Current Clinical PathologyAntonio Giordano, Md, Phd

SERIES EDITOR

For further volumes:http://www.springer.com/series/7632

Antonio Russo ● Stefano Iacobelli ● Juan IovannaEditors

Diagnostic, Prognostic and Therapeutic Value of Gene Signatures

EditorsAntonio Russo, MD, PhD Section of Medical Oncology Department of Surgical and Oncological SciencesUniversity of PalermoPalermo, Italyantonio.russo@usa.net

Juan Iovanna, MD, PhDINSERM U624Marseille 13288, Franceiovanna@marseille.inserm.fr

Stefano Iacobelli, MDNational Consortium for Research on Cancer (CINBO)University D’AnnunzioChieti 66013, Italyiacobell@unich.it

ISBN 978-1-61779-357-8 e-ISBN 978-1-61779-358-5DOI 10.1007/978-1-61779-358-5Springer New York Dordrecht Heidelberg London

Library of Congress Control Number: 2011937026

© Springer Science+Business Media, LLC 2012All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, c/o Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden.The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights.While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein.

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v

Preface

Gene expression studies have revealed diagnostic profiles and upregulation of specific pathways in many solid tumors. Some gene-expression signatures are already used as predictors of relapse in early breast cancer patients. The explosion of new information in gene expression profiling could potentially lead to the development of tailored treatments in many solid tumors. In addition, many studies are ongoing to validate these signatures also in predicting response to hormonal, chemo-therapeutic, and targeted agents in breast cancer as well as in other tumors.

This book has been carried out with the aim of providing readers a useful and comprehensive resource about the range of applications of microarray technology on oncological diseases.

The book is principally addressed to resident and fellow physicians, medical oncologists, molec-ular biologists, biotechnologists, and those who study oncological diseases. The chapters have been written by leading international researchers on these topics who have prepared their manuscripts according to current literature and field experience with microarray technology.

Palermo, Italy Antonio RussoChieti, Italy Stefano IacobelliMarseille, France Juan Iovanna

vii

Contents

1 Gene Signatures and Soft Tissue Sarcomas: Status of Art and Perspectives ..................................................................................................... 1Bruno Vincenzi, Anna Maria Frezza, Daniele Santini, and Giuseppe Tonini

2 Heterogeneity of Breast Cancer: Gene Signatures and Beyond ................................... 13Gaia Schiavon, Marcel Smid, Gaorav P. Gupta, Stefania Redana, Daniele Santini, and John W.M. Martens

3 Gene Signatures in CRC and Liver Metastasis .............................................................. 27Daniele Fanale, Lidia Corsini, Sergio Rizzo, and Antonio Russo

4 Gene Signatures in Gastrointestinal Stromal Tumors ................................................... 35Piotr Rutkowski, Giuseppe Badalamenti, Laura La Paglia, Joanna Przybył, and Maria Debiec-Rychter

5 Pancreatic Cancer Genetics ............................................................................................. 51Juan Iovanna, Ezequiel Luis Calvo, Jean Charles Dagorn, and Nelson Dusetti

6 Diagnostic, Prognostic, and Therapeutic Value of Gene Signatures in Non-Small Cell Lung Cancer....................................................................................... 81Rafael Rosell, Miquel Taron, Christian Diego Rolfo, Delvys Rodriguez-Abreu, and Jia Wei

7 Gene Signatures in Gastric Cancer ................................................................................. 95Laura Ottini, Mario Falchetti, and Gabriella Nesi

8 Gene Signatures in Colorectal Cancer ............................................................................ 115Alessandro Lugli and Inti Zlobec

9 The Role of Epigenetics in Cancer: From Molecular Function to High-Throughput Assays ............................................................................................. 137Aleksandra Pekowska, Joaquin Zacarias-Cabeza, Jinsong Jia, Pierre Ferrier, and Salvatore Spicuglia

viii Contents

10 Primary Epithelial Ovarian Neoplasms: New Concepts Concerning Origin, Pathogenesis and Classifi cation Based on Morphology, Immunomarkers, Molecular Features, and Gene Expression Studies ........................................................................................... 153Bernard Czernobilsky, Leonor Leider-Trejo, Daniele Fanale, and Antonio Russo

11 Thyroid Carcinoma: Molecular Signature by Histotype-Specifi c Mutations and Gene Expression Patterns ...................................................................... 165Umberto Malapelle, Claudio Bellevicine, Lajos Pustzai, and Giancarlo Troncone

Index ........................................................................................................................................... 179

ix

Contributors

Giuseppe Badalamenti , MD, PhD Section of Medical Oncology , Department of Surgical and Oncological Sciences, University of Palermo , Palermo , Italy

Claudio Bellevicine , MD Scienze Biomorfologiche e Funzionali , Universita degli Studi di Napoli Federico II , Naples , Italy

Ezequiel Luis Calvo , MD, PhD Centre de Recherche du CHUL (CHUQ) , Quebec , PQ , Canada

Lidia Corsini , PhD Section of Medical Oncology, Department of Surgical and Oncological Sciences , University of Palermo , Palermo , Italy

Bernard Czernobilsky , MD Patho-Lab Diagnostics , Ness Ziona , Israel

Jean Charles Dagorn , PhD INSERM U624 , Marseille , France

Maria Debiec-Rychter , MD, PhD Department of Human Genetics , Catholic University of Leuven , Leuven , Belgium

Nelson Dusetti , PhD INSERM U624 , Marseille , France

Mario Falchetti , PhD Department of Molecular Medicine, Policlinico Umberto I, Sapienza University of Rome , Rome , Italy

Daniele Fanale , PhD Section of Medical Oncology, Department of Surgical and Oncological Sciences , University of Palermo , Palermo , Italy

Pierre Ferrier , PhD Centre d’Immunologie de Marseille-Luminy, Université Aix-Marseille, France

CNRS, UMR6102, Marseille, France

Inserm, U631, Marseille, France

Anna Maria Frezza , MD Department of Medical Oncology , University Campus Bio-Medico , Rome , Italy

Gaorav P. Gupta , MD, PhD Department of Radiation Oncology , Memorial Sloan-Kettering Cancer Center , New York , NY , USA

Stefano Iacobelli , MD National Consortium for Research on Cancer (CINBO), University D’Annunzio , Chieti , Italy

Juan Iovanna , MD, PhD INSERM U624 , Marseille , France

x Contributors

Jinsong Jia , MD, PhD Centre d’Immunologie de Marseille-Luminy, Université Aix-Marseille , France

CNRS, UMR6102, Marseille, France

Inserm, U631, Marseille, France

Institute of Hematology, People’s Hospital, Beijing University, Beijing, People’s Republic of China

Laura La Paglia , PhD Section of Medical Oncology, Department of Surgical and Oncological Sciences , University of Palermo , Palermo , Italy

Leonor Leider-Trejo , MD Institute of Pathology, Sourasky Medical Center , Tel Aviv , Israel

Alessandro Lugli , MD Institute of Pathology, University of Bern , Bern , Switzerland

Umberto Malapelle , MD, BS Scienze Biomorfologiche e Funzionali , Universita degli Studi di Napoli Federico II , Naples , Italy

John W. M. Martens , PhD Department of Medical Oncology , Daniel den Hoed Cancer Center, Erasmus Medical Center , Rotterdam , The Netherlands

Gabriella Nesi , MD, PhD Department of Critical Care Medicine, Division of Pathological Anatomy, University of Florence , Florence , Italy

Laura Ottini , MD, PhD Department of Molecular Medicine , Policlinico Umberto I, Sapienza University of Rome , Rome , Italy

Aleksandra Pekowska , PhD Centre d’Immunologie de Marseille-Luminy, Université Aix-Marseille, France

CNRS, UMR6102, Marseille, France

Inserm, U631, Marseille, France

Joanna Przybył , MSc Department of Molecular Biology , Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology , Warsaw , Poland

Lajos Pustzai , MD, DPhil Department of Breast Medical Oncology , MD Anderson Cancer Center, University of Texas , Houston , TX , USA

Stefania Redana , MD Department of Medical Oncology I , Institute for Cancer Research and Treatment, Fondazione Piemontese per L’Oncologia , Candiolo , Italy

Sergio Rizzo , MD, PhD Section of Medical Oncology, Department of Surgical and Oncological Sciences , University of Palermo , Palermo , Italy

Delvys Rodriguez-Abreu , MD Department of Medical Oncology , Universitario Insular de Gran Canaria , Las Palmas de Gran Canaria , Spain

Christian Diego Rolfo , MD, PhD Medical Oncology, Oncology Unit, Clinica Rotger , Palma de Mallorca , Spain

Rafael Rosell , PhD Department of Medical Oncology , Germans Trias I Pujol, Catalan Institute of Oncology , Badalona , Spain

Antonio Russo , MD, PhD Section of Medical Oncology, Department of Surgical and Oncological Sciences , University of Palermo , Palermo , Italy

Piotr Rutkowski , MD, PhD Department of Soft Tissue/Bone Sarcoma and Melanoma , Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology , Warsaw , Poland

xiContributors

Daniele Santini , MD, PhD Department of Medical Oncology , University Campus Bio-Medico , Rome , Italy

Gaia Schiavon , MD Department of Medical Oncology , Daniel den Hoed Cancer Center, Erasmus Medical Center , Rotterdam , The Netherlands

Marcel Smid , BSc Department of Medical Oncology , Daniel den Hoed Cancer Center, Erasmus Medical Center , Rotterdam , The Netherlands

Salvatore Spicuglia , PhD Centre d’Immunologie de Marseille-Luminy, Université Aix-Marseille, France

CNRS, UMR6102, Marseille, France

Inserm, U631, Marseille, France

Miquel Taron , PhD Department of Medical Oncology, Germans Trias I Pujol, Catalan Institute of Oncology , Badalona , Spain

Giuseppe Tonini , MD, PhD Department of Medical Oncology , University Campus Bio-Medico , Rome , Italy

Giancarlo Troncone , MD, PhD Scienze Biomorfologiche e Funzionali , Universita degli Studi di Napoli Federico II , Naples , Italy

Bruno Vincenzi , MD, PhD Department of Medical Oncology , University Campus Bio-Medico , Rome , Italy

Jia Wei , MD Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, The Comprehensive Cancer Centre of Drum Tower Hospital , Nanjing , China

Joaquin Zacarias-Cabeza , PhD Centre d’Immunologie de Marseille-Luminy, Université Aix-Marseille, France

CNRS, UMR6102, Marseille, France

Inserm, U631, Marseille, France

Inti Zlobec , PhD Institute of Pathology, University of Bern , Bern , Switzerland

1A. Russo et al. (eds.), Diagnostic, Prognostic and Therapeutic Value of Gene Signatures, Current Clinical Pathology, DOI 10.1007/978-1-61779-358-5_1, © Springer Science+Business Media, LLC 2012

B. Vincenzi (�) • A. M. Frezza • D. Santini • G. Tonini Department of Medical Oncology , University Campus Bio-Medico , Rome , Italy e-mail: b.vincenzi@unicampus.it

Introduction

Soft tissue sarcomas represent an extremely heterogeneous group of tumors comprising more than 70 different histotypes, as described in the current World Health Organization classification from 2002 [ 1 ] . To date, the diagnosis of soft tissue sarcomas is still challenging and based on morphologi-cal appearance; moreover, some conventional names included in the classification results pathobio-logically inaccurate (e.g., synovial sarcoma) although they denote well-defined entities mutually understood by both pathologists and clinicians.

Some well-known inherited syndromes are associated with the onset of soft tissue sarcoma, underlining the importance of genetic alterations in the pathogenesis of this aggressive disease. For example, hereditary retinoblastoma syndrome [ 2 ] , a rare genetic disorder deriving from an RB gene mutation, is known to be associated with a higher risk of developing osteosarcoma [ 3 ] ; type 1 neu-rofibromatosis [ 4 ] , due to the mutation of NF1 gene on chromosome 17, bring to the onset of malignant peripheral nerve sheet tumors (MPNSTs) and gastrointestinal stromal tumors (GISTs), often multiples and arising from the small bowel [ 5 ] . At the same time, Li–Fraumeni syndrome (deriving from a germ line p53 mutation) [ 6 ] , Gardner syndrome [ 7 ] (due to an APC mutation), and Beckwith–Wiedemann syndrome, the pathogenesis of which is still not completely understood [ 8 ] , are associated with a higher incidence of soft tissue and bone sarcoma.

Despite these data, the majority of soft tissue sarcomas arise sporadically, but are often character-ized by molecular aberrations. Genetically, sarcomas can be broadly divided into two groups: the first group, usually characteristic of older patients, comprise those with a complex karyotype bringing nonspecific genetic alterations, such as genetic deletions and amplifications, nonbalanced transloca-tions, and changes in chromosome number. These aberrations are usually not helpful for diagnosis, but they are often prognostically relevants. The second group is made up of sarcomas characterized by simple karyotypes, which create specific genetic alterations usually represented by chromosomal translocations or oncogenic mutations (e.g., the KIT mutation in GISTs). These kinds of sarcomas often arise during childhood or adolescence and the detection of their tumor-specific genetic altera-tions by cytogenetic or molecular genetic techniques are extremely diagnostically useful.

Chapter 1 Gene Signatures and Soft Tissue Sarcomas: Status of Art and Perspectives

Bruno Vincenzi , Anna Maria Frezza , Daniele Santini , and Giuseppe Tonini