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Integrated pathway analysis identifies a 3-gene signature predicting platinum response and outcome of high-grade serous ovarian carcinoma patientsEliana Bignotti1,2u00a7, Giuseppe Benvenuto3u00a7, Lara Paracchini4u00a7, Laura Zanotti1, Chiara Romani1,5, Germana Tognon2, Enrica Calura3, Debora Vicini6, Marco Adorni6, Maria Chiara Paderno6, Tommaso Bianchi6, Franco E. Odicino7, Enrico Sartori7, Antonella Ravaggi1, Maurizio Du2019Incalci4, Paola Todeschini1*, Sergio Marchini4*, Chiara Romualdi 3* 1'Angelo Nocivelli' Institute of Molecular Medicine, University of Brescia and ASST-Spedali Civili of Brescia, Brescia, Italy; 2Division of Obstetrics and Gynecology, ASST Spedali Civili di Brescia, Brescia, Italy; 3Department of Biology, University of Padova, Padova, Italy; 4Department of Oncology, IRCCS - u201cMario Negriu201d Institute for Pharmacological Research, Milano, Italy; 5Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; 6Clinic of Obstetrics and Gynecology, University of Milano Bicocca, San Gerardo Hospital, Monza, Italy; 7Department of Clinical and Experimental Sciences, Division of Obstetrics and Gynecology University of Brescia, Brescia, Italy.u00a7EB, GB and LP contribute equally to this work*PT, SM and CR are co-last authorsIntroduction/BackgroundHigh-grade serous ovarian carcinoma (HGSOC), the most common and deadly epithelial ovarian cancer histotype is characterized by a heterogeneous genomic landscape. After surgery, all patients are treated with adjuvant platinum (Pt)-based chemotherapy to which the response is heterogeneous, ranging from cases sensitive (Platinum-sensitive, Pt-s cases), to intrinsically resistant patients, who relapse within 6 months from the end of therapy (Pt-resistant, Pt-r). The aim of the study was to investigate the mechanisms characterizing the biology of primary resistance to upfront Pt-based chemotherapy through an integrated pathway analysis.MethodologyGene and miRNA microarray experiments were carried out on 36 Pt-s and 41 Pt-r tumor samples. Gene and miRNA expression have been integrated using Micrographite algorithm. Expression levels of selected predictive and prognostic genes were validated on a total of 242 HGSOC samples by qRT-PCR and on the Curated Ovarian Database (including 838 HGSOC).ResultsExpression profiles of 131 mRNAs and five miRNAs, belonging to five different and functionally-related molecular pathways, discriminate Pt-s and Pt-r cases. We selected 23 elements of the networks for orthogonal validation and 19 coding genes confirmed as differentially expressed between Pt-r and Pt-s cases. Among them, 16 elements also showed independent prognostic value in terms of PFS and OS in multivariate analysis. The prognostic impact of this signature was in silico validated on the Curated Ovarian Database, resulting in a 3-gene signature as independent prognostic biomarker of survival for HGSOC.ConclusionIn the current study, we used an integrated pathway analysis on miRNA and gene expression signatures to capture the key pathways shaping the different biology of Pt-r and Pt-s tumors, validating our results using two independent cohorts of HGSOC biopsies. Finally, we investigated the association of the validated signature with survival across multiple HGSOC databases. This strategy identified a three-gene signature with predictive and prognostic impact in HGSOC.
This book comprehensively summarizes the biology, etiology, and pathology of ovarian cancer and explores the role of deep molecular and cellular profiling in the advancement of precision medicine. The initial chapter discusses our current understanding of the origin, development, progression and tumorigenesis of ovarian cancer. In turn, the book highlights the development of resistance, disease occurrence, and poor prognosis that are the hallmarks of ovarian cancer. The book then reviews the role of deep molecular and cellular profiling to overcome challenges that are associated with the treatment of ovarian cancer. It explores the use of genome-wide association analysis to identify genetic variants for the evaluation of ovarian carcinoma risk and prognostic prediction. Lastly, it highlights various diagnostic and prognostic ovarian cancer biomarkers for the development of molecular-targeted therapy.
In an era of promising advances in cancer research, there are considerable and even alarming gaps in the fundamental knowledge and understanding of ovarian cancer. Researchers now know that ovarian cancer is not a single disease-several distinct subtypes exist with different origins, risk factors, genetic mutations, biological behaviors, and prognoses. However, persistent questions have impeded progress toward improving the prevention, early detection, treatment, and management of ovarian cancers. Failure to significantly improve morbidity and mortality during the past several decades is likely due to several factors, including the lack of research being performed by specific disease subtype, lack of definitive knowledge of the cell of origin and disease progression, and incomplete understanding of genetic and non-genetic risk factors. Ovarian Cancers examines the state of the science in ovarian cancer research, identifies key gaps in the evidence base and the challenges to addressing those gaps, considers opportunities for advancing ovarian cancer research, and examines avenues for translation and dissemination of new findings and communication of new information to patients and others. This study makes recommendations for public- and private-sector efforts that could facilitate progress in reducing the incidence of morbidity and mortality from ovarian cancers.
This book provides the readers with an up-to-date review of the design, structure and function of a representative selection of fibrous proteins in both health and disease. The importance of the α-helical coiled coil, a conformational motif based on the heptad repeat in the amino acid sequence of all α-fibrous proteins (and parts of some globular proteins) is underlined by three Chapters devoted to its design, structure, function and topology. Specific proteins covered in the text and which depend on the coiled coil for their structure and function, include the intermediate filament proteins, tropomyosin, myosin, paramyosin, fibrin and members of the spectrin superfamily. Also described are fibrous proteins based on the β-pleated sheet and collagen conformations. Recombinant structural proteins, especially of silk and collagen, are discussed in the context of developing new biomaterials with varied applications. Established researchers and postgraduate students in the fields of protein chemistry, biochemistry and structural biophysics will find Fibrous Proteins: Structures and Mechanisms to be an invaluable collection of topical reviews that describe the basic advances made in the field of fibrous proteins over the past decade. This book, written by recognized authorities in the field, provides a clear account of the current status of fibrous protein research and, in addition, establishes the basis for deciding the most appropriate directions for future activity, including the applications of protein engineering and the commercial exploitation of new biomaterials.
Ovarian cancer management is a rapidly changing field with new treatment agents available as a result of a greater understanding of the pathogenesis of this disease. In addition, both surgical and chemotherapeutic treatment strategies are evolving to maximise response in this disease. This book brings together leading specialists from around the world to discuss and outline a variety of new concepts in ovarian cancer, ranging from molecular biology and genetics through screening to both surgical and chemotherapeutic management.
WHO Classification of Tumours of Female Reproductive Organs is the sixth volume in the 4th Edition of the WHO series on histological and genetic typing of human tumours. This authoritative, concise reference book provides an international standard for oncologists and pathologists and will serve as an indispensable guide for use in the design of studies monitoring response to therapy and clinical outcome. Diagnostic criteria, pathological features, and associated genetic alterations are described in a strictly disease-oriented manner. Sections on all recognized neoplasms and their variants include new ICD-O codes, epidemiology, clinical features, macroscopy, pathology, genetics, and prognosis and predictive factors. The book, prepared by 91 authors from 19 countries, contains more than 400 colour images and tables, and more than 2100 references
Epithelial ovarian cancer (EOC) is the most lethal gynecological disorder due to a lack of effective early detection strategies. Worldwide, approximately 230,000 women are diagnosed annually, whereas 150,000 die. It represents the seventh most commonly diagnosed cancer among women in the world with 5-year survival rate of 46%. More than one-fifth of EOC have been related to hereditary conditions. Considerable efforts have been made to implement screening of the general population to diagnose EOC early; nevertheless, this has been ineffective and there is no approved strategy. Nowadays, new approaches for early diagnosis and prevention based on molecular genomics are in development. Whole genome sequencing has established the potency of the somatic genome, characterised with diverse DNA repair deficiencies that can be used to stratify EOCs into distinct biological groups with predictive signatures of resistance or relapse. The incorporation of next-generation sequencing (NGS) into clinical practice remains challenging for two reasons. Firstly, the EOC risk is not clear for some of the included genes and secondly, the variant of uncertain significance rates increase as more genes are analyzed. Finally, beyond germline pathogenic variants, somatic mutations may also affect therapeutic choices, and as such upfront tumor sequencing may be equally important to NGS, particularly as we continue to challenge treatment paradigms in the first‐line management of EOC.
This contributed volume offers a comprehensive and detailed overview of the various aspects of long non-coding RNAs and discusses their emerging significance. Written by leading experts in the field, it motivates young researchers around the globe, and offers graduate and postgraduate students fascinating insights into genes and their regulation in eukaryotes and higher organisms.
Written with the busy practice in mind, this book delivers clinically focused, evidence-based gynecology guidance in a quick-reference format. It explores etiology, screening, tests, diagnosis, and treatment for a full range of gynecologic health issues. The coverage includes the full range of gynecologic malignancies, reproductive endocrinology and infertility, infectious diseases, urogynecologic problems, gynecologic concerns in children and adolescents, and surgical interventions including minimally invasive surgical procedures. Information is easy to find and absorb owing to the extensive use of full-color diagrams, algorithms, and illustrations. The new edition has been expanded to include aspects of gynecology important in international and resource-poor settings.
This updated second edition of Diagnosis and Management of Ovarian Disorders provides thorough, yet succinct insight into the ever-changing realm of ovarian disorders. It presents a novel multidisciplinary approach to the subject as described by clinicians, surgeons, pathologists, basic scientists and related medical researchers. Topics covered include reproductive technology, early diagnosis of ovarian cancer, and management of menopause among others. The breadth of information provided by this book will appeal to clinicians and researchers involved in the study and treatment of ovarian disorders.KEY FEATURES* Includes updated information on early diagnosis of ovarian cancer* Reviews new diagnostic techniques for ovarian disorders* Discusses latest information on reproductive technology* Presents translational treatment linking laboratory research with clinical medicine