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https://www.readbyqxmd.com/read/29158190/prevalence-of-microsatellite-instability-in-intraductal-papillary-mucinous-neoplasms-of-the-pancreas
#1
R M Lupinacci, A Goloudina, O Buhard, J B Bachet, R Maréchal, P Demetter, J Cros, A Bardier-Dupas, A Collura, P Cervera, A Scriva, S Dumont, P Hammel, A Sauvanet, C Louvet, J-R Delpéro, F Paye, J-C Vaillant, T André, J Closset, J-F Emile, J-L Van Laethem, V Jonchère, I Abd Alsamad, M Antoine, A Rodenas, J F Fléjou, N Dusetti, J Iovanna, A Duval, M Svrcek
Microsatellite instability (MSI) due to mismatch repair deficiency (dMMR) is detected in a small proportion of pancreatic ductal adenocarcinomas (PDACs). dMMR and MSI have been associated with responses of metastatic tumors, including PDACs, to immune checkpoint inhibitor therapy. We performed immunohistochemical analyses of a 445 PDAC specimens, collected from consecutive patients at multiple centers, to identify those with dMMR, based on loss of mismatch repair proteins MLH1, MSH2, MSH6, and/or PMS2. We detected dMMR in 1...
November 17, 2017: Gastroenterology
https://www.readbyqxmd.com/read/29147930/snp-association-study-in-pms2-associated-lynch-syndrome
#2
Sanne W Ten Broeke, Fadwa A Elsayed, Lisa Pagan, Maran J W Olderode-Berends, Encarna Gomez Garcia, Hans J P Gille, Liselot P van Hest, Tom G W Letteboer, Lizet E van der Kolk, Arjen R Mensenkamp, Theo A van Os, Liesbeth Spruijt, Bert J W Redeker, Manon Suerink, Yvonne J Vos, Anja Wagner, Juul T Wijnen, E W Steyerberg, Carli M J Tops, Tom van Wezel, Maartje Nielsen
Lynch syndrome (LS) patients are at high risk of developing colorectal cancer (CRC). Phenotypic variability might in part be explained by common susceptibility loci identified in Genome Wide Association Studies (GWAS). Previous studies focused mostly on MLH1, MSH2 and MSH6 carriers, with conflicting results. We aimed to determine the role of GWAS SNPs in PMS2 mutation carriers. A cohort study was performed in 507 PMS2 carriers (124 CRC cases), genotyped for 24 GWAS SNPs, including SNPs at 11q23.1 and 8q23.3...
November 17, 2017: Familial Cancer
https://www.readbyqxmd.com/read/29146522/germline-genetic-features-of-young-individuals-with-colorectal-cancer
#3
Elena M Stoffel, Erika Koeppe, Jessica Everett, Peter Ulintz, Mark Kiel, Jenae Osborne, Linford Williams, Kristen Hanson, Stephen B Gruber, Laura S Rozek
BACKGROUND & AIMS: The incidence of colorectal cancer (CRC) in individuals younger than 50 years old is increasing. We sought to ascertain the proportion of young CRC cases associated with genetic predisposition. METHODS: We performed a retrospective study of individuals diagnosed with CRC at an age younger than 50 years, evaluated by the clinical genetics service at a single tertiary care cancer center from 1998 through 2015. We collected data on patient histories, tumor phenotypes, and results of germline DNA sequencing...
November 12, 2017: Gastroenterology
https://www.readbyqxmd.com/read/29137657/p53-aberrations-in-low-grade-endometrioid-carcinoma-of-the-endometrium-with-nodal-metastases-possible-insights-on-pathogenesis-discerned-from-immunohistochemistry
#4
Oluwole Fadare, Vinita Parkash
BACKGROUND: TP53 mutations are rarely identified in low grade endometrioid carcinoma of the endometrium, and their pathogenic significance in such tumors is evidenced by the fact that TP53 aberrations have been associated with reduced recurrence-free survival in this subset of tumors. However, TP53 aberrations may not always represent a driving molecular event in a given endometrial cancer with a mutation. In this case study, the immunophenotype of a distinctive low grade endometrioid adenocarcinoma with an unusual pattern of lymph node metastases is used to explore the possible roles for underlying TP53-related molecular events in its pathogenesis...
November 14, 2017: Diagnostic Pathology
https://www.readbyqxmd.com/read/29133960/divergent-roles-for-clusterin-in-lung-injury-and-repair
#5
David M Habiel, Ana Camelo, Milena Espindola, Timothy Burwell, Richard Hanna, Elena Miranda, Alan Carruthers, Matthew Bell, Ana Lucia Coelho, Hao Liu, Fernanda Pilataxi, Lori Clarke, Ethan Grant, Arthur Lewis, Bethany Moore, Darryl A Knight, Cory M Hogaboam, Lynne A Murray
Lung fibrosis is an unabated wound healing response characterized by the loss and aberrant function of lung epithelial cells. Herein, we report that extracellular Clusterin promoted epithelial cell apoptosis whereas intracellular Clusterin maintained epithelium viability during lung repair. Unlike normal and COPD lungs, IPF lungs were characterized by significantly increased extracellular Clusterin whereas the inverse was evident for intracellular Clusterin. In vitro and in vivo studies demonstrated that extracellular Clusterin promoted epithelial cell apoptosis while intercellular Clusterin modulated the expression of the DNA repair proteins, MSH2, MSH6, OGG1 and BRCA1...
November 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29133142/dedifferentiated-endometrial-carcinomas-with-neuroendocrine-features-a-clinicopathologic-immunohistochemical-and-molecular-genetic-study
#6
Iñigo Espinosa, Antonio De Leo, Emanuela D'Angelo, Juan M Rosa-Rosa, Marina Corominas, Alan Gonzalez, José Palacios, Jaime Prat
Undifferentiated endometrial carcinoma is an aggressive type of uterine cancer which is occasionally associated with a low-grade endometrioid carcinoma component. This combination is referred to as "dedifferentiated endometrioid endometrial carcinoma." Neuroendocrine expression may occur in undifferentiated endometrial carcinoma but its significance in dedifferentiated endometrial carcinomas is unknown. To gain insight into the pathogenesis of these tumors we have analyzed the immunophenotype (ARID1A, MLH1, PMS2, MSH2, MSH6, p53, b-catenin, SMARCB1, synaptophysin, chromogranin A, and CD56) and mutational status (PTEN, KRAS, PIK3CA, TP53 and POLE) of 4 dedifferentiated endometrial carcinomas with strong and diffuse neuroendocrine expression...
November 10, 2017: Human Pathology
https://www.readbyqxmd.com/read/29107668/universal-screening-for-lynch-syndrome-in-endometrial-cancers-frequency-of-germline-mutations-and-identification-of-patients-with-lynch-like-syndrome
#7
Jessica L Dillon, Jorge L Gonzalez, Leslie DeMars, Katarzyna J Bloch, Laura J Tafe
Lynch syndrome (LS) is an inherited clinical syndrome characterized by a high risk of colorectal, endometrial (lifetime risk of up to 60%), ovarian and urinary tract cancers. The diagnosis is confirmed by identification of germline mutations in the DNA mismatch repair (MMR) genes MLH1, PMS2, MSH2, MSH6, or EPCAM. In 2015, our institution implemented universal screening of endometrial cancer hysterectomy specimens by MMR immunohistochemistry (IHC) with reflex MLH1 promoter hypermethylation analysis for tumors with loss of MLH1/PMS2 expression...
October 28, 2017: Human Pathology
https://www.readbyqxmd.com/read/29091773/sensing-and-processing-of-dna-interstrand-crosslinks-by-the-mismatch-repair-pathway
#8
Niyo Kato, Yoshitaka Kawasoe, Hannah Williams, Elena Coates, Upasana Roy, Yuqian Shi, Lorena S Beese, Orlando D Schärer, Hong Yan, Max E Gottesman, Tatsuro S Takahashi, Jean Gautier
DNA interstrand crosslinks (ICLs) that are repaired in non-dividing cells must be recognized independently of replication-associated DNA unwinding. Using cell-free extracts from Xenopus eggs that support neither replication nor transcription, we establish that ICLs are recognized and processed by the mismatch repair (MMR) machinery. We find that ICL repair requires MutSα (MSH2-MSH6) and the mismatch recognition FXE motif in MSH6, strongly suggesting that MutSα functions as an ICL sensor. MutSα recruits MutLα and EXO1 to ICL lesions, and the catalytic activity of both these nucleases is essential for ICL repair...
October 31, 2017: Cell Reports
https://www.readbyqxmd.com/read/29084048/clinical-targeted-next-generation-sequencing-shows-increased-mutational-load-in-endometrioid-type-endometrial-adenocarcinoma-with-deficient-dna-mismatch-repair
#9
Paul J Lee, Samantha McNulty, Eric J Duncavage, Jonathan W Heusel, Ian S Hagemann
A subset of endometrial adenocarcinomas (EACs) exhibit microsatellite instability and have deficient DNA mismatch repair (dMMR). The overall aim of the study was to compare the spectrum of mutations in endometrioid-type EAC with and without dMMR by using a clinically validated next-generation sequencing assay. We retrospectively identified 19 EACs with known mismatch repair status that had undergone targeted sequencing of a panel of cancer-related genes. The mismatch repair status was ascertained by immunohistochemistry against MLH1, PMS2, MSH2, and MSH6 mismatch proteins...
October 27, 2017: International Journal of Gynecological Pathology
https://www.readbyqxmd.com/read/29079180/mixed-endometrial-carcinomas-with-a-low-grade-serous-like-component-a-clinicopathologic-immunohistochemical-and-molecular-genetic-study
#10
Iñigo Espinosa, Emanuela D'Angelo, Marina Corominas, Alan Gonzalez, Jaime Prat
Recently, we reported 2 mixed endometrioid endometrial carcinomas with a low-grade serous-like component which doesn't fit into any of the 4 molecular groups described by The Cancer Genome Atlas (TCGA). In order to understand the nature of these tumors, we have done an immunohistochemical and molecular genetic study of these two cases and added a third case. Immunoreactivity for p53, ER, Ki67, WT1, MLH1, PMS2, MSH2, and MSH6 were assessed. Targeted next-generation sequencing for somatic mutations, including genes commonly implicated in carcinogenesis including TP53, KRAS, and PIK3CA, and Sanger sequencing for PTEN and POLE were also performed...
October 24, 2017: Human Pathology
https://www.readbyqxmd.com/read/29069866/germline-mutations-in-pancreatic-cancer-and-potential-new-therapeutic-options
#11
REVIEW
Rille Pihlak, Juan W Valle, Mairéad G McNamara
Due to short-lived treatment responses in unresectable disease, pancreatic ductal adenocarcinoma (PDAC) continues to be one of the deadliest cancers. There is availability of new information about germline and sporadic mutations in the deoxyribonucleic acid (DNA) damage repair pathway in PDAC in recent decades and the expectation is that novel targeted therapies will thus be developed. A variety of germline mutations (BRCA2, BRCA1, PALB2, CDKN2A, ATM, TP53 and mismatch repair genes MLH1, MSH2, MSH6) have been reported in these patients with the highest prevalence being BRCA1/2...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29069084/involvement-of-dna-mismatch-repair-in-the-maintenance-of-heterochromatic-dna-stability-in-saccharomyces-cerevisiae
#12
Basanta K Dahal, Lyudmila Y Kadyrova, Kristin R Delfino, Igor B Rogozin, Vaibhavi Gujar, Kirill S Lobachev, Farid A Kadyrov
Heterochromatin contains a significant part of nuclear DNA. Little is known about the mechanisms that govern heterochromatic DNA stability. We show here that in the yeast Saccharomyces cerevisiae (i) DNA mismatch repair (MMR) is required for the maintenance of heterochromatic DNA stability, (ii) MutLα (Mlh1-Pms1 heterodimer), MutSα (Msh2-Msh6 heterodimer), MutSβ (Msh2-Msh3 heterodimer), and Exo1 are involved in MMR at heterochromatin, (iii) Exo1-independent MMR at heterochromatin frequently leads to the formation of Pol ζ-dependent mutations, (iv) MMR cooperates with the proofreading activity of Pol ε and the histone acetyltransferase Rtt109 in the maintenance of heterochromatic DNA stability, (v) repair of base-base mismatches at heterochromatin is less efficient than repair of base-base mismatches at euchromatin, and (vi) the efficiency of repair of 1-nt insertion/deletion loops at heterochromatin is similar to the efficiency of repair of 1-nt insertion/deletion loops at euchromatin...
October 2017: PLoS Genetics
https://www.readbyqxmd.com/read/29063235/prognostic-values-of-dna-mismatch-repair-genes-in-ovarian-cancer-patients-treated-with-platinum-based-chemotherapy
#13
Chuchu Zhao, Saisai Li, Menghuang Zhao, Haiyan Zhu, Xueqiong Zhu
PURPOSE: DNA mismatch repair (MMR) is a highly conserved biological pathway that plays a key role in maintaining genomic stability. MMR has been reported as a prognostic marker in certain cancers; however, the results are controversial. Therefore, identification of the prognostic value of MMR genes in ovarian cancer based on a large sample size is pivotal. METHODS: In the current study, we systemically investigated the prognostic roles of seven MMR genes, MSH2, MSH3, MSH6, MLH1, MLH3, PMS1 and PMS2, in ovarian cancer patients treated with platinum-based chemotherapy through "The Kaplan-Meier plotter" (KM plotter) database, which contains gene expression data and survival information of ovarian cancer patients...
October 23, 2017: Archives of Gynecology and Obstetrics
https://www.readbyqxmd.com/read/29054568/genetic-epidemiology-of-ovarian-cancer-and-prospects-for-polygenic-risk-prediction
#14
REVIEW
Michelle R Jones, Daniella Kamara, Beth Y Karlan, Paul D P Pharoah, Simon A Gayther
Epithelial ovarian cancer (EOC) is a heterogeneous disease with a major heritable component. The different histotypes of invasive disease - high grade serous, clear cell, endometrioid and mucinous - are associated with different underlying genetic susceptibility and epidemiological and lifestyle risk factors, all of which contribute to the different biology and clinical characteristics of each histotype. A combination of familial and population based sequencing studies, and genome wide association studies (GWAS) have identified a range of genetic susceptibility alleles for EOC comprising rare but highly penetrant genes (e...
October 17, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/29053726/prevalence-of-deleterious-germline-variants-in-risk-genes-including-brca1-2-in-consecutive-ovarian-cancer-patients-ago-tr-1
#15
Philipp Harter, Jan Hauke, Florian Heitz, Alexander Reuss, Stefan Kommoss, Frederik Marmé, André Heimbach, Katharina Prieske, Lisa Richters, Alexander Burges, Guido Neidhardt, Nikolaus de Gregorio, Ahmed El-Balat, Felix Hilpert, Werner Meier, Rainer Kimmig, Karin Kast, Jalid Sehouli, Klaus Baumann, Christian Jackisch, Tjoung-Won Park-Simon, Lars Hanker, Sandra Kröber, Jacobus Pfisterer, Heidrun Gevensleben, Andreas Schnelzer, Dimo Dietrich, Tanja Neunhöffer, Mathias Krockenberger, Sara Y Brucker, Peter Nürnberg, Holger Thiele, Janine Altmüller, Josefin Lamla, Gabriele Elser, Andreas du Bois, Eric Hahnen, Rita Schmutzler
BACKGROUND: Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in BRCA1/2 in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated...
2017: PloS One
https://www.readbyqxmd.com/read/29046615/integrated-genomic-characterization-of-cancer-genes-in-glioma
#16
Aijun Liang, Bin Zhou, Wei Sun
BACKGROUND: Cancers are caused by the acquisition of somatic mutations. Numerous efforts have been made to characterize the key driver genes and pathways in glioma, however, the etiology of glioma is still not completely known. This study was implemented to characterize driver genes in glioma independently of somatic mutation frequencies. METHODS: Driver genes and pathways were predicted by OncodriveCLUST, OncodriveFM, Icages, Drgap and Dendrix in glioma using 31,958 somatic mutations from TCGA, followed by an integrative characterization of driver genes...
2017: Cancer Cell International
https://www.readbyqxmd.com/read/29033182/pd-l1-expression-in-hnpcc-associated-colorectal-cancer
#17
Naila Shiraliyeva, Jacqueline Friedrichs, Reinhard Buettner, Nicolaus Friedrichs
BACKGROUND: PD-L1 immunohistochemistry is predictive for molecular inhibitors of PD-1/PD-L1 immune checkpoint. Therefore, this study evaluated the PD-L1 expression in patients with Hereditary Non-Polyposis Colorectal Cancer (HNPCC). METHODS: Immunohistochemical expression of PD-L1 in carcinoma cells, stromal macrophages and lymphocytes of 40 HNPCC-patients with colorectal cancer was scored semi-quantitatively. RESULTS: Focal (2 cases) to extensive (2 cases) PD-L1-immunopositivity of carcinoma cells was detected in 4 out of 40 cases (10...
September 18, 2017: Pathology, Research and Practice
https://www.readbyqxmd.com/read/29025352/risk-of-colorectal-polyps-and-of-malignancies-in-asymptomatic-carriers-of-mutations-in-the-main-dna-mismatch-repair-genes
#18
Maurizio Ponz de Leon, Monica Pedroni, Annalisa Pezzi, Blerta Sulce, Luca Roncucci, Federica Domati, Giuseppina Rossi, Luca Reggiani Bonetti
OBJECTIVE: Mutation carriers (Mut+) in DNA mismatch repair genes are predisposed to cancer of various organs and to adenomatous polyps; however, they may remain asymptomatic and cancer or polyp-free for several years. We purposed to analyse the clinical follow-up of individuals carrying constitutional mutations in the MLH1, MSH2 or MSH6 genes who were unaffected by benign polyps or malignant tumours at diagnosis. MATERIAL AND METHODS: Mut + subjects (n.81) were members of Lynch syndromes in whom mutations were detected between 1993 and 2015; all were asymptomatic at diagnosis...
October 12, 2017: Scandinavian Journal of Gastroenterology
https://www.readbyqxmd.com/read/28981733/prognostic-factors-for-primary-central-nervous-system-lymphomas-treated-with-high-dose-methotrexate-based-chemo-radiotherapy
#19
Jeunghun Lee, Yukiko Shishido-Hara, Kaori Suzuki, Saki Shimizu, Keiichi Kobayashi, Hiroshi Kamma, Yoshiaki Shiokawa, Motoo Nagane
Background: Primary central nervous system lymphoma (PCNSL) remains an aggressive and refractory tumor despite high-dose methotrexate-based chemo-radiotherapy. Age and performance status have been shown to be important clinical prognostic factors, however others, especially molecular factors, affecting the prognosis are still uncertain. Methods: We investigate clinical, neuroimaging and immunohistochemical data in tissue from 41 PCNSL patients treated primarily with methotrexate-based chemo-radiotherapy and evaluate the influence of potential prognostic factors on clinical outcome as well as correlation among these factors...
October 1, 2017: Japanese Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28961847/intratumoural-evolutionary-landscape-of-high-risk-prostate-cancer-the-progeny-study-of-genomic-and-immune-parameters
#20
M Linch, G Goh, C Hiley, Y Shanmugabavan, N McGranahan, A Rowan, Y N S Wong, H King, A Furness, A Freeman, J Linares, A Akarca, J Herrero, R Rosenthal, N Harder, G Schmidt, G A Wilson, N J Birkbak, R Mitter, S Dentro, P Cathcart, M Arya, E Johnston, R Scott, M Hung, M Emberton, G Attard, Z Szallasi, S Punwani, S A Quezada, T Marafioti, M Gerlinger, H U Ahmed, C Swanton
Background: Intratumoural heterogeneity (ITH) is well recognised in prostate cancer (PC), but its role in high-risk disease is uncertain. A prospective, single-arm, translational study using targeted multiregion prostate biopsies was carried out to study genomic and T-cell ITH in clinically high-risk PC aiming to identify drivers and potential therapeutic strategies. Patients and methods: Forty-nine men with elevated prostate-specific antigen and multiparametric-magnetic resonance imaging detected PC underwent image-guided multiregion transperineal biopsy...
October 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
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