المؤلفون: Fischer, Alessa, Bankel, Lorenz, Hiltbrunner, Stefanie, Rechsteiner, Markus, Rüschoff, Jan H, Rushing, Elisabeth Jane, Britschgi, Christian, Curioni-Fontecedro, Alessandra

المساهمون: University of Zurich, Curioni-Fontecedro, Alessandra

مصطلحات موضوعية: Proto-Oncogene Proteins B-raf, Cancer Research, Lung Neoplasms, DNA Copy Number Variations, 610 Medicine & health, Genomics, Proto-Oncogene Proteins c-met, B7-H1 Antigen, Proto-Oncogene Proteins p21(ras), Oncology, Carcinoma, Non-Small-Cell Lung, 10049 Institute of Pathology and Molecular Pathology, Mutation, 10032 Clinic for Oncology and Hematology, Humans, 2736 Pharmacology (medical), Pharmacology (medical), 2730 Oncology, 1306 Cancer Research

الوصف: Mesenchymal-to-epithelial transition (MET) exon 14 skipping mutations and MET gene amplification occur in 3-5% of non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKIs) targeting MET alterations have shown promising results in these patients.The aim of this study was to describe the genomic profile, PD-L1 expression and clinicopathological features of MET dysregulated NSCLC.We identified 188 patients with advanced-stage NSCLC with data on MET expression by immunohistochemistry (IHC). IHC for PD-L1 expression was performed in 131 patient samples, and next-generation sequencing (NGS) analysis was performed in 109 patient samples.MET exon 14 skipping alterations were identified in 16 (14.7%) samples, MET amplifications with cut-off ≥4 copy number variations were identified in 11 (10.1%) samples, and an oncogenic MET mutation (MET p.D1228N) was identified in 1 (0.9%) sample. 12/15 tumors (80.0%) harboring MET exon 14 alterations and 7/11 (63.6%) MET-amplified tumors expressed PD-L1 in ≥1% of tumor cells. Tumors harboring MET exon 14 skipping alterations expressed PD-L1 more frequently than MET wild-type IHC-positive tumors (p = 0.045). Twenty-five percent of MET exon 14-altered cases and 33% of MET-amplified cases harbored potentially targetable oncogenic co-mutations in KRAS, BRAF, and EGFR. The most frequent co-occurring mutations in all MET-altered tumors were TP53, KRAS, BRAF, and CDK4.We demonstrated that MET exon 14 skipping alterations and MET amplification are not mutually exclusive to other oncogenic co-mutations, and report the association of genomic MET alterations with PD-L1 expression. Since genomic MET alterations are emerging targets requiring upfront treatment, optimal understanding of the co-mutational landscape for this patient population is needed.

وصف الملف: s11523_022_00918_6.pdf - application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a1f073ff4371173c179b55963effa647Test
https://www.zora.uzh.ch/id/eprint/222020Test/

المؤلفون: Holger Moch, Marlene Thomas, Andreas Beringer, Ethan Sokol, Alwin Krämer, Jeffrey S. Ross, Ferran Losa, Giulia Baciarello, Julia A. Elvin, Dexter X. Jin, Linda Mileshkin, Nhu Ngo

المساهمون: University of Zurich

المصدر: The Oncologist

مصطلحات موضوعية: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Cancer Diagnostics and Molecular Pathology, Lung Neoplasms, medicine.medical_treatment, 610 Medicine & health, Targeted therapy, law.invention, Loss of heterozygosity, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, 10049 Institute of Pathology and Molecular Pathology, Proto-Oncogene Proteins, ROS1, Carcinoma, Biomarkers, Tumor, Medicine, Unknown primary tumors, Genetic profiling, Humans, Molecular targeted therapy, Retrospective Studies, business.industry, Gene Expression Profiling, Microsatellite instability, Genomics, Protein-Tyrosine Kinases, medicine.disease, Clinical trial, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Adenocarcinoma, Neoplasms, Unknown Primary, business

الوصف: Background Carcinoma of unknown primary origin (CUP) accounts for 2%–5% of newly diagnosed advanced malignancies, with chemotherapy as the standard of care. CUPISCO (NCT03498521) is an ongoing randomized trial using comprehensive genomic profiling (CGP) to assign patients with CUP to targeted or immunotherapy treatment arms based on genomic profiling. We performed a retrospective analysis of CUP cases referred for CGP to determine how many were potentially eligible for enrollment into an experimental CUPISCO arm. Materials and Methods Centrally reviewed adenocarcinoma and undifferentiated CUP specimens in the FoundationCore database were analyzed using the hybrid capture‐based FoundationOne CDx assay (mean coverage, >600×). Presence of genomic alterations, microsatellite instability (MSI), tumor mutational burden (TMB), genomic loss of heterozygosity (gLOH), and programmed death‐ligand 1 (PD‐L1) positivity were determined. Results A total of 96 of 303 patients (31.7%) could be matched to an experimental CUPISCO arm. Key genomic alterations included ERBB2 (7.3%), PIK3CA (6.3%), NF1 (5.6%), NF2 (4.6%), BRAF (4.3%), IDH1 (3.3%), PTEN, FGFR2, EGFR (3.6% each), MET (4.3%), CDK6 (3.0%), FBXW7, CDK4 (2.3% each), IDH2, RET, ROS1, NTRK (1.0% each), and ALK (0.7%). Median TMB was 3.75 mutations per megabase of DNA; 34 patients (11.6%) had a TMB ≥16 mutations per megabase. Three patients (1%) had high MSI, and 42 (14%) displayed high PD‐L1 expression (tumor proportion score ≥50%). gLOH could be assessed in 199 of 303 specimens; 19.6% had a score of >16%. Conclusions Thirty‐two percent of patients would have been eligible for targeted therapy in CUPISCO. Future studies, including additional biomarkers such as PD‐L1 positivity and gLOH, may identify a greater proportion potentially benefiting from CGP‐informed treatment. Clinical trial identification number. NCT03498521 Implications for Practice The findings of this retrospective analysis of carcinoma of unknown primary origin (CUP) cases validate the experimental treatment arms being used in the CUPISCO study (NCT03498521), an ongoing randomized trial using comprehensive genomic profiling to assign patients with CUP to targeted or immunotherapy treatment arms based on the presence of pathogenic genomic alterations. The findings also suggest that future studies including additional biomarkers and treatment arms, such as programmed death‐ligand 1 positivity and genomic loss of heterozygosity, may identify a greater proportion of patients with CUP potentially benefiting from comprehensive genomic profiling‐informed treatment.
This article focuses on the ability of comprehensive genomic profiling to identify potentially targetable genetic alterations in cancers of unknown primary, based on the inclusion criteria for the CUPISCO clinical trial and aiming for more effective therapeutic options for patients.

وصف الملف: Ross_onco.13597.pdf - application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9a38f83a4848676e9d8a5048d7c48d41Test
http://europepmc.org/articles/PMC7930409Test

المؤلفون: Xiaoyu Qu, David W. Woolston, Jerry P. Radich, Min Fang, Olga Sala-Torra, Cecilia Yeung

المصدر: Cancer Medicine
Cancer Medicine, Vol 10, Iss 16, Pp 5629-5642 (2021)

مصطلحات موضوعية: Adult, Male, Cancer Research, DNA Mutational Analysis, next‐generation sequencing, Antineoplastic Agents, Computational biology, Biology, DNA sequencing, chemistry.chemical_compound, Young Adult, molecular pathology, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Gene expression, medicine, Humans, Radiology, Nuclear Medicine and imaging, Multiplex, RNA-Seq, Gene, RC254-282, Research Articles, Cancer Biology, Aged, Oligonucleotide Array Sequence Analysis, medicine.diagnostic_test, leukemia, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RNA, Chromosome, Middle Aged, Oncology, chemistry, Drug Resistance, Neoplasm, Mutation, Female, Gene Fusion, RT‐qPCR, DNA, Fluorescence in situ hybridization, Research Article

الوصف: Background Comprehensive molecular and cytogenetic profiling of acute lymphoblastic leukemia (ALL) is important and critical to the current standard of care for patients with B‐acute lymphoblastic leukemia (B‐ALL). Here we propose a rapid process for detecting gene fusions whereby FusionPlex RNA next‐generation sequencing (NGS) and DNA chromosome genomic array testing (CGAT) are combined for a more efficient approach in the management of patients with B‐ALL. Methods We performed RNA NGS and CGAT on 28 B‐ALL samples and, in four patients, compared fixed cell pellets to paired cryo‐preserved samples as a starting material to further assess the utility of cytogenetic fixed pellets for gene expression analysis. Results Among the fixed specimens, when using alternative techniques as references, including karyotype, fluorescence in situ hybridization, CGAT, and RT‐qPCR, fusions were detected by RNA NGS with 100% sensitivity and specificity. In the four paired fixed versus fresh cryopreserved samples, fusions were also 100% concordant. Four of the 28 patients showed mutations that were detected by RNA sequencing and three of four of these mutations had well‐known drug resistance implications. Conclusions We conclude that FusionPlex is a robust and reliable anchored multiplex RNA sequencing platform for use in the detection of fusions in both fresh cryopreserved and cytogenetic fixed pellets. Gene expression data could only be obtained from fresh samples and although limited variant data are available, critical hotspot variants can be determined in conjunction with the fusions.
This study describes a novel RNA next‐generation sequencing assay used in tandem with chromosomal genomic array testing upon fixed cell pellets typically used for cytogenetic studies to detect the molecular profiles of B‐acute lymphoblastic leukemia.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bbb85fa84f8291e3e143f1d12aadca8aTest
http://europepmc.org/articles/PMC8366081Test

المؤلفون: Rodolfo Montironi, Antonio Lopez-Beltran, Alessia Cimadamore, Liang Cheng

المصدر: Human Pathology. 113:67-83

مصطلحات موضوعية: 0301 basic medicine, medicine.medical_specialty, precision medicine, DNA Mutational Analysis, Antineoplastic Agents, Translational research, Disease, Pathology and Forensic Medicine, Genetic Heterogeneity, taxonomy, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Molecular genetics, Biomarkers, Tumor, Humans, Medicine, Genetic Predisposition to Disease, Molecular Targeted Therapy, Pathology, Molecular, Urothelium, Bladder cancer, heterogeneity, molecular classification, molecular genetics, Urinary bladder, business.industry, Molecular pathology, Carcinoma, Prognosis, Precision medicine, medicine.disease, Immunohistochemistry, Phenotype, 030104 developmental biology, medicine.anatomical_structure, Urinary Bladder Neoplasms, 030220 oncology & carcinogenesis, Mutation, Cancer research, business

الوصف: Summary The current personalized oncology era has witnessed significant efforts to integrate clinical, pathological, and molecular classifications. The growing need for molecular biomarkers to feed personalized oncology, together with the unprecedented wealth of knowledge on the molecular basis of bladder cancer, has led to a novel approach to this disease, incorporating molecularly generated data in clinical practice for locally advanced or metastatic disease. Translational research allows a better understanding of the early events in the development of urothelial carcinoma in the urinary bladder. Thus, mutations in the KMT2D and KDM6A chromatin-modifying genes confer competitive advantages that drive cells to colonize larger regions of the urothelium. Additional mutations in TP53, PIK3CA, FGFR3, or RB1 genes then trigger the process of malignant transformation in the urothelium. In the current review, we provide an overview of what could be the expected transition from the morphology-based classification to a combined, molecularly enriched reporting of clinically meaningful parameters aiming to promote personalized oncology of urothelial carcinoma.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::91930ac991bdf1dd47a0c5dc04df4ca1Test
https://doi.org/10.1016/j.humpath.2021.04.001Test

المؤلفون: Loudy P Priesterbach-Ackley, Pieter Wesseling, Bjarne Winther Kristensen, Jeanette Krogh Petersen

المصدر: Annals of Oncology, 30(8), 1265. Oxford University Press
Kristensen, B W, Priesterbach-Ackley, L P, Petersen, J K & Wesseling, P 2019, ' Molecular Pathology of Tumors of the Central Nervous System ', Annals of Oncology, vol. 30, no. 8, pp. 1265-1278 . https://doi.org/10.1093/annonc/mdz164Test
Kristensen, B W, Priesterbach-Ackley, L P, Petersen, J K & Wesseling, P 2019, ' Molecular pathology of tumors of the central nervous system ', Annals of Oncology, vol. 30, no. 8, pp. 1265-1278 . https://doi.org/10.1093/annonc/mdz164Test
Annals of Oncology

مصطلحات موضوعية: 0301 basic medicine, Ependymoma, Solitary fibrous tumor, Neoplasms, Germ Cell and Embryonal/diagnosis, 0302 clinical medicine, molecular pathology, glioma, Antineoplastic Combined Chemotherapy Protocols, Molecular Targeted Therapy, Molecular pathology, Brain Neoplasms, Brain, Glioma/diagnosis, Hematology, Neoplasms, Germ Cell and Embryonal, Prognosis, Immunohistochemistry, Gene Expression Regulation, Neoplastic, Survival Rate, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Atypical teratoid rhabdoid tumor, integrated diagnosis, IDH1, embryonal tumor, Reviews, Drug Resistance, Neoplasm/genetics, Antineoplastic Combined Chemotherapy Protocols/pharmacology, medulloblastoma, Biomarkers, Tumor/analysis, 03 medical and health sciences, Glioma, medicine, Biomarkers, Tumor, Journal Article, Humans, Brain/pathology, Hemangiopericytoma, Medulloblastoma, Brain Neoplasms/diagnosis, business.industry, DNA Methylation, medicine.disease, 030104 developmental biology, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic/drug effects, Mutation, Cancer research, business, Molecular Targeted Therapy/methods, CNS tumor

الوصف: Since the update of the 4th edition of the WHO Classification of Central Nervous System (CNS) Tumors published in 2016, particular molecular characteristics are part of the definition of a subset of these neoplasms. This combined ‘histo-molecular’ approach allows for a much more precise diagnosis of especially diffuse gliomas and embryonal CNS tumors. This review provides an update of the most important diagnostic and prognostic markers for state-of-the-art diagnosis of primary CNS tumors. Defining molecular markers for diffuse gliomas are IDH1/IDH2 mutations, 1p/19q codeletion and mutations in histone H3 genes. Medulloblastomas, the most frequent embryonal CNS tumors, are divided into four molecularly defined groups according to the WHO 2016 Classification: wingless/integrated (WNT) signaling pathway activated, sonic hedgehog (SHH) signaling pathway activated and tumor protein p53 gene (TP53)-mutant, SHH-activated and TP53-wildtype, and non-WNT/non-SHH-activated. Molecular characteristics are also important for the diagnosis of several other CNS tumors, such as RELA fusion-positive subtype of ependymoma, atypical teratoid rhabdoid tumor (AT/RT), embryonal tumor with multilayered rosettes, and solitary fibrous tumor/hemangiopericytoma. Immunohistochemistry is a helpful alternative for further molecular characterization of several of these tumors. Additionally, genome-wide methylation profiling is a very promising new tool in CNS tumor diagnostics. Much progress has thus been made by translating the most relevant molecular knowledge into a more precise clinical diagnosis of CNS tumors. Hopefully, this will enable more specific and more effective therapeutic approaches for the patients suffering from these tumors.

وصف الملف: text/plain; application/pdf; image/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::878a37f0fbef4c9facbc0f76ef647cdcTest
https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85072721345&origin=inwardTest

المؤلفون: Aodi Wang, Yusheng Wang, Xiang-Dong Cheng, Pengfei Yu, Ming Yao, Wenjing Liu, Yuan Zhang, Yanfei Yu, Haiyan Wu, Yian Du, Ling Huang

المصدر: The Oncologist

مصطلحات موضوعية: 0301 basic medicine, Oncology, China, Epstein-Barr Virus Infections, Herpesvirus 4, Human, Cancer Research, medicine.medical_specialty, Cancer Diagnostics and Molecular Pathology, ARID1A, Microorganisms, Adenocarcinoma, Gene mutation, medicine.disease_cause, Phosphatidylinositol 3-Kinases, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Asian People, Japan, Stomach Neoplasms, Internal medicine, Republic of Korea, medicine, Humans, Next‐generation sequencing, Mutation, Gastric adenocarcinoma, biology, business.industry, Australia, High-Throughput Nucleotide Sequencing, Microsatellite instability, Cancer, Helicobacter pylori, biology.organism_classification, medicine.disease, Tumor mutational burden, 030104 developmental biology, Trypsin Inhibitor, Kazal Pancreatic, 030220 oncology & carcinogenesis, KRAS, business

الوصف: Introduction Gastric cancer (GC) has a high incidence and mortality rate, especially in East Asians, and about 90% of GCs are adenocarcinomas. Histological and etiological heterogeneity and ethnic diversity make molecular subtyping of GC complicated, thus making it difficult to determine molecular division systems and standard treatment modalities. Limited cohorts from South Korea, Singapore, Australia, and Japan have been studied; however, the mutational landscape of gastric adenocarcinomas in Chinese patients is still unknown. Methods We performed a targeted sequencing panel focusing on cancer‐related genes and tumor‐associated microorganisms of 529 gastric adenocarcinoma samples with matched blood controls. We identified 449 clinically relevant gene mutations. Results Approximately 47.1% of Chinese patients with GC harbored at least one actionable mutation. The top somatic mutations were TP53, ARID1A, LRP1B, PIK3CA, ERBB2, CDH1, KRAS, FAT4, CCNE1, and KMT2D. Truncation mutations of ARID1A, KMT2D, RNF43, TGFBR2, and CIC occurred in patients with high tumor mutational burden. Gene amplifications of ERBB2, CCNE1, CDK12, and CCND1 were detected in patients with low tumor mutational burden. Pathway analysis revealed common gene alterations in the Wnt and PI3K/Akt signaling pathways. The ratio of patients with high microsatellite instability was significantly lower than other cohorts, and high microsatellite instability and Epstein‐Barr virus (EBV)–positive features seemed mutually inclusive in Chinese patients with GC. In 44 (8.3%) patients, 45 germline mutations were identified, among which SPINK1 mutations, all SPINK1 c.194 + 2T > C, were present in 15.9% (7/44) of patients. Microorganisms found in Chinese patients with GC included Helicobacter pylori, EBV, hepatitis B virus, and human papillomavirus types 16 and 18. Conclusion Identification of varied molecular features by targeted next‐generation sequencing provides more insight into patient stratification and offers more possibilities for both targeted therapies and immunotherapies of Chinese patients with GC. Implications for Practice This study investigated the genomic alteration profile of 529 Chinese patients with gastric adenocarcinoma by deep targeting sequencing, which might be the largest Chinese cohort on the genomic research of gastric adenocarcinoma up to now.
Novel molecular targeted therapies for gastric cancer are urgently needed. This article explores the mutational landscape covering somatic, germline, and microorganisms among a cohort of Chinese patients with gastric cancer. Findings provide insight on patient stratification and potential molecular targets, and for developing new treatment strategies for patients in China and worldwide.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::de4e9e600688c6e23786bdffba69e1c0Test
https://doi.org/10.1002/onco.13695Test

المؤلفون: Philipp Ströbel, Cleo-Aron Weis, Berthold Schalke, Djeda Belharazem, Zoran V. Popovic, Sebastian Schölch, Christoph Reißfelder, De-Hyung Lee, Alexander Marx, Yosuke Yamada

المصدر: Virchows Archiv

مصطلحات موضوعية: 0301 basic medicine, Thymoma, Immune checkpoint inhibitors, DNA Mutational Analysis, chemical and pharmacologic phenomena, Biology, medicine.disease_cause, Pathology and Forensic Medicine, Autoimmunity, 03 medical and health sciences, 0302 clinical medicine, AIRE, SMARCA4, hemic and lymphatic diseases, microRNA, Biomarkers, Tumor, medicine, Humans, Pathology, Molecular, neoplasms, Myasthenia gravis, Molecular Biology, Molecular pathology, Point mutation, Microsatellite instability, MicroRNA, Thymus Neoplasms, Cell Biology, General Medicine, medicine.disease, Review and Perspectives, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Cancer research

الوصف: Thymomas exhibit a unique genomic landscape, comprising the lowest on average total mutational burden among adult human cancers; a unique point mutation in the GTF2I gene in WHO type A and AB thymomas (and rarely others); almost unique KMT2A-MAML2 translocations in rare WHO type B2 and B3 thymomas; a unique YAP1-MAML2 translocation in almost all metaplastic thymomas; and unique miRNA profiles in relation to GTF2I mutational status and WHO histotypes. While most thymomas can be diagnosed solely on the basis of morphological features, mutational analyses can solve challenging differential diagnostic problems. No molecular biomarkers have been identified that predict the response of unresectable thymomas to chemotherapy or agents with known molecular targets. Despite the common and strong expression of PDL1 in thymomas, immune checkpoint inhibitors are rarely applicable due to the poor predictability of common, life-threatening autoimmune side effects that are related to the unrivaled propensity of thymomas towards autoimmunity.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::da5bbbd0e833a2a1ea3a9ccdf6277823Test
https://doi.org/10.1007/s00428-021-03068-8Test

المؤلفون: Shinichiro Suzuki, Kazuya Fukuoka, Hisato Kawakami, Soichi Fumita, Kazuhiko Nakagawa, Hidetoshi Hayashi, Chihiro Sato, Kazuko Sakai, Shigeki Shimizu, Tatsuya Okuno, Koji Haratani, Akihiko Ito, Yoshikane Nonagase, Kazumasa Saigoh, Kimio Yonesaka, Hisashi Handa, Takeshi Yoshida, Masayuki Takeda, Tetsuya Mitsudomi, Kazuto Nishio, Takayuki Takahama, Naoki Takegawa, Satomi Watanabe, Kaoru Tanaka

المصدر: The Oncologist

مصطلحات موضوعية: 0301 basic medicine, Oncology, FoundationOne CDx, Cancer Research, medicine.medical_specialty, Cancer Diagnostics and Molecular Pathology, medicine.medical_treatment, medicine.disease_cause, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Japan, Internal medicine, Solid tumors, medicine, Biomarkers, Tumor, Humans, Prospective Studies, Prospective cohort study, Lung cancer, Next‐generation sequencing, business.industry, Microsatellite instability, High-Throughput Nucleotide Sequencing, Therapeutic decision making, medicine.disease, Exact test, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Personalized medicine, KRAS, Neoplasm Recurrence, Local, business

الوصف: Background Implementation of personalized medicine requires the accessibility of tumor molecular profiling in order to allow prioritization of appropriate targeted therapies for individual patients. Our aim was to study the role of comprehensive genomic profiling assays that may inform treatment recommendations for patients with solid tumors. Materials and Methods We performed a prospective study to evaluate the feasibility of application of the FoundationOne CDx panel—which detects substitutions, insertions and deletions, and copy number alterations in 324 genes, select gene rearrangements, and genomic signatures including microsatellite instability and tumor mutation burden (TMB)—to patients with advanced or recurrent solid tumors before its approval in Japan. Results A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%. The median turnaround time was 41 days (range, 21–126 days). The most common known or likely pathogenic variants were TP53 mutations (n = 113), PIK3CA mutations (n = 33), APC mutations (n = 32), and KRAS mutations (n = 29). Among the 153 patients assessed for TMB, the median TMB was 4 mutations/Mb, and tumors with a high TMB (≥10 mutations/Mb) were more prevalent for lung cancer (11/32) than for other solid tumor types (9/121, Fisher's exact test p < .01). No clear trend toward increased efficacy for immune checkpoint inhibitor (ICI) monotherapy or ICI combination chemotherapy in patients with a high programmed cell death–ligand 1 tumor proportion score or a high TMB was apparent. Among the 174 patients found to harbor known or likely pathogenic actionable alterations, 24 individuals (14%) received matched targeted therapy. Conclusion The FoundationOne CDx assay was performed with formalin‐fixed, paraffin‐embedded tumor specimens with a success rate of >95%. Such testing may inform the matching of patients with cancer with investigational or approved targeted drugs. Implications for Practice This prospective cohort study was initiated to investigate the feasibility and utility of clinical application of FoundationOne CDx. A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%, and 24 individuals (14%) received matched targeted therapy.
Comprehensive genomic profiling assays can identify multiple actionable genetic alterations that may inform treatment recommendations for patients with solid tumors. This article evaluates the feasibility of the application of the FoundationOne CDx panel to patients with advanced or recurrent solid tumors.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fc318dce87b8526689c6b4d1f95fe532Test
http://europepmc.org/articles/PMC8018334Test

المؤلفون: Paola Vignali, Rossella Elisei, Agnese Proietti, Alessio Basolo, Clara Ugolini, Elisabetta Macerola, Fulvio Basolo, Liborio Torregrossa, Anello Marcello Poma, Ferruccio Santini, Gabriele Materazzi

المصدر: Cancers, Vol 13, Iss 3123, p 3123 (2021)
Cancers
Volume 13
Issue 13

مصطلحات موضوعية: Neuroblastoma RAS viral oncogene homolog, Cancer Research, endocrine system diseases, Gene fusion, Gene mutation, Molecular pathology, Papillary thyroid carcinoma, Pediatric thyroid cancer, 030209 endocrinology & metabolism, pediatric thyroid cancer, medicine.disease_cause, Article, Fusion gene, Thyroid carcinoma, 03 medical and health sciences, 0302 clinical medicine, molecular pathology, medicine, gene mutation, Pathological, RC254-282, Mutation, business.industry, Point mutation, gene fusion, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, humanities, Oncology, 030220 oncology & carcinogenesis, Cancer research, papillary thyroid carcinoma, business

الوصف: Papillary thyroid carcinoma (PTC) presents distinct clinico-pathological and molecular differences in children compared with adult patients. Whether the presence of rearrangements or point mutations is associated with aggressive PTC clinical presentation is still controversial. In this study, PTCs diagnosed in patients aged less than 18 years were retrospectively searched from the institutional archive and tumor tissue was tested for point mutations in BRAF and RAS genes and for rearrangements in RET, NTRK1, NTRK3, ALK, PPARG, BRAF and THADA. A total of 163 PTCs were analyzed. Point mutations were found in 83 (51%) and gene fusions in 48 cases (30%). The most frequent alteration was the BRAFV600E mutation (36.8%), followed by NTRK3 fusion (11%), NRAS mutation (10.4%) and RET fusion (10.4%). Fusion-driven PTCs showed more frequently infiltrative growth, larger tumors, extrathyroidal extension and N1b disease. PTCs showing solid growth pattern were significantly enriched in gene fusions. This is one of the largest cohorts of pediatric PTCs. Fusion-driven tumors most frequently show aggressive pathological features
the search for rearrangements, especially in tumors with solid areas, could improve the characterization of pediatric PTCs and offer possible therapeutic options.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::624e9eaf50f614912f5d98688d70c8e4Test
https://www.mdpi.com/2072-6694/13/13/3123Test

المؤلفون: Weifeng Wang, Xinyu Chen, Jian Wang, Yun Guo, Kai Wang, Samuel J. Klempner, Jiaochun Shi, Min Xiao, Shuang Wang, Xian-Ling Guo

المصدر: The Oncologist

مصطلحات موضوعية: Male, 0301 basic medicine, Oncology, China, Cancer Research, medicine.medical_specialty, Cancer Diagnostics and Molecular Pathology, DNA Copy Number Variations, Receptor, ErbB-2, Colorectal cancer, medicine.disease_cause, Fusion gene, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, ERBB2 amplification, Copy-number variation, Receptor, trkA, Poly-ADP-Ribose Binding Proteins, Indel, neoplasms, Gene, business.industry, Microsatellite instability, DNA Polymerase II, Genomics, Middle Aged, medicine.disease, DNA polymerase ε, Tumor mutational burden, digestive system diseases, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Cohort, Tropomyosin receptor kinase, Female, Microsatellite Instability, KRAS, Colorectal Neoplasms, business

الوصف: Background The increasing molecular characterization of colorectal cancers (CRCs) has spurred the need to look beyond RAS, BRAF, and microsatellite instability (MSI). Genomic alterations, including ERBB2 amplifications and mutations, POLE mutations, MSI, and NTRK1–3 fusions, have emerged as targets for matched therapies. We sought to study a clinically annotated Chinese cohort of CRC subjected to genomic profiling to explore relative target frequencies. Methods Tumor and matched whole blood were collected from 609 Chinese patients with CRC. Extracted DNA was analyzed for all classes of genomic alterations across 450 cancer‐related genes, including single‐nucleotide variations (SNVs), short and long insertions and deletions (indels), copy number variations, and gene rearrangements. Next‐generation sequencing–based computational algorithms also determined tumor mutational burden and MSI status. Results Alterations in TP53 (76%), APC (72%), and KRAS (46%) were common in Chinese patients with CRC. For the first time, the prevalence of NTRK gene fusion was observed to be around 7% in the MSI‐high CRC cohort. Across the cohort, MSI was found in 9%, ERBB2 amplification in 3%, and POLE pathogenic mutation in 1.5% of patients. Such results mostly parallel frequencies observed in Western patients. However, POLE existed at a higher frequency and was associated with large tumor T‐cell infiltration. Conclusion Comparing to the Western counterparts, POLE mutations were increased in our cohort. The prevalence of NTRK gene fusion was around 7% in the MSI‐high CRC cohort. Increased adoption of molecular profiling in Asian patients is essential for the improvement of therapeutic outcomes. Implications for Practice The increasing use of genomic profiling assays in colorectal cancer (CRC) has allowed for the identification of a higher number of patient subsets benefiting from matched therapies. With an increase in the number of therapies, assays simultaneously evaluating all candidate biomarkers are critical. The results of this study provide an early support for the feasibility and utility of genomic profiling in Chinese patients with CRC.
The emergence of precision medicine has identified genomic variants, such as NTRK gene fusion, microsatellite instability (MSI), HER2 amplification, and POLE pathogenic mutation, as potential agonistic biomarkers for immune or targeted therapies. This article examines NTRK, HER2, and POLE in a cohort of Chinese patients with colorectal cancer.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::470570bd1c4c8a8e6727614425b574e3Test
https://doi.org/10.1634/theoncologist.2020-0356Test