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Journal of Pathology

Katja Närhi, Ashwini S Nagaraj, Elina Parri, Riku Turkki, Petra W van Duijn, Annabrita Hemmes, Jenni Lahtela, Virva Uotinen, Mikko I Mäyränpää, Kaisa Salmenkivi, Jari Räsänen, Nina Linder, Jan Trapman, Antti Rannikko, Olli Kallioniemi, Taija Af Hällström, Johan Lundin, Wolfgang Sommergruber, Simon Anders, Emmy W Verschuren
A key question in precision medicine is how functional heterogeneity in solid tumors informs therapeutic sensitivity. We demonstrate that spatial characteristics of oncogenic signaling and therapy response can be modeled in precision-cut slices from Kras-driven non-small cell lung cancer (NSCLC) of varying histopathologies. Unexpectedly, profiling of in situ tumors demonstrates that signaling stratifies mostly according to histopathology, showing enhanced AKT and SRC activity in adenosquamous carcinoma (ASC), and MAPK activity in adenocarcinoma (AC)...
February 14, 2018: Journal of Pathology
Ian J Groves, Nicholas Coleman
Human papillomavirus (HPV) infection is associated with ~5% of all human cancers, including a range of squamous cell carcinomas (SCCs). Persistent infection by high-risk HPVs (HRHPVs) is associated with the integration of virus genomes (which are usually stably maintained as extrachromosomal episomes) into host chromosomes. Although HRHPV integration rates differ across human sites of infection, this process appears to be an integral event in HPV-associated neoplastic progression, leading to deregulation of virus oncogene expression, host gene expression modulation and further genomic instability...
February 14, 2018: Journal of Pathology
David G Huntsman, Marc Ladanyi
As the cancer genomics of most major cancer types have been comprehensively catalogued over the past decade through a variety of national and international efforts, the delineation of cancer subtypes has been refined, and our understanding of critical cancer drivers and of the potentially targetable vulnerabilities they create has grown tremendously. The 2018 Annual Review Issue of The Journal of Pathology provides in-depth assessments of how these pan-genomic approaches have enabled advances in cancer classification, targeted therapy selection, and assessment of cancer progression, all of which are now genomically informed, using several cancer types as examples...
February 13, 2018: Journal of Pathology
Andre F Batista, Leticia Forny-Germano, Julia R Clarke, Natalia M Lyra E Silva, Jordano Brito-Moreira, Susan E Boehnke, Andrew Winterborn, Brian C Coe, Ann Lablans, Juliana F Vital, Suelen A Marques, Ana M B Martinez, Matthias Gralle, Christian Holscher, William L Klein, Jean-Christophe Houzel, Sergio T Ferreira, Douglas P Munoz, Fernanda G De Felice
Alzheimer's disease (AD) is a devastating neurological disorder that still lacks an effective treatment, and this has stimulated an intense pursuit of disease-modifying therapeutics. Given the increasingly recognized link between AD and defective brain insulin signaling, we investigated the actions of liraglutide, a glucagon-like peptide-1 (GLP-1) analog marketed for treatment of type 2 diabetes, in experimental models of AD. Insulin receptor pathology is an important feature of AD brains that impairs the neuroprotective actions of central insulin signaling...
February 12, 2018: Journal of Pathology
Jian Cui, Wan Huang, Bo Wu, Jin Jin, Lin Jing, Wen-Pu Shi, Zhen-Yu Liu, Lin Yuan, Dan Luo, Ling Li, Zhi-Nan Chen, Jian-Li Jiang
While the importance of protein N-glycosylation in cancer cell migration is well appreciated, the precise mechanisms by which N-acetylglucosaminyltransferase V (GnT-V) regulates cancer processes remain largely unknown. In the current study, we report that GnT-V mediated N-glycosylation of CD147/Basigin, a tumor-associated glycoprotein that carries β1,6 N-acetylglucosamine (β1,6 GlcNAc) glycans, is upregulated during TGF-β1-induced epithelial-to-mesenchymal transition (EMT), which correlates with tumor metastasis in patients with hepatocellular carcinoma (HCC)...
February 12, 2018: Journal of Pathology
Jue Er Amanda Lee, Na Li, Simone M Rowley, Dane Cheasley, Magnus Zethoven, Simone McInerny, Kylie L Gorringe, Paul A James, Ian G Campbell
PALB2 is established as the most clinically important moderate to high penetrance breast cancer predisposition gene after BRCA1 and BRCA2. Mutations in classical familial cancer predisposition genes are presumed to be recessive at the cellular level and therefore a second inactivating somatic mutation is required in the tumour tissue. However, from the limited data that exists, PALB2 may be an example of a cancer predisposition gene that does not conform to Knudsen's "two hit" paradigm. We conducted genome-wide copy number analysis and targeted sequencing of PALB2 and other breast cancer driver genes in 15 invasive breast cancers from individuals carrying pathogenic germline mutations in PALB2...
February 12, 2018: Journal of Pathology
Sarah Watson, Virginie Perrin, Delphine Guillemot, Stephanie Reynaud, Jean-Michel Coindre, Marie Karanian, Jean-Marc Guinebretière, Paul Freneaux, François Le Loarer, Megane Bouvet, Louise Galmiche-Rolland, Frédérique Larousserie, Elisabeth Longchampt, Dominique Ranchere-Vince, Gaelle Pierron, Olivier Delattre, Franck Tirode
Sarcoma represents a highly heterogeneous group of tumours. We report here the first unbiased and systematic search for gene fusions combined with unsupervised expression analysis of a series of 184 small round cell sarcomas. Fusion genes were detected in 59% percent of samples, with half of them being observed recurrently. We identified biologically homogeneous groups of tumours such as the CIC-fused (to DUX4, FOXO4 or NUTM1) and BCOR-rearranged (BCOR-CCNB3, BCOR-MAML3, ZC3H7B-BCOR and BCOR internal duplication) tumour groups...
February 12, 2018: Journal of Pathology
Matthew Alderdice, Susan D Richman, Simon Gollins, Peter Stewart, Chris Hurt, Richard Adams, Amy McCorry, Aideen Roddy, Dale Vimalachandran, Claudio Isella, Enzo Medico, Tim Maughan, Darragh G McArt, Mark Lawler, Philip D Dunne
Colorectal cancer (CRC) biopsies underpin accurate diagnosis, but are also relevant for patient stratification in molecularly-guided clinical trials. The consensus molecular subtypes (CMS) and colorectal cancer intrinsic subtypes (CRIS) transcriptional signatures have potential clinical utility for improving prognostic/predictive patient assignment. However, their ability to provide robust classification, particularly in pre-treatment biopsies from multiple regions or at different time points remains untested...
February 7, 2018: Journal of Pathology
Raúl Catena, Luis M Montuenga, Bernd Bodenmiller
Imaging mass cytometry is a novel imaging modality that enables simultaneous antibody-based detection of more than 40 epitopes and molecules in tissue sections at subcellular resolution using isotopically pure metal tags. Essential for any imaging approach where antigen detection is performed is the so-called counterstaining that reveals the overall structure of the tissue. Counterstaining is necessary since antigens of interest are often present only in a small subset of cells while the rest of tissue structures are not visible...
February 5, 2018: Journal of Pathology
Caitlin M Stewart, Prachi D Kothari, Florent Mouliere, Richard Mair, Saira Somnay, Ryma Benayed, Ahmet Zehir, Britta Weigelt, Sarah-Jane Dawson, Maria E Arcila, Michael F Berger, Dana Wy Tsui
Over the past decade, advances in molecular biology and genomics techniques have revolutionized the diagnosis and treatment of cancer. The technological advances in tissue profiling have also been applied to the study of cell-free nucleic acids, an area of increasing interest for molecular pathology. Cell-free nucleic acids are released from tumour cells into the surrounding body fluids and can be assayed non-invasively. The repertoire of genomic alterations in circulating tumour DNA (ctDNA) is reflective of primary tumours as well as distant metastatic sites and can be sampled multiple times, thereby overcoming the limitations of the analysis of single biopsies...
January 30, 2018: Journal of Pathology
Sarah Craig, Charles H Earnshaw, Amaya Virós
Melanoma is a clinically heterogeneous disease and current treatment strategies of the primary tumour are based on pathological criteria alone. In the recent past, several DNA and RNA sequencing studies of primary and advanced melanoma samples have identified unique relationships between somatic mutations, genomic aberrations and the genetic fingerprint of ultraviolet light radiation (UVR). The recurrent patterns of genomic alterations reveal different disease pathways, drug targets and mechanisms limiting drug response...
January 30, 2018: Journal of Pathology
Yoshinori Yasuda, Shintaro Iwama, Atsushi Kiyota, Hisakazu Izumida, Kohtaro Nakashima, Naoko Iwata, Yoshihiro Ito, Yoshiaki Morishita, Motomitsu Goto, Hidetaka Suga, Ryoichi Banno, Atsushi Enomoto, Masahide Takahashi, Hiroshi Arima, Yoshihisa Sugimura
Autoimmune hypophysitis (AH) is thought to be an autoimmune disease characterized by lymphocytic infiltration of the pituitary gland. Among AH pathologies, lymphocytic infundibulo-neurohypophysitis (LINH) represents infiltration of the neurohypophysis and/or the hypothalamic infundibulum, causing central diabetes insipidus due to insufficiency of arginine vasopressin (AVP) secretion. The pathophysiological and pathogenetic mechanisms underlying LINH are largely unknown. Clinically, differentiating LINH from other pituitary diseases accompanied by mass lesions, including tumors, has been often difficult because of similar clinical manifestations...
January 29, 2018: Journal of Pathology
Yuri Tolkach, Glen Kristiansen
High-grade prostatic intraepithelial neoplasia (HGPIN) is a documented putative precursor lesion for invasive prostate adenocarcinoma. However, the precise mechanisms of the carcinoma's development from HGPIN are unclear. Many studies have attempted a comparative molecular genetic characterisation of HGPIN and its corresponding carcinoma to study this transformation. However, to date, some HGPIN mimickers, such as intraductal carcinoma, which can engage in retrograde colonisation of the prostatic acini in an HGPIN-like manner, have been described...
January 29, 2018: Journal of Pathology
Brian Goodman, Humphrey Gardner
Humans coexist with a vast bacterial, fungal, and viral microbiome with which we have coevolved for billions of years. The oncogenic mechanisms of particular bacteria with longstanding epidemiological relationships are increasingly understood at the molecular level. At the same time the arrival of next generation sequencing technology has permitted a thorough exploration of microbiomes such as that of human gut, enabling observation of taxonomic and metabolomic relationships between the microbiome and cancer...
January 27, 2018: Journal of Pathology
Slaven Crnkovic, Leigh M Marsh, Elie El Agha, Robert Voswinckel, Bahil Ghanim, Walter Klepetko, Elvira Stacher-Priehse, Horst Olschewski, Wilhelm Bloch, Saverio Bellusci, Andrea Olschewski, Grazyna Kwapiszewska
Pulmonary vascular remodeling is the main pathological hallmark of pulmonary hypertension disease. We undertook a comprehensive and multilevel approach to investigate the origin of smooth muscle actin-expressing cells in remodeled vessels. Transgenic mice that allow for specific, inducible and permanent labeling of endothelial (Cdh5-tdTomato), smooth muscle (Acta2-, Myh11-tdTomato), pericyte (Cspg4-tdTomato) and fibroblast (Pdgfra-tdTomato) lineages were used to delineate the cellular origins of pulmonary vascular remodeling...
January 23, 2018: Journal of Pathology
Fong Chun Chan, Emilia Lim, Robert Kridel, Christian Steidl
High-throughput sequencing has significantly contributed to revealing the molecular underpinnings of B-cell lymphomagenesis and disease progression. It is now a widely accepted concept that the diversity of clinical responses to front-line therapy and the development of relapsed/refractory disease are in part explained by "interpatient" genetic heterogeneity measurable by individual sets of somatic gene alterations in tumor genomes. Moreover, extensive "intratumor" heterogeneity on the genotypic and phenotypic levels is the product of ongoing tumor evolution and adaptation to various selective pressures during cancer initiation, progression and therapeutic intervention...
January 23, 2018: Journal of Pathology
Matthew J McBride, Cigall Kadoch
Soft-tissue sarcomas are increasingly characterized and subclassified by genetic abnormalities that represent underlying drivers of their pathology. Hallmark tumor suppressor gene mutations and pathognomonic gene fusions collectively account for approximately one-third of all sarcomas. These genetic abnormalities most often result in global transcriptional misregulation via disruption of protein regulatory complexes which govern chromatin architecture. Specifically, alterations to mammalian SWI/SNF (mSWI/SNF or BAF) ATP-dependent chromatin remodeling complexes and Polycomb repressive complexes cause disease-specific changes in chromatin architecture and gene expression across a number of sarcoma subtypes...
January 23, 2018: Journal of Pathology
Kenji Mark Fujihara, Nicholas James Clemons
The pathogenesis of oro-esophaeal squamous cell carcinoma is causally linked to the consumption of alcohol. Beyond the carcinogenic effects of ethanol and its metabolites via DNA damage, the precise mechanisms by which alcohol drives tumorigenesis remain to be fully elucidated. A novel contributor now revealed is aberrant differentiation and proliferation mediated by suppression of PAX9, a key regulator of normal squamous maturation in oro-esophageal tissues.
January 18, 2018: Journal of Pathology
Amy E McCart Reed, Jamie R Kutasovic, Katia Nones, Jodi M Saunus, Leonard Da Silva, Felicity Newell, Stephen Kazakoff, Lewis Melville, Janani Jayanthan, Ana Cristina Vargas, Lynne E Reid, Jonathan Beesley, Xiao Qing Chen, Anne Marie Patch, D David Clouston, Alan Porter, Elizabeth Evans, John V Pearson, Georgia Chenevix-Trench, Margaret C Cummings, Nic Waddell, Sunil R Lakhani, Peter T Simpson
Mixed ductal-lobular carcinomas (MDL) display both ductal and lobular morphology, and are an archetypal example of intra-tumour morphological heterogeneity. The mechanisms underlying coexistence of these different morphologic entities are poorly understood, although theories include that these components either represent 'collision' of independent tumours or evolve from a common ancestor. We performed comprehensive clinico-pathological analysis of a cohort of 82 MDLs and found: i) MDLs more frequently co-exist with ductal carcinoma in situ (DCIS) than lobular carcinoma in situ (LCIS); ii) the E-cadherin-catenin complex was normal in the ductal component in 77...
January 18, 2018: Journal of Pathology
Jennifer X Ji, Yi Kan Wang, Dawn R Cochrane, David G Huntsman
Clear cell ovarian carcinoma (CCOC) and clear cell renal cell carcinoma (ccRCC) both feature clear cytoplasm due to the accumulation of cytoplasmic glycogen. Genomic studies have demonstrated several mutational similarities between these two diseases including frequent alterations in the chromatin remodeling SWI/SNF and cellular proliferation PI3K/mTOR pathways, as well as a shared hypoxia-like mRNA expression signature. Although many targeted treatment options have been approved for advance stage ccRCC, CCOC patients are still treated with conventional platinum and taxane chemotherapy, to which they are resistant...
January 17, 2018: Journal of Pathology
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