Sarcoma treatment in the era of molecular medicine

EMBO Molecular Medicine, Journal Year: 2020, Volume and Issue: 12(11)

Published: Oct. 13, 2020

Review13 October 2020Open Access Sarcoma treatment in the era of molecular medicine Thomas GP Grünewald Corresponding Author [email protected] orcid.org/0000-0003-0920-7377 Max-Eder Research Group for Pediatric Biology, Institute Pathology, Faculty Medicine, LMU Munich, Germany Division Translational Research, German Cancer Center (DKFZ), Hopp Children's (KiTZ), Consortium (DKTK), Heidelberg, Heidelberg University Hospital, Search more papers by this author Marta Alonso orcid.org/0000-0002-7520-7351 Program Solid Tumors and Biomarkers, Foundation Applied Medical Navarra Pamplona, Spain Sofia Avnet Orthopedic Pathophysiology Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy Ana Banito Soft Tissue Group, Stefan Burdach Department Pediatrics (CCRC), Technische Universität München, Florencia Cidre-Aranaz orcid.org/0000-0002-0246-7179 Gemma Di Pompo Martin Distel Institute, Vienna, Austria Heathcliff Dorado-Garcia Oncology/Hematology, Charité-Universitätsmedizin Berlin, Javier Garcia-Castro Cellular Biotechnology Instituto de Salud Carlos III, Madrid, Laura González-González Agamemnon E Grigoriadis Centre Craniofacial King's College London, UK Merve Kasan Christian Koelsche Manuela Krumbholz Pediatrics, Erlangen, Fernando Lecanda Oncology, Adhesion Metastasis Laboratory, Navarra, Silvia Lemma Dario L Longo Biostructures Bioimaging (IBB), Italian National Council (CNR), Turin, Claudia Madrigal-Esquivel Oncology Metabolism, Sheffield, Álvaro Morales-Molina Julian Musa General, Visceral Transplantation Surgery, Shunya Ohmura Benjamin Ory Université Nantes, Inserm, U1238, France Miguel Pereira-Silva Pharmaceutical Technology, Pharmacy, Coimbra, Portugal Francesca Perut Rene Rodriguez orcid.org/0000-0002-0768-7306 Investigación Sanitaria del Principado Asturias, Oviedo, CIBER en oncología (CIBERONC), Carolin Seeling Ulm University, Ulm, Nada Al Shaaili Shabnam Shaabani Drug Design, Groningen, The Netherlands Kristina Shiavone Snehadri Sinha Oral Maxillofacial Diseases, Helsinki, Finland Eleni M Tomazou Marcel Trautmann orcid.org/0000-0002-5842-1196 Gerhard-Domagk-Institute Münster Münster, Maria Vela Hospital La Paz Health (IdiPAZ), Yvonne MH Versleijen-Jonkers Radboud Center, Nijmegen, Julia Visgauss Duke Durham, NC, USA Zalacain Sebastian J Schober Andrej Lissat Children′s Zurich – Eleonoren Foundation, Kanton Zürich, Switzerland William R English Nicola Baldini orcid.org/0000-0003-2228-3833 Biomedical Neuromotor Sciences, Dominique Heymann orcid.org/0000-0001-7777-0669 Institut Cancérologie l'Ouest, Tumor Heterogeneity Precision Saint-Herblain, Information *,1,2,3, Alonso4, Avnet5, Banito6, Burdach7, Cidre-Aranaz1, Pompo5, Distel8, Dorado-Garcia9, Garcia-Castro10, González-González10, Grigoriadis11, Kasan1, Koelsche3, Krumbholz12, Lecanda13, Lemma5, Longo14, Madrigal-Esquivel15, Morales-Molina10, Musa1,16, Ohmura1, Ory17, Pereira-Silva18, Perut5, Rodriguez19,20, Seeling21, Shaaili15, Shaabani22, Shiavone15, Sinha23, Tomazou8, Trautmann24, Vela25, Versleijen-Jonkers26, Visgauss27, Zalacain14, Schober7, Lissat28, English15, *,5,29 *,15,30 1Max-Eder 2Division 3Institute 4Program 5Orthopedic 6Pediatric 7Department 8Children's 9Department 10Cellular 11Centre 12Department 13Division 14Institute 15Department 16Department 17Université 18Department 19Instituto 20CIBER 21Institute 22Department 23Department 24Division 25Hospital 26Department 27Medical 28University 29Department 30Université *Corresponding author. Tel: +49 6221 42 3718; E-mail: +39 (0) 516 366 549; +33 240 679 841; EMBO Mol Med (2020)12:e11131https://doi.org/10.15252/emmm.201911131 See Glossary abbreviations used article. PDFDownload PDF article text main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Sarcomas are heterogeneous clinically challenging soft tissue bone cancers. Although constituting only 1% all human malignancies, sarcomas represent second most common type solid tumors children adolescents comprise an important group secondary malignancies. More than 100 histological subtypes have been characterized date, many being discovered due profiling. Owing their mostly aggressive biological behavior, relative rarity, occurrence at virtually every anatomical site, sarcoma particular difficult-to-treat categories. Current multimodal concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements enabled a precise characterization revealed novel therapeutic targets prognostic/predictive biomarkers. This review aims providing comprehensive overview latest advances biology effects on clinical oncology; it is meant broad readership ranging from novices experts field sarcoma. stem cells (CSCs) Cells within tumor found very small fractions that thought be responsible resistance cancer treatments thus relapse. Cell dormancy Stage progression during which cease dividing but survive quiescent state while waiting appropriate environmental conditions. Chorioallantoic Membrane (CAM) models Chick embryo CAM study formation, angiogenesis, metastasis. Circulating (CTCs) leak into vasculature or lymphatics primary carried around body blood circulation. Epigenomic alterations Heritable change does not affect DNA sequence results gene expression. Extracellular vesicles (EVs) Heterogeneous family generated different subcellular compartments released extracellular space Genomic Permanent modifications including somatic mutations, copy-number variations (CNVs), fusions. Immunotherapy Type aids immune system fight tumors. Oncolytic viruses Viruses that, intrinsic properties through genetic engineering, specifically replicate kill cells. Orthotopic xenografts Animal based injection cell lines location where typically appear humans. Patient-derived (PDXs) model transplantation biopsies encompass TME immunodeficient animals. arise between 0–14 years age. Approach patient care allows physicians select likely help patients understanding disease. Malignant neoplasms originate skeleton tissues. microenvironment (TME) environment reside encompassing matrix stromal (endothelial cells, fibroblasts, cells) Epidemiology rare among adult they 12–15% pediatric (Stiller et al, 2013). Despite implementation continuous optimization therapies, one-third still succumb Historically, clustered two large subgroups, according site occurrence—sarcomas tissues (hereafter referred as "bone sarcomas" "soft [STSs], respectively). Both subgroups variety subtypes, recent technological decipher constantly increasing number level (Fig 1; Baldauf 2018a; Watson 2018; Weidema 2020). Table 1 summarizes major discussed features. Figure 1. Diversity highlighted methylation profilingt-distributed stochastic neighbor embedding (t-SNE) plot n = 18 genome-wide profiling Illumina EPIC arrays (Koelsche 2018a,b). Web-link classifier: www.molecularsarcomapathology.org. Download figure PowerPoint Main characteristics subtype Abbreviation features Bone Chondrosarcomaa CHS Localization: Cartilage, surface, centrally Histopathology: Lobules composed malignant chondrocytes entrapped chondroid with calcified foci Identified mutations IDH1/2, EXT1/2 Ewing sarcomaa EwS Long flat bones (˜85%), extraskeletal sites (˜15%) Undifferentiated round cells; strong membranous CD99 immunoreactivity PAS-positive cytoplasm Harbor FET-ETS translocations (˜85% EWSR1-FLI1; ˜10% EWSR1-ERG; ˜5% subtypes) Osteosarcomaa OS surface Neoplastic mesenchymal morphology frequent polymorphism (epithelioid, fusiform, round, spindled, etc.) associated osteoid Various telangiectatic numerous hemorrhagic areas Complex highly aneuploidy karyotypes multiple chromosomal aberrations (numerical structural) Frequent TP53 RB other defining "BRCAness" signature (STSs) Fibrosarcomaa Deep extremities, trunk, head neck Composed monomorphic fibroblastic collagenous GastroIntestinal Stromal GIST Gastrointestinal track (main site: stomach intestine) morphological spectrum mainly spindle epithelioid (˜20% cases) mixed histology differentiation toward interstitial Cajal. Usually immunopositive CD117 (KIT) DOG1 activating KIT PDGFRA Leiomyosarcoma LMS Most commonly detected peritoneum uterus (rarely bone) Mesenchymal, spindle-shaped smooth muscle (SMA, desmin h-Caldesmon positivity) Highly complex genomic instability Liposarcomaa LPS Variable (most retroperitoneal space) variable adipocytic heterogenous embedded vascularized stroma (in case myxoid stroma) Rhabdomyosarcoma RMS Mesenchymal phenotype myogenic (usually positive myogenin MYOD) pleomorphic UPS frequently extremities high degree cellular atypia pleomorphism Synovial SS Mostly deep Spindle epithelial (i.e., monophasic/biphasic SS) specific SS18-SSX1/2/4 fusion oncogenes STS (WHO Classification Tumours: Tumours, Among sarcomas, osteosarcoma (OS) (Heymann, 2014). primarily affects young adults, first largest peak incidence age ~10–14 years. Coinciding pubertal growth spurt, rate 4 (3.5–4.6) range 5 (4.6–5.6) 0–19 per year million persons (Ottaviani Jaffe, 2009). current standard was introduced late 1970s remains largely unaltered despite efforts improve outcomes (Rosen 1976). Nowadays, localized disease face 5-year overall survival rates < 70%, 20% who develop metastatic relapse > 3 (Roberts 2019). (EwS) included because both (~85% (~15% cases), has similar OS. subgroup comprises ~70–80% 70 STSs cancers, highest Overall, estimated ~57–62% can vary widely depending stage interplay (Lyu Unfortunately, epidemiological data limited incomplete. initiatives ongoing databases, will benefit use "big data"

Language: Английский

---

Circulating biomarkers for early detection and clinical management of colorectal cancer

Molecular Aspects of Medicine, Journal Year: 2019, Volume and Issue: 69, P. 107 - 122

Published: June 14, 2019

New non-invasive approaches that can complement and improve on current strategies for colorectal cancer (CRC) screening management are urgently needed. A growing number of publications have documented components tumors, which shed into the circulation, be detected in form liquid biopsies used to detect CRC at early stages, predict response certain therapies recurrence a minimally invasive way. The analysis circulating tumor DNA (ctDNA), tumor-derived cells (CTC, cells) or microRNA (miRNA) blood other body fluids, great potential different aspects management. challenge now is find types components, biofluids detection methods would most suitable applied steps treatment. This chapter will provide an up date review ctDNA, CTCs miRNAs as new biomarkers CRC, either clinical detection, highlighting their advantages limitations.

Language: Английский

---

Inference of transcription factor binding from cell-free DNA enables tumor subtype prediction and early detection

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Oct. 11, 2019

Deregulation of transcription factors (TFs) is an important driver tumorigenesis, but non-invasive assays for assessing factor activity are lacking. Here we develop and validate a minimally invasive method TF based on cell-free DNA sequencing nucleosome footprint analysis. We analyze whole genome data >1,000 samples from cancer patients healthy controls using bioinformatics pipeline developed by us that infers accessibility binding sites fragmentation patterns. observe patient-specific as well tumor-specific patterns, including accurate prediction tumor subtypes in prostate cancer, with clinical implications the management patients. Furthermore, show profiling capable detection early-stage colorectal carcinomas. Our approach mapping vivo blood makes key part noncoding amenable to

Language: Английский

---

Cell-Free DNA and Apoptosis: How Dead Cells Inform About the Living

Trends in Molecular Medicine, Journal Year: 2020, Volume and Issue: 26(5), P. 519 - 528

Published: Feb. 17, 2020

Language: Английский

---

Orientation-aware plasma cell-free DNA fragmentation analysis in open chromatin regions informs tissue of origin

Genome Research, Journal Year: 2019, Volume and Issue: 29(3), P. 418 - 427

Published: Feb. 26, 2019

Cell-free DNA (cfDNA) in human plasma is a class of biomarkers with many current and potential future diagnostic applications. Recent studies have shown that cfDNA molecules are not randomly fragmented possess information related to their tissues origin. Pathologies causing death cells from particular result perturbations the relative distribution affected tissues. Such tissue-of-origin analysis particularly useful development liquid biopsies for cancer. It therefore value accurately determine contributions pool simultaneous manner. In this work, we report open chromatin regions, show characteristic fragmentation patterns reflected by sequencing coverage imbalance differentially phased fragment end signals. The latter refers differences read densities sequences corresponding orientation upstream downstream ends relation reference genome. preferentially occur tissue-specific regions where contributed into plasma. Quantitative analyses such signals allow measurement various toward pool. These findings were validated data obtained pregnant women, organ transplantation recipients, cancer patients. Orientation-aware has applications noninvasive prenatal testing, monitoring, biopsy.

Language: Английский

---