المؤلفون: Robert W. Ricciotti, Yajuan J. Liu, Christopher D.M. Fletcher, Yu Wu, Wenjing Wang, Eleanor Y. Chen, Jeffrey Yeh, Jose G. Mantilla

المصدر: Modern Pathology. 34:1373-1383

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Soft Tissue Neoplasm, Soft Tissue Neoplasms, Biology, Pathology and Forensic Medicine, 03 medical and health sciences, Exon, 0302 clinical medicine, medicine, Humans, Oncogene Fusion, Receptor, Fibroblast Growth Factor, Type 1, Receptor Tyrosine Kinase Gene, Receptor, trkA, Aged, Neoplasms, Connective Tissue, c-Mer Tyrosine Kinase, Cartilage, Calcinosis, Soft tissue, Middle Aged, MERTK, medicine.disease, Receptor, TIE-2, Fibronectins, stomatognathic diseases, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, Fibroblast Growth Factor 2, Tyrosine kinase, Calcification

الوصف: Translocations involving FN1 have been described in a variety of neoplasms that share the presence of a cartilage matrix and may also contain a variable extent of calcification. Fusions of FN1 to FGFR1 or FGFR2 have been reported in nine soft tissue chondromas, mostly demonstrated indirectly by FISH analysis. Delineation of FN1 fusions with various partner genes will facilitate our understanding of the pathogenesis and diagnostic classification of these neoplasms. In this study, we present molecular, clinical, and pathologic features of 12 cartilaginous soft tissue neoplasms showing a predilection for the TMJ region and the distal extremities. We analyzed for gene fusions with precise breakpoints using targeted RNA-seq with a 115-gene panel. We detected gene fusions in ten cases, including three novel fusions, FN1-MERTK, FN1-NTRK1, and FN1-TEK, each in one case, recurrent FN1-FGFR2 fusion in five cases, FN1-FGFR1 in one case, and FGFR1-PLAG1 in one case. The breakpoints in the 5' partner gene FN1 ranged from exons 11-48, retaining the domains of a signal peptide, FN1, FN2, and/or FN3, while the 3' partner genes retained the transmembrane domain, tyrosine kinase (TK) domains, and/or Ig domain. The tumors are generally characterized by nodular/lobular growth of polygonal to stellate cells within a chondroid matrix, often accompanied by various patterns of calcification, resembling those described for the chondroblastoma-like variant of soft tissue chondroma. Additional histologic findings include extensive calcium pyrophosphate dihydrate deposition in two cases and features resembling tenosynovial giant cell tumor (TGCT). Overall, while the tumors from our series show significant morphologic overlap with chondroblastoma-like soft tissue chondroma, we describe findings that expand the morphologic spectrum of these neoplasms and therefore refer to them as "calcified chondroid mesenchymal neoplasms." These neoplasms represent a spectrum of chondroid/cartilage matrix-forming tumors harboring FN1-receptor TK fusions that include those classified as soft tissue chondroma as well as chondroid TGCT.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ebdcdb2c178048b82eedd4c87036ff7bTest
https://doi.org/10.1038/s41379-021-00786-xTest

المؤلفون: Kyohei Yamada, Hiroaki Miyoshi, Naoko Asano, Joji Shimono, Masao Seto, Kensaku Sato, Noriaki Yoshida, Mai Takeuchi, Kazutaka Nakashima, Eriko Yanagida, Koichi Ohshima, Fumiko Arakawa

المصدر: Modern Pathology. 34:314-326

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, T cell, Retroviridae Proteins, Human leukocyte antigen, Virus, Adult T-cell leukemia/lymphoma, Pathology and Forensic Medicine, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Biomarkers, Tumor, medicine, Humans, Leukemia-Lymphoma, Adult T-Cell, Aged, Aged, 80 and over, Human T-lymphotropic virus 1, business.industry, Gene Products, tax, Middle Aged, medicine.disease, HTLV-I Infections, Lymphoma, Leukemia, Basic-Leucine Zipper Transcription Factors, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, RNA, Viral, Clinicopathological features, Female, business

الوصف: Adult T-cell leukemia/lymphoma (ATLL) is caused by human T-cell leukemia virus type 1 (HTLV-1). HTLV-1-associated mRNA, including HBZ and tax, is deeply involved in the pathogenesis of ATLL. Using 88 ATLL tissue samples, we performed in situ mRNA analysis of HBZ and tax, and investigated its association with clinicopathological characteristics of ATLL. The median value of HBZ signals (/1000 ATLL cells) was 795.2 (range: 0.4–4013.1) and of tax signals (/1000 ATLL cells) was 5.1 (range: 0.1–891.2). The low-expression HBZ group displayed significant increase in the number of skin lesion (P = 0.0283). The high-expression tax group displayed significant increase in the number of PD-1-positive tumor-infiltrating lymphocytes (P

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::215613b62397bc1e005f136b6fa8ff65Test
https://doi.org/10.1038/s41379-020-00654-0Test

المؤلفون: Luis J Leandro-García, Guillermo Velasco, Bruna Calsina, Georgia Anguera, Pablo Maroto, Rocío Letón, Maria José Santos, María Monteagudo, Ángel M Martínez-Montes, Eduardo Caleiras, Jesús García-Donas, Cristina Rodríguez-Antona, Cristina Montero-Conde, Alberto Cascón, Javier Lanillos, Mercedes Robledo, Juan María Roldan-Romero

المصدر: MODERN PATHOLOGY
r-IIB SANT PAU: Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, DNA Mutational Analysis, Chromophobe Renal Cell Carcinoma, medicine.disease_cause, Tuberous Sclerosis Complex 1 Protein, Pathology and Forensic Medicine, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Tuberous Sclerosis Complex 2 Protein, Biomarkers, Tumor, Carcinoma, Humans, Medicine, PTEN, Genetic Predisposition to Disease, Phosphorylation, Carcinoma, Renal Cell, PI3K/AKT/mTOR pathway, Survival analysis, Aged, Aged, 80 and over, Mutation, biology, business.industry, Ribosomal Protein S6 Kinases, TOR Serine-Threonine Kinases, PTEN Phosphohydrolase, High-Throughput Nucleotide Sequencing, Middle Aged, medicine.disease, Immunohistochemistry, Kidney Neoplasms, Phenotype, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Female, Tumor Suppressor Protein p53, business

الوصف: Chromophobe renal cell carcinoma (chRCC) is a histologically and molecularly distinct class of rare renal tumor. TCGA studies revealed low mutational burden, with only TP53 and PTEN recurrently mutated, and discovered alterations in TERT promoter and in the electron transport chain Complex I genes. However, knowledge on drug targetable genes is limited and treatments at metastatic stage do not follow a molecular rationale. In a large series of 92 chRCC enriched with metastatic cases, we performed an in-depth characterization of mTOR pathway alterations through targeted NGS and immunohistochemistry (IHC) of phospho-S6, tuberin, and PTEN. Mutations in mitochondria, telomere maintenance and other renal cancer related genes and p53 IHC, were also assessed. The impact on metastasis development and disease specific survival was determined, using TCGA-KICH series (n = 65) for validation. mTOR pathway mutations (MTOR, TSC1, TSC2) were present in 17% of primary tumors, most of them being classified as pathogenic. Mutations were associated with positive IHC staining of phospho-S6 and PTEN (P = 0.009 and P = 0.001, respectively) and with chRCC eosinophilic variant (P = 0.039), supporting a biological relevance of the pathway. mTOR pathway mutations were associated with worse clinical outcomes. Survival analysis gave a hazard ratio of 5.5 (P = 0.027), and this association was confirmed in TCGA-KICH (HR = 10.3, P = 0.006). TP53 mutations were enriched in metastatic cases (P = 0.018), and mutations in telomere maintenance genes showed a trend in the same direction. p53 IHC staining pattern was associated with the underlying TP53 defect, and negative PTEN IHC staining (82% of cases) suggested PTEN loss as a chRCC hallmark. In conclusion, our study provides with novel genomic knowledge in chRCC and identifies novel markers of poor survival. Furthermore, this is the first study showing that mTOR pathway mutations correlate with poor prognosis, and may help to identify patients with increased sensitivity to mTOR inhibitors.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6a50154d9d97b395a18bd54a21f25602Test
https://doi.org/10.1038/s41379-020-0607-zTest

المؤلفون: Sébastien Aubert, Jean-Marc Guinebretière, Anne Gomez-Brouchet, François Le Loarer, Jessica Baud, Frédérique Larousserie, Virginie Audard, Gonzague de Pinieux, Corinne Bouvier, Nicolas Macagno, Daniel Pissaloux, Damien Geneste, Franck Tirode, Béatrice Marie

المساهمون: Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut Bergonié [Bordeaux], UNICANCER, CHU Lille, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital René HUGUENIN (Saint-Cloud), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Gall, Valérie, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)

المصدر: Modern Pathology
Modern Pathology, Nature Publishing Group: Open Access Hybrid Model Option B, 2020, 33 (7), pp.1360-1368. ⟨10.1038/s41379-020-0493-4⟩
Modern Pathology, 2020, 33 (7), pp.1360-1368. ⟨10.1038/s41379-020-0493-4⟩

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Nucleolus, [SDV]Life Sciences [q-bio], CD34, Soft Tissue Neoplasms, Biology, Receptors, G-Protein-Coupled, Pathology and Forensic Medicine, Fingers, Thrombospondin 1, Fusion gene, 03 medical and health sciences, 0302 clinical medicine, Stroma, Eosinophilic, medicine, Humans, Oncogene Fusion, Neoplasms, Connective Tissue, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Myoepithelial cell, Soft tissue, Middle Aged, Toes, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, 030220 oncology & carcinogenesis, Immunohistochemistry, Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology

الوصف: International audience; Acral soft tissue tumors are common neoplasms, a subset of which pose a diagnostic challenge. We report 10 cases of a previously unrecognized acral benign soft tissue tumor. These tumors arose on the fingers and toes and involved bone in half of cases. Histologically, the tumors were lobulated and displayed an abundant stroma made of variable fibrous, chondroid and myxoid material reminiscent of cartilaginous or myoepithelial differentiation. Tumor cells harbored small round to reniform nuclei with clear chromatin and inconspicuous nucleoli along with scant eosinophilic cytoplasm. The cells were mostly arranged haphazardly in the stroma but also in small clusters. No mitotic activity was detected. No specific feature was identified in recurrent cases. By immunohistochemistry, the cells consistently stained for CD34 (10/10), ERG (9/10), and SOX9 (7/10). Whole RNA sequencing identified a previously undescribed recurrent in frame THBS1-ADGRF5 gene fusion in all cases. The transcript was confirmed by RT-PCR and was not found in the control group of mimickers including soft tissue chondromas. We propose the name of Acral FibroChondroMyxoid Tumors for this new entity.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::507d12f7967af61b9f9a673feacdbac5Test
https://doi.org/10.1038/s41379-020-0493-4Test

المؤلفون: Serena Wong, Natalia Buza, Pei Hui

المصدر: Modern Pathology. 33:1172-1181

مصطلحات موضوعية: Adult, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Pathology, medicine.medical_specialty, MLH1, DNA Mismatch Repair, Pathology and Forensic Medicine, Endometrium, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Biomarkers, Tumor, PMS2, Humans, Medicine, Mismatch Repair Endonuclease PMS2, business.industry, Endometrial cancer, nutritional and metabolic diseases, Microsatellite instability, DNA Methylation, Middle Aged, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Immunohistochemistry, digestive system diseases, Lynch syndrome, DNA-Binding Proteins, MSH6, 030104 developmental biology, MSH2, 030220 oncology & carcinogenesis, Mutation, Female, MutL Protein Homolog 1, business

الوصف: Lynch syndrome is most often caused by a germline mutation in one of four DNA mismatch repair (MMR) genes (MLH1, PMS2, MSH2, or MSH6) or EPCAM and is associated with a significantly increased risk of endometrial cancer in affected women. Although universal screening of endometrial cancer for Lynch syndrome is becoming increasingly common by various algorithms using MMR immunohistochemistry and/or microsatellite instability testing by PCR, establishing the diagnosis of Lynch syndrome can be still challenging. MMR-deficient nonneoplastic colonic crypts have been recently described in Lynch syndrome patients with colorectal carcinoma, and have been proposed to be a novel indicator of Lynch syndrome. Presence of MMR-deficient nonneoplastic endometrial glands have not yet been systematically evaluated in Lynch syndrome patients. We performed MMR protein immunohistochemistry in prophylactic hysterectomies and endometrial curettings/biopsies from 27 patients with known Lynch syndrome confirmed by germline mutation analysis. A total of 56 control benign endometrial tissues were also analyzed, and included benign endometrium adjacent to MMR-deficient sporadic (MLH1 promoter hypermethylated) endometrial carcinoma (n = 9), adjacent to MMR-intact sporadic endometrial carcinoma (n = 27), and normal endometrium from hysterectomies performed for benign disease (n = 20). MMR protein deficient nonneoplastic endometrial glands were identified in 70% (19 of 27) of Lynch syndrome patients. In all 19 cases the MMR protein loss was specific for the patients' known germline mutation. None of the control cases showed loss of MMR protein expression in nonneoplastic endometrium. Our findings suggest that MMR-deficient nonneoplastic endometrial glands may be a unique, specific marker of Lynch syndrome, and may provide an important insight into the pathogenesis of Lynch syndrome-associated endometrial cancer. Evaluation of MMR protein expression of benign background endometrium in endometrial cancer patients may be further explored as a possible useful addition to the Lynch syndrome screening algorithm.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c72e2c252bd2f232326548a042137d90Test
https://doi.org/10.1038/s41379-020-0455-xTest

المؤلفون: Elena Miranda, Roberto Tirabosco, Paul Cool, Daniel Baumhoer, Fernanda Amary, Lucia Cottone, Paul O'Donnell, Luis Perez-Casanova, William Aston, Maia Rocha, Hongtao Ye, Anna-Christina Strobl, Nischalan Pillay, Fitim Berisha, Adrienne M. Flanagan, Edward Hookway

المصدر: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Adolescent, Activin Receptors, Type II, Soft Tissue Neoplasms, Biology, Article, Pathology and Forensic Medicine, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Synovial chondromatosis, medicine, Humans, Oncogene Fusion, Receptor, Fibroblast Growth Factor, Type 1, Receptor, Fibroblast Growth Factor, Type 2, Child, Aged, Aged, 80 and over, Gene Rearrangement, Soft tissue, Gene rearrangement, Middle Aged, medicine.disease, Phosphaturic mesenchymal tumor, Fibronectins, Fibroblast Growth Factor-23, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Chondromatosis, Sarcoma, Chondrosarcoma, Chondromatosis, Synovial, Chondroma, Calcification

الوصف: A fusion between fibronectin 1 (FN1) and activin receptor 2A (ACVR2A) has been reported previously in isolated cases of the synovial chondromatosis. To analyze further and validate the findings, we performed FISH and demonstrated recurrent FN1-ACVR2A rearrangements in synovial chondromatosis (57%), and chondrosarcoma secondary to synovial chondromatosis (75%), showing that FN1 and/or AVCR2A gene rearrangements do not distinguish between benign and malignant synovial chondromatosis. RNA sequencing revealed the presence of the FN1-ACVR2A fusion in several cases that were negative by FISH suggesting that the true prevalence of this fusion is potentially higher than 57%. In soft tissue chondromas, FN1 alterations were detected by FISH in 50% of cases but no ACVR2A alterations were identified. RNA sequencing identified a fusion involving FN1 and fibroblast growth factor receptor 2 (FGFR2) in the case of soft tissue chondroma and FISH confirmed recurrent involvement of both FGFR1 and FGFR2. These fusions were present in a subset of soft tissue chondromas characterized by grungy calcification, a feature reminiscent of phosphaturic mesenchymal tumor. However, unlike the latter, fibroblast growth factor 23 (FGF23) mRNA expression was not elevated in soft tissue chondromas harboring the FN1-FGFR1 fusion. The mutual exclusivity of ACVR2A rearrangements observed in synovial chondromatosis and FGFR1/2 in soft tissue chondromas suggests these represent separate entities. There have been no reports of malignant soft tissue chondromas, therefore differentiating these lesions will potentially alter clinical management by allowing soft tissue chondromas to be managed more conservatively.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cd62c3c000cb7353f1e741e5ba50607dTest
https://doi.org/10.1038/s41379-019-0315-8Test

المؤلفون: Kiyong Na, Jae Yol Lim, Sun Och Yoon, Juan C. Hernandez-Prera, Ha Young Woo

المصدر: Modern Pathology

مصطلحات موضوعية: 0301 basic medicine, Adult, Male, Pathology, medicine.medical_specialty, Adolescent, Biology, Protein Serine-Threonine Kinases, medicine.disease_cause, Article, Translocation, Genetic, Pathology and Forensic Medicine, DNA Glycosylases, Fusion gene, 03 medical and health sciences, Young Adult, 0302 clinical medicine, AMP-Activated Protein Kinase Kinases, MUTYH, medicine, Cancer genomics, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Trypsin, Head and neck cancer, Child, Cancer genetics, Aged, Hereditary pancreatitis, Mutation, medicine.diagnostic_test, Proto-Oncogene Proteins c-ets, Carcinoma, Histone-Lysine N-Methyltransferase, Middle Aged, medicine.disease, Salivary Gland Neoplasms, Repressor Proteins, ETV6, 030104 developmental biology, 030220 oncology & carcinogenesis, Adenocarcinoma, Female, Carcinogenesis, MutL Protein Homolog 1, Fluorescence in situ hybridization

الوصف: Secretory carcinoma is a salivary gland tumor with a characteristic chromosomal translocation that results in an ETV6-NTRK3 fusion gene. Secretory carcinoma shows relatively frequent rates of lymph-node metastasis and tumor recurrence and has a characteristic histology. Except for the ETV6 translocation, genomic alterations in secretory carcinoma have not been reported. In the present study, we characterized the novel recurrent genetic mutations of secretory carcinoma. On the basis of histology, immunohistochemistry, and ETV6 gene break-apart fluorescence in situ hybridization assays, 22 tumors were classified as secretory carcinomas (19 ETV6 translocation-positive and 3 ETV6 translocation-negative secretory carcinomas) and their clinicopathologic characteristics were reviewed. Targeted deep sequencing analyses were performed on 20 secretory carcinomas (17 ETV6 translocation-positive and 3 ETV6 translocation-negative secretory carcinomas) to investigate their genetic alterations. The A16V (C→T) mutation in PRSS1, which encodes a cationic trypsinogen and has a mutation associated with hereditary pancreatitis and pancreatic adenocarcinoma, was observed in 40% (8/20) (7/17 of ETV6 translocation-positive and 1/3 of ETV6 translocation-negative secretory carcinomas). Pathogenic variants of MLH1, MUTYH, and STK11 were also identified. Variants of uncertain significance included mutations in KMT5A. These novel characteristic genetic alterations may advance current understandings of secretory carcinoma tumorigenesis and progression, leading to improved diagnoses and treatment strategies.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8fb4af46e8209c001c15eee938ccf856Test
http://europepmc.org/articles/PMC7113190Test

المؤلفون: Jaclyn F. Hechtman, Efsevia Vakiani, Monika Vyas, David S. Klimstra, Canan Firat, Avani Desai, Jinru Shia, Lik Hang Lee, Karuna Ganesh, Zsofia K. Stadler, Peter Ntiamoah, Liying Zhang, Arnold J. Markowitz, Martin R. Weiser, Neil H. Segal, Tao Wang

المصدر: Modern Pathology. 32:1551-1562

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Colorectal cancer, Somatic cell, medicine.disease_cause, DNA Mismatch Repair, Article, Pathology and Forensic Medicine, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, Germline mutation, Biomarkers, Tumor, medicine, Humans, Pathological, Aged, Mutation, business.industry, Microsatellite instability, Middle Aged, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Immune checkpoint, Treatment Outcome, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, Female, Microsatellite Instability, DNA mismatch repair, Colorectal Neoplasms, MutL Protein Homolog 1, business

الوصف: Double somatic mismatch-repair-gene mutation/alteration is a recently recognized molecular mechanism that underlies microsatellite instability-high in some colorectal carcinomas. It remains to be determined whether and how microsatellite instability-high tumors with this molecular defect differ from their counterparts caused by other mechanisms, specifically, Lynch syndrome-associated and MLH1-promoter hypermethylated. In this study, we evaluated the clinical and pathological characteristics of a series of 15 double somatic mutation/alteration-associated microsatellite instability-high colorectal carcinomas identified from our genetics service and 68 such cases reported in the literature. We observed that these cases presented at an age similar to MLH1-promoter hypermethylated (n = 20) and microsatellite-stable (n = 39) cases but older than Lynch syndrome-associated cases (n = 20, p 0.05). While these tumors simulated other microsatellite instability-high tumors in their prevalent right-sided location, they appeared to differ in TNM stages at presentation (73% stage III/IV versus 25% stage III/IV in other microsatellite instability-high tumors, p = 0.04). Histologically, 40% of them had a dominant solid growth pattern. Inter-tumoral heterogeneity was a striking feature, spanning the spectrum from medullary type (with a tumor-infiltrating-lymphocyte/high-power-field count as high as 59) to conventional-type with only few tumor-infiltrating-lymphocytes (1/high-power-filed). As a group, these tumors seemed less likely to show robustly high lymphocytic infiltration than other microsatellite instability-high tumors (only 20% had ≥10 tumor-infiltrating-lymphocytes/high-power-filed, whereas this rate in Lynch syndrome-associated and MLH1-promoter hypermethylated tumors was 60% and 75%, respectively). Three double somatic mutation/alteration-associated tumors were treated with a PD1/PD-L1 checkpoint inhibitor. While all three had an elevated tumor-mutation-burden (47 mut/megabase), only one had tumor-infiltrating-lymphocytes10/high-power-field, yet all three exhibited measurable response. In summary, microsatellite instability-high colorectal carcinomas caused by double somatic mismatch-repair-gene mutation/alteration may have varied clinical and pathological characteristics, and some may have relatively low tumor-infiltrating-lymphocytes; response to immune checkpoint inhibitors can be achieved in this group even when the lymphocytic infiltration is not abundant.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::75f2933b539afb3585edefbbecfa8697Test
https://doi.org/10.1038/s41379-019-0289-6Test

المؤلفون: Ran Hirano, Satoshi Miuma, Harmeet Malhi, Katsuya Matsuda, Kazuhiko Nakao, Seigo Abiru, Koji Okamaoto, Junya Fukuoka, Hisamitsu Miyaaki, Ryoma Nakashima, Masahiro Nakashima, Yuko Akazawa, Hiroko Kawasaki, Hisayohi Kondo, Masahiro Itoh

المصدر: Modern Pathology. 32:997-1007

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Cirrhosis, DNA damage, Apoptosis, Genomic Instability, Cell Line, Pathology and Forensic Medicine, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Fibrosis, Nonalcoholic fatty liver disease, medicine, Animals, Humans, Aged, Cell Nucleus, chemistry.chemical_classification, business.industry, Fatty liver, Fatty acid, Middle Aged, medicine.disease, Rats, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Disease Progression, Hepatocytes, Female, Tumor Suppressor p53-Binding Protein 1, business, DNA Damage

الوصف: Nonalcoholic fatty liver disease is a major liver disease that leads to cirrhosis and/or hepatocellular carcinoma in a subset of patients. The mechanism underlying disease progression is largely unknown. p53-binding protein 1 (53BP1) is a DNA damage response protein that rapidly localizes at the site of DNA double-strand breaks. In this study, we investigated nuclear 53BP1-positive foci formation as an indicator of DNA double-strand breaks in human nonalcoholic fatty liver disease liver tissues by immunofluorescence microscopy. A total of 52 liver tissue samples, including 43 nonalcoholic fatty liver disease samples and 9 controls, were studied. Our results show that the number of abnormal 53BP1-positive foci in hepatocytes (defined as three or more discrete nuclear foci and/or large foci greater than 1 μM) was significantly increased in nonalcoholic fatty liver disease patients compared to that in controls, both in nonalcoholic fatty liver (p

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::957a9b2b1b2594f3c520e60a3d1d5d2bTest
https://doi.org/10.1038/s41379-019-0218-8Test

المؤلفون: Anne M. Mills, Susan C. Modesitt, Kari L. Ring, Zachary Chinn, Sara L. Zadeh, Emily A. Sloan

المصدر: Modern Pathology. 31:1282-1290

مصطلحات موضوعية: Adult, 0301 basic medicine, Pathology, medicine.medical_specialty, medicine.medical_treatment, MLH1, B7-H1 Antigen, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Immune system, Biomarkers, Tumor, medicine, Carcinoma, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, Aged, Retrospective Studies, business.industry, Endometrial cancer, Immunotherapy, DNA Methylation, Middle Aged, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Lynch syndrome, Endometrial Neoplasms, 030104 developmental biology, 030220 oncology & carcinogenesis, Immunohistochemistry, Female, Tumor Escape, DNA mismatch repair, MutL Protein Homolog 1, business

الوصف: Mismatch repair-deficient endometrial carcinomas are optimal candidates for immunotherapy given their high neoantigen loads, robust lymphoid infiltrates, and frequent PD-L1 expression. However, co-opting the PD-1/PD-L1 pathway is just one mechanism that tumors can utilize to evade host immunity. Another immune modulatory molecule that has been demonstrated in endometrial carcinoma is indoleamine 2,3-dioxygenase (IDO). We herein evaluate IDO expression in 60 endometrial carcinomas and assess results in relation to PD-L1 and mismatch repair status. IDO immunohistochemistry was performed on 60 endometrial carcinomas (20 Lynch syndrome (LS)-associated, 20 MLH1 promoter hypermethylated, and 20 mismatch repair-intact). Eight-five percent of endometrial carcinomas showed IDO tumor staining in >1% of cells. Twenty-five percent were positive in >25% of tumor cells and only 7% exceeded 50% staining. Mismatch repair-deficient cancers were more likely than mismatch repair-intact cancers to be >25% IDO-positive (35% vs. 5% p = 0.024). Differences were amplified when Lynch syndrome-associated cases were evaluated in isolation (50% Lynch syndrome-associated vs. 10% mismatch repair-intact and MLH1-hypermethylated, p = 0.001). Of the four cases showing >50% staining, three were Lynch syndrome-associated and one was MLH1-hypermethylated; no mismatch repair-intact cases had >50% staining. Forty-three percent of IDO-positive tumors were also positive for PD-L1, whereas only two cases showed tumoral PD-L1 in the absence of IDO. In summary, IDO expression is prevalent in endometrial carcinomas and diffuse staining is significantly more common in mismatch repair-deficient cancers, particularly Lynch syndrome-associated cases. Given that the majority of PD-L1 positive cancers also express IDO, synergistic combination therapy with anti-IDO and anti-PD1/PD-L1 may be relevant in this tumor type. Furthermore, anti-IDO therapy may be an option for a small subset of mismatch repair-intact cancers.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::14726d4faf1d79b827d05884827bc4e9Test
https://doi.org/10.1038/s41379-018-0039Test-1