jaiswal, Raquibul Hannan, Ze Zhang, Ivan Pedrosa, Jason J Luke, He Zhang, Leonard D Goldstein, Qurratulain Yousuf, Yi-Feng Gu, Tiffani McKenzie, Allison Joyce, Min S Kim, Xinlei Wang, Danni Luo, Oreoluwa Onabolu, Christina Stevens, Zhiqun Xie, Mingyi Chen, Alexander Filatenkov, Jose Torrealba, Xin Luo, Wenbin Guo, Jingxuan He, Eric Stawiski, Zora Modrusan, Steffen Durinck, Somasekar Seshagiri, James Brugarolas
By leveraging tumorgraft (PDX) RNA-Seq data, we developed an empirical approach, DisHet, to dissect the tumor microenvironment (eTME). We found that 65% of previously defined immune signature genes are not abundantly expressed in Renal Cell Carcinoma (RCC), and identified 610 novel immune/stromal transcripts. Using eTME, genomics, pathology and medical record data involving >1,000 patients, we established an inflamed pan-RCC subtype (IS) enriched for Tregs, NK cells, Th1 cells, neutrophils, macrophages, B cells, and CD8+ T cells...
June 8, 2018: Cancer Discovery
Mohamed E Salem, Alberto Puccini, Joanne Xiu, Derek Raghavan, Heinz-Josef Lenz, W Michael Korn, Anthony F Shields, Philip A Philip, John L Marshall, Richard M Goldberg
BACKGROUND: Gastroesophageal cancers are often grouped together even though cancers that originate in the esophagus often exhibit different histological features, geographical distribution, risk factors, and clinical characteristics than those originating in the stomach. Herein, we aimed to compare the molecular characteristics of three different gastroesophageal cancer types: esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), and gastric adenocarcinoma (GAC)...
June 4, 2018: Oncologist
Maeve A Lowery, Ryan N Ptashkin, Emmet J Jordan, Michael F Berger, Ahmet Zehir, Marinela Capanu, Nancy E Kemeny, Eileen M O'Reilly, Imane El Dika, William R Jarnagin, James J Harding, Michael I D'Angelica, Andrea Cercek, Jaclyn F Hechtman, David B Solit, Nikolaus Schultz, David M Hyman, David S Klimstra, Leonard Saltz, Ghassan K Abou-Alfa
PURPOSE: Various genetic driver aberrations have been identified among distinct anatomic and clinical subtypes of intrahepatic and extrahepatic cholangiocarcinoma, and these molecular alterations may be prognostic biomarkers and/or predictive of drug response. EXPERIMENTAL DESIGN: Tumor samples from patients with cholangiocarcinoma who consented prospectively were analyzed using the MSK-IMPACT platform, a targeted next generation sequencing assay that analyzes all exons and selected introns of 410 cancer-associated genes...
May 30, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Ben Davidson, Martin Tötsch, Jeremias Wohlschlaeger, Thomas Hager, Maurizio Pinamonti
The aim of this study was to analyze the diagnostic role of BAP1 in effusion cytology. Effusions (n=258), consisting of 53 malignant mesotheliomas and 205 other cancers, the majority carcinomas (62 breast, 60 ovarian, 31 lung, 51 carcinomas of other origin, 1 melanoma), were analyzed for BAP1 expression using immunohistochemistry. BAP1 was lost in 46 (87%) mesotheliomas, compared to 4/205 (2%) loss in other cancers (P<.001), resulting in sensitivity and specificity of 87% and 98%, respectively. There was no significant difference between peritoneal (n=14) and pleural (n=39) mesotheliomas...
May 23, 2018: Human Pathology
(no author information available yet)
Mutations in the MLL3 PHD domain promote oncogenesis by disrupting its interaction with BAP1.
May 25, 2018: Cancer Discovery
Ana M Hurtado, Gines Luengo-Gil, Tzu H Chen-Liang, Fabio Amaral, Kiran Batta, Laura Palomo, Eva Lumbreras, Bartlomiej Przychodzen, Eva Caparros, Marıa L Amigo, Maria Dıez-Campelo, Lurdes Zamora, Eduardo J Salido Fierrez, Jaroslaw P Maciejewski, Francisco J Ortuño, Vicente Vicente, Marıa Del Canizo, Francesc Sole, Francisca Ferrer-Marin, Daniel H Wiseman, Andres Jerez
Despite the absence of mutations in the DNA repair machinery in myeloid malignancies, the advent of high-throughput sequencing and discovery of splicing and epigenetics defects in chronic myelomonocytic leukaemia (CMML) prompted us to revisit a pathogenic role for genes involved in DNA damage response. We screened for misregulated DNA repair genes by enhanced RNA-sequencing on bone marrow from a discovery cohort of 27 CMML patients and 9 controls. We validated 4 differentially expressed candidates in CMML CD34+ bone marrow selected cells and in an independent cohort of 74 CMML patients, mutationally contextualized by targeted sequencing, and assessed their transcriptional behavior in 70 myelodysplastic syndrome, 66 acute myeloid leukaemia and 25 chronic myeloid leukaemia cases...
May 24, 2018: British Journal of Haematology
Yingzhou Li, Xiao Zhang, Yang Gao, Jinming Shi, Liping Tang, Guangchao Sui
Accumulating evidence suggests a key role of BAP1 in oncogenesis, but mechanisms regulating BAP1 gene expression remain unexplored. In this report, we revealed that the BAP1 promoter contains multiple G-tracts in its negative strand with high potential of forming G-quadruplex (G4) structures. In circular dichroism studies, synthesized oligonucleotides within these G-rich regions upstream the BAP1 transcription start site showed molar ellipticity at specific wavelengths characteristic of G4 structures. Analyses of these oligonucleotides by native polyacrylamide gel electrophoresis revealed formation of multiple types of G4 structures...
May 19, 2018: Experimental Cell Research
Lu Wang, Zibo Zhao, Patrick A Ozark, Damiano Fantini, Stacy A Marshall, Emily J Rendleman, Kira A Cozzolino, Nundia Louis, Xingyao He, Marc A Morgan, Yoh-Hei Takahashi, Clayton K Collings, Edwin R Smith, Panagiotis Ntziachristos, Jeffrey N Savas, Lihua Zou, Rintaro Hashizume, Joshua J Meeks, Ali Shilatifard
The lysine methyltransferase KMT2C (also known as MLL3), a subunit of the COMPASS complex, implements monomethylation of Lys4 on histone H3 (H3K4) at gene enhancers. KMT2C (hereafter referred to as MLL3) frequently incurs point mutations across a range of human tumor types, but precisely how these lesions alter MLL3 function and contribute to oncogenesis is unclear. Here we report a cancer mutational hotspot in MLL3 within the region encoding its plant homeodomain (PHD) repeats and demonstrate that this domain mediates association of MLL3 with the histone H2A deubiquitinase and tumor suppressor BAP1...
May 21, 2018: Nature Medicine
Asmaa Mosbeh, Khalil Halfawy, Wael S Abdel-Mageed, Dina Sweed, Mohamed H Abdel Rahman
Deletion in the 3p21 region, the chromosomal location of BAP1, has been reported in a subset of hepatocellular carcinoma (HCC), biliary and pancreatic cancers. This suggests that BAP1 could play a role in the pathogenesis of these tumors. We assessed the frequency of BAP1 loss by immunohistochemistry in 103 hepatic, biliary and pancreatic cancers. We also assessed chromosomal alterations in the BAP1 region in the same tumors by genotyping. We identified high frequency 4/8 (50%) of BAP1 loss in intrahepatic cholangicarcinoma (ICC)...
August 2018: Cancer Genetics
Nikola Hajkova, Jan Hojny, Kristyna Nemejcova, Pavel Dundr, Jan Ulrych, Katerina Jirsova, Johana Glezgova, Ivana Ticha
We performed comprehensive molecular analysis of five cases of metastasizing uveal malignant melanoma (UM) (fresh-frozen samples) with an NGS panel of 73 genes. A likely pathogenic germline TP53 mutation c.760A > G (p.I254V) was found in two tumor samples and matched nontumor tissue. In three cases, pathogenic BAP1 mutation was detected together with germline missense variants of uncertain significance in ATM. All cases carried recurrent activating GNAQ or GNA11 mutation. Moreover, we analyzed samples from another 16 patients with primary UM by direct Sanger sequencing focusing only on TP53 coding region...
May 16, 2018: Scientific Reports
Hee Eun Lee, Julian R Molina, William R Sukov, Anja C Roden, Eunhee S Yi
Literature on BRCA1-associated protein 1 (BAP1) expression status in well-differentiated papillary mesothelioma (WDPM) is limited. In the present study, we examined the prevalence of BAP1 loss in WDPM by immunohistochemistry with clinical correlation, along with CDKN2A deletion status by fluorescence in situ hybridization (FISH). Eight patients diagnosed as WDPM were identified from the surgical pathology file. Adenomatoid tumors (n=8) and malignant mesothelioma (MM) (n=39) were included for comparison. BAP1 immunohistochemistry was performed on representative block(s) from each case...
May 12, 2018: Human Pathology
James B Massengill, Klarke M Sample, Robert Pilarski, Joseph McElroy, Frederick H Davidorf, Colleen M Cebulla, Mohamed H Abdel-Rahman
The BAP1-tumor predisposition syndrome (BAP1-TPDS) has been recently identified to predispose patients to a variety of cancers and preneoplastic lesions. About 130 unrelated probands have been identified worldwide; however, the impact of the syndrome is suspected to be much larger given the diversity of the cancer phenotype. To evaluate the frequency of germline BAP1 mutations in the general and cancer populations, we analyzed the Exome Aggregation Consortium (ExAC), a database that contains 53105 exomes of unrelated individuals unaffected by cancer (general population) and exomes of 7601 unrelated individuals affected by cancer provided by the Cancer Genome Atlas (TCGA, cancer subjects)...
May 15, 2018: Genes, Chromosomes & Cancer
Jianming Tang, Yanxin Li, Youzhou Sang, Bo Yu, Deguan Lv, Weiwei Zhang, Haizhong Feng
Recent molecularly targeted approach gains advance in breast cancer treatment. However, the estimated 5-year survival rate has not met the desired expectation for improvement, especially for patients with triple-negative breast cancer (TNBC). Here we report that the lncRNA PVT1 promotes KLF5/beta-catenin signaling to drive TNBC tumorigenesis. PVT1 is upregulated in clinical TNBC tumors. Using genetic approaches targeting PVT1 in TNBC cells, we found that PVT1 depletion inhibited cell proliferation, colony formation, and orthotopic xenograft tumor growth...
May 15, 2018: Oncogene
Amy C Schefler, Ryan S Kim
Retinoblastoma and uveal melanoma are the most common intraocular malignancies observed in pediatric and adult populations, respectively. For retinoblastoma, intra-arterial chemotherapy has dramatically improved treatment outcomes and eye salvage rates compared with traditional salvage rates of systemic chemotherapy and external beam radiation therapy. Intravitreal injections of chemotherapy have also demonstrated excellent efficacy for vitreous seeds. Uveal melanoma, on the other hand, is treated predominantly with iodine-125 plaque brachytherapy or with proton beam therapy...
2018: F1000Research
Andrew S Fischer, Whitney A High
BACKGROUND: BAP1 negative melanocytic tumors were unrecognized in the medical literature until 2011. While the clinical significance of these tumors is poorly understood, there is concern such lesions represent processes in transition, and malignant degeneration is a concern. We investigated use of a 23-gene expression profiling (23-GEP) test for distinction from melanoma with the aim of better characterizing the biologic potential of such tumors. METHODS: Twenty BAP1 negative melanocytic tumors, subjected to 23-GEP (Myriad Genetic Laboratories, Inc...
May 12, 2018: Journal of Cutaneous Pathology
Ying Guo, Hui Yang, Shi Chen, Peng Zhang, Rong Li, Stephen D Nimer, J William Harbour, Mingjiang Xu, Feng-Chun Yang
No abstract text is available yet for this article.
April 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
John J Park, Russell J Diefenbach, Anthony M Joshua, Richard F Kefford, Matteo S Carlino, Helen Rizos
Uveal melanoma is the most common primary cancer of the eye, and despite rapidly emerging insights into the molecular profile of this disease, prognosis of patients with metastatic uveal melanoma remains poor with mortality rates unchanged in over 35 years. Early genetic events activate G protein-coupled receptor signaling in nearly all uveal tumors via mutually exclusive mutations in the GNAQ, GNA11, CYSLTR2, or PLCB4 genes. A multitude of signaling cascades downstream of G protein activation, including protein kinase C and mitogen-activated protein kinase activity, are actionable, and many ongoing clinical trials are targeting these pathways...
May 8, 2018: Pigment Cell & Melanoma Research
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