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Molecular OncologyCauses of Cancer and Targets for Treatment

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Cambridge University Press978-0-521-87662-9 - Molecular Oncology: Causes of Cancer and Targets for TreatmentEdited by Edward P. Gelmann, Charles L. Sawyers and Frank J. Rauscher IIIFrontmatterMore information

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Molecular OncologyCauses of Cancer and Targets for TreatmentEdited byEdward P. GelmannChief, Division of Hematology/Oncology and Deputy Director for Clinical Research, Herbert Irving Comprehensive Cancer Centerand Columbia University Medical Center, New York, NY, USA

Charles L. SawyersChair, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, and Investigator,Howard Hughes Medical Institute, Chevy Chase, MD, USA

Frank J. Rauscher IIIProfessor, Gene Expression and Regulation Program; Professor, Tumor Microenvironment and Metastasis Program;Deputy Director for Basic Research, Wistar Institute Cancer Center, Philadelphia, PA, USA






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Library of Congress Cataloging in Publication dataMolecular oncology : causes of cancer and targets for treatment /edited by Edward P. Gelmann, Chief, Division ofHematology/Oncology and Deputy Director for Clinical Research,Herbert Irving Comprehensive Cancer Center and ColumbiaUniversity Medical Center, New York, NY, USA, Charles L. Sawyers,Chair, Human Oncology and Pathogenesis Program, MemorialSloan-Kettering Cancer Center, New York, NY, USA, Frank J.Rauscher III, Professor, Gene Expression and Regulation Program,Professor, Tumor Microenvironment and Metastasis Program, DeputyDirector for Basic Research, Wistar Institute Cancer Center,Philadelphia, PA, USA.pages cm

Includes bibliographical references and index.ISBN 978-0-521-87662-9 (hardback)1. Cancer – Molecular aspects. 2. Tumor markers.3. Carcinogenesis. I. Gelmann, Edward P., 1953– II. Sawyers,Charles L. III. Rauscher, F. J. (Frank Joseph), 1957–RC268.4.M675 2014616.99′4 – dc23 2013012165

ISBN 978-0-521-87662-9 Hardback

Cambridge University Press has no responsibility for the persistenceor accuracy of URLs for external or third-party internet websitesreferred to in this publication, and does not guarantee that anycontent on such websites is, or will remain, accurate or appropriate.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Every effort has been made in preparing this book to provide accurateand up-to-date information which is in accord with acceptedstandards and practice at the time of publication. Although casehistories are drawn from actual cases, every effort has been made todisguise the identities of the individuals involved. Nevertheless, theauthors, editors, and publishers can make no warranties that theinformation contained herein is totally free from error, not leastbecause clinical standards are constantly changing through researchand regulation. The authors, editors, and publishers therefore disclaimall liability for direct or consequential damages resulting from the useof material contained in this book. Readers are strongly advised to paycareful attention to information provided by the manufacturer of anydrugs or equipment that they plan to use.






This book is dedicated to the scientists who made the discoveries,to the members of industry who developed the pharmaceuticals,to the clinicians whose trials turned medicines into therapies,and to the patients whose participation in research isessential and whose diseases we work to relieve.






Contents

List of contributors xiPreface xxi

Part 1.1 Analytical techniques: analysis of DNA1. Cancer genome sequencing 1

Abizar Lakdawalla, Jeffrey Fisher, Mostafa Ronaghi, andJian-Bing Fan

2. Genome-wide association studies of cancerpredisposition 10Zsofia K. Stadler, Sohela Shah, and Kenneth Offit

3. Comparative genomic hybridization 21Donna G. Albertson and Daniel Pinkel

4. Chromosome analysis: molecular cytogeneticapproaches 28Thomas Ried

5. DNAmethylation 37Marsha Reyngold and Timothy A. Chan

Part 1.2 Analytical techniques: analysis of RNA6. The application of high-throughput analyses to

cancer diagnosis and prognosis 46Edward P. Gelmann

7. Cancer proteomics 52Samir Hanash and Ayumu Taguchi

8. Tyrosine kinome profiling: oncogenic mutationsand therapeutic targeting in cancer 58Paramita Ghosh, Yun Qiu, Ling-Yu Wang, andHsing-Jien Kung

9. In situ techniques for protein analysis in tumortissue 76Valsamo K. Anagnostou and David L. Rimm

Part 2.1 Molecular pathways underlyingcarcinogenesis: signal transduction

10. HER 85Wolfgang J. Kostler and Yosef Yarden

11. The insulin–insulin-like growth-factor receptorfamily as a therapeutic target in oncology 110Michael Pollak

12. TGF-� signaling in stem cells andtumorigenesis 119Ying Li, Ruth He, and Lopa Mishra

13. Platelet-derived growth factor 135Arne Ostman and Carl-Henrik Heldin

14. FMS-related tyrosine kinase 3 144Soheil Meshinchi and Derek L. Stirewalt

15. ALK: Anaplastic lymphoma kinase 162Karen Pulford

16. The FGF signaling axis in prostatetumorigenesis 190Fen Wang, Yongde Luo, and Wallace L. McKeehan

17. Hepatocyte growth factor/Met signalingin cancer 204Fabiola Cecchi, Young H. Lee, and Donald P. Bottaro

18. PI3K 218Kevin D. Courtney and Lewis C. Cantley

19. Intra-cellular tyrosine kinase 231Rosalyn B. Irby and Timothy J. Yeatman

20. WNT signaling in neoplasia 243Masaru Katoh

21. Ras 258Adrienne D. Cox and Molly J. DeCristo

22. BRAFmutations in human cancer: biologic andtherapeutic implications 272Moriah H. Nissan and David B. Solit

23. Aurora kinases in cancer: an opportunity fortargeted therapy 278Vikas Sehdev, Altaf A. Dar, and Wael El-Rifai

24. 14-3-3 proteins in cancer 293Alexandra K. Gardino and Michael B. Yaffe

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Contents

25. STAT signaling as amolecular target for cancertherapy 305Hua Yu and Richard Jove

26. TheMYC oncogene family in humancancer 313Michael D. Cole

27. Jun proteins and AP-1 in tumorigenesis 319Shira Anzi and Eitan Shaulian

28. Forkhead box proteins: the tuningforks in cancer development andtreatment 328Eric W.-F. Lam, Kyle W. Muir, andChuay-Yeng Koo

29. NF-�B and cancer 336Willscott E. Naugler and Michael Karin

Part 2.2 Molecular pathways underlyingcarcinogenesis: apoptosis

30. Apoptosis: the extrinsic pathway 353Xinchen Teng and J. Marie Hardwick

31. Apoptosis: the intrinsic pathway 367Jody White

Part 2.3 Molecular pathways underlyingcarcinogenesis: nuclear receptors

32. Androgens and the androgen receptor (AR) 378Nicole L. Moore, Margaret M. Centenera,Lisa M. Butler, Theresa E. Hickey, andWayne D. Tilley

33. Emerging roles of peroxisomeproliferator-activated receptor gammain cancer 392Chenguang Wang, Xuemin Zhang, Lifeng Tian, andRichard G. Pestell

Part 2.4 Molecular pathways underlyingcarcinogenesis: DNA repair

34. The ATM-mediated DNA-damage response 403Yosef Shiloh

35. Werner syndrome: association of premature agingand cancer predisposition 423Byungchan Ahn, Tinna Stevnsner, and Vilhelm A. Bohr

36. Hereditary disorders of DNA repair and DNAdamage tolerance that predispose to neoplastictransformation 434Errol C. Friedberg and Roger A. Schultz

37. Telomerase: target for cancer treatment 442Jerry W. Shay and Woodring E. Wright

Part 2.5 Molecular pathways underlyingcarcinogenesis: cell cycle

38. Cell cycle: mechanisms of control and dysregulationin cancer 452Erik S. Knudsen, Ryan J. Bourgo, Elizabeth L. Gosnell,Jeffry L. Dean, and A. Kathleen McClendon

39. DNA-damage-induced apoptosis 465Shun J. Lee, Benjamin F. O’Connor, Scott A. Stuart, andJean Y. J. Wang

Part 2.6 Molecular pathways underlyingcarcinogenesis: other pathways

40. The ubiquitin/proteasome pathway inneoplasia 473Robert C. A. M. van Waardenburg andMary-Ann Bjornsti

41. Small silencing non-coding RNAs: cancerconnections and significance 481Milena S. Nicoloso and George A. Calin

Part 3.1 Molecular pathology: carcinomas42. Head and neck cancer 497

Kelly Quesnelle, Jennifer Grandis, Karl Munger, andMarshall R. Posner

43. Lung cancer 506Jill E. Larsen and John D. Minna

44. Esophageal cancer 526DuyKhanh P. Ceppa andThomas A. D’Amico

45. Gastric cancer 532Yoshiaki Ito and Khay Guan Yeoh

46. Small-bowel tumors: molecular mechanisms andtargeted therapy 542Allan D. Spigelman and Janindra Warusavitarne

47. Colon and rectal cancer 547Erin M. Perchiniak and Joanna Groden

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Contents

48. Pancreatic cancer 557Siong-Seng Liau and David A. Tuveson

49. Hepatocellular carcinoma 569Augusto Villanueva, Yujin Hoshida, Derek Y. Chiang,and Josep M. Llovet

50. Renal-cell carcinomas 579Kyle A. Furge and Bin T. Teh

51. Bladder cancer 584Robert S. Svatek and Colin P. Dinney

52. Prostate cancer 591Kaustubh Datta and Donald J. Tindall

53. Targeted therapies in breast cancer 598Nancy E. Hynes and Gwen MacDonald

54. Molecular targets for epithelial ovarian cancer 606Grace K. Suh, Bryan T. Hennessy, Roeland Verhaak,Ji-Yeon Yang, Gordon B. Mills, and Robert C. Bast, Jr.

55. Testicular cancer: germ-cell tumors (GCTs) 619J. Wolter Oosterhuis and Leendert H. J. Looijenga

56. Cervical cancer 630John Doorbar

Part 3.2 Molecular pathology: cancers of thenervous system

57. Brain tumors 641Chang-Hyuk Kwon, Dennis K. Burns, and Luis F. Parada

58. Mechanisms of pituitary tumorigenesis 652Shereen Ezzat and Sylvia L. Asa

59. Molecular oncology of neuroblastoma 669Vandana Batra, Rebecca J. Deyell, and John M. Maris

60. Neurofibromatosis type I 679Rachel S. Darken and David H. Gutmann

Part 3.3 Molecular pathology: cancersof the skin

61. Squamous-cell carcinoma 686Carter Van Waes, Yansong Bian, Clint T. Allen, John C.Morris, and Zhong Chen

62. Molecular oncology of basal cell carcinomas 693Ervin H. Epstein, Jr.

63. Melanoma 698Adina Vultur, Keiran Smalley, and Meenhard Herlyn

Part 3.4 Molecular pathology: endocrinecancers

64. Oncogenic events and therapeutic targets inthyroid cancer 704James A. Fagin and Julio C. Ricarte Filho

65. The parathyroid glands 712Edward M. Brown and Andrew Arnold

66. Multiple endocrine neoplasia type 2 (MEN2) 720Jo W. M. Hoppener and C. J. M. Lips

Part 3.5 Molecular pathology: adult sarcomas67. Sarcomas 731

Lee J. Helman

Part 3.6 Molecular pathology: lymphoma andleukemia

68. Molecular pathology of lymphoma 738Christof Schneider, Laura Pasqualucci, and RiccardoDalla-Favera

69. Themolecular basis of acute myeloid leukemia 751Kim L. Rice, Monica Buzzai, Jessica Altman, andJonathan D. Licht

70. Molecular oncology of acute promyelocyticleukemia (APL) 769Valerie Lallemand-Breittenbach and HuguesdeThe

71. Acute lymphoblastic leukemia (ALL) 777Ido Paz-Priel and Alan D. Friedman

72. B-cell chronic lymphocytic leukemia 786Francesco Bertoni, Francesco Forconi, Michele Dal-Bo,Antonella Zucchetto, Riccardo Bomben, Giovanni DelPoeta, and Valter Gattei

73. Chronic myeloid leukemia: imatinib andnext-generation ABL inhibitors 793Charles L. Sawyers

74. Multiple myeloma 799W. Michael Kuehl and P. Leif Bergsagel

75. EMS: the 8p11myeloproliferative syndrome 809Donald H. C. Macdonald, Andreas Reiter, and NicholasC. P. Cross

76. JAK2 andmyeloproliferative neoplasms 818Ross L. Levine

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Contents

Part 3.7 Molecular pathology: pediatricsolid tumors

77. Pediatric solid tumors: embryonal celloncogenesis 826Jeffrey A. Toretsky and Aerang Kim

Part 4 Pharmacologic targeting of oncogenicpathways

78. Oncology drug discovery for biologics: antibodydevelopment strategies and considerations 836Bryan C. Barnhart, Marco M. Gottardis, and Matthew V.Lorenzi

79. Targeting the EGFR family of receptor tyrosinekinases 843Siyuan Zhang and Dihua Yu

80. Therapeutic approaches with antibodies tocell-surface receptors 854Antonio Gualberto

81. Signal transduction in tumor angiogenesis 861Timothy Hla, Nasser Altorki, and Vivek Mittal

82. Tyrosine-kinase inhibitors in oncology 872Anne S. Tsao, Vassiliki Papadimitrakopoulou, andRoy S. Herbst

83. Anti-estrogens and selective estrogen-receptormodulators 884Ping Fan and V. Craig Jordan

84. Therapeutic applications of anti-sensemechanismsfor the treatment of cancer 893A. Robert MacLeod and C. Frank Bennett

85. Induction of apoptosis 903Dario C. Altieri

86. DNA-methylation inhibitors 908Jean-Pierre Issa

87. Histone deacetylase inhibitor 912Paul A. Marks

88. Drug resistance: as complex and diverse as thedisease itself 921Antonio Tito Fojo

89. Molecular profiling and therapeuticdecision-making: the promise of personalizedmedicine 929Susan M. Henshall and Andrew V. Biankin

90. DNA repair inhibition in anti-cancertherapeutics 936Brian M. Alexander and Alan D. D’Andrea

Index 945

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Contributors

Byungchan AhnDepartment of Life Sciences, University of Ulsan, Ulsan,Korea

Donna G. AlbertsonHelen Diller Family Comprehensive Cancer Center,University of California San Francisco, San Francisco,CA, USA

Brian M. AlexanderDepartment of Radiation Oncology, Dana-Farber CancerInstitute, Harvard Medical School, Boston, MA, USA

Clint T. Allen, MDHead and Neck Surgery Branch, National Institute onDeafness and Other Communication Disorders, NIH,Bethesda, MD, USA

Dario C. Altieri, MDTheWistar Institute, Philadelphia, PA, USA

Jessica AltmanDivision of Hematology/Oncology, Robert H. LurieComprehensive Cancer Center, Northwestern UniversityFeinberg School of Medicine, Chicago, IL, USA

Nasser AltorkiDepartment of Cardiothoracic Surgery and NeubergerBerman Lung Cancer Research Center, Weill Medical Collegeof Cornell University, New York, NY, USA

Valsamo K. Anagnostou, MDDepartment of Pathology, Yale University School of Medicine,New Haven, CT, USA

Shira AnziDepartment of Developmental Biology and Cancer Research,IMRIC, The Hebrew University – Hadassah Medical School,Jerusalem, Israel

Andrew Arnold, MDCenter for Molecular Medicine and Department of Geneticsand Developmental Biology, University of Connecticut Schoolof Medicine, Farmington, CT, USA

Sylvia L. AsaDepartment of Pathology and Laboratory Medicine,University of Toronto, Department of Pathology, UniversityHealth Network, Toronto, Ontario, Canada

Bryan C. BarnhartOncology Drug Discovery, Bristol-Myers Squibb, Co.,Princeton, NJ, USA

Robert C. Bast, Jr., MDDepartments of Experimental Therapeutics, GynecologicMedical Oncology, Bioinformatics and ComputationalBiology, and Systems Biology, University of Texas M.D.Anderson Cancer Center, Houston, TX, USA

Vandana Batra MDCenter for Childhood Cancer Research, Department ofPediatrics, Childrens Hospital of Philadelphia, Philadelphia,PA, USA

C. Frank BennettDepartment of Antisense Drug Discovery, IsisPharmaceuticals, Inc., Carlsbad, CA, USA

P. Leif Bergsagel, MDDivision of Hematology-Oncology, Comprehensive CancerCenter, Mayo Clinic, Scottsdale, AZ, USA

Francesco BertoniLymphoma and Genomics Research Program, Institute ofOncology Research, and Lymphoma Unit, Oncology Instituteof Southern Switzerland, Bellinzona, Switzerland

Yansong Bian, MD, PhDLaboratory of Cell and Developmental Biology, NationalInstitute of Dental and Craniofacial Research, NIH, Bethesda,MD, USA

Andrew V. Biankin MB, BS, FRACS, PhDCancer Research Program, Garvan Institute of MedicalResearch, Darlinghurst, Sydney, NSW, Australia

Mary-Ann BjornstiDepartment of Pharmacology and Toxicology, University ofAlabama at Birmingham, Birmingham AL, USA

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List of contributors

Vilhelm A. BohrLaboratory of Molecular Gerontology, GerontologyResearch Center, National Institute on Aging, NIH,Baltimore, MD, USA

Riccardo BombenClinical and Experimental Onco-Hematology Unit,Centro di Riferimento Oncologico, I.R.C.C.S., Aviano,Pordenone, Italy

Donald P. BottaroUrologic Oncology Branch, Center for Cancer Research,National Cancer Institute, National Institutes of Health,Bethesda, MD, USA

Ryan J. BourgoKimmel Cancer Center, Department of Cancer Biology,Thomas Jefferson University, Philadelphia, PA, USA

Edward M. Brown, MDDivision of Endocrinology, Diabetes, and Hypertension,Brigham andWomen’s Hospital, Boston, MA, USA

Dennis K. BurnsDepartment of Pathology, University of Texas SouthwesternMedical Center, Dallas, TX, USA

Lisa M. ButlerDame Roma Mitchell Cancer Research Laboratories,Adelaide University/Hanson Institute, Adelaide, SouthAustralia

Monica BuzzaiNovartis, Origgio, VA, Italy

George A. Calin, MA, PhDRNA Interference and Non-coding RNA Center and theDepartment of Experimental Therapeutics, Universityof Texas, M.D. Anderson Cancer Center, Houston, TX,USA

Lewis C. Cantley, PhDWeill Cornell Cancer Center, New York – PresbyterianHospital, Weill Cornell Medical College, New York, NY,USA

Fabiola CecchiUrologic Oncology Branch, Center for Cancer Research,National Cancer Institute, National Institutes of Health,Bethesda, MD, USA

Margaret M. CenteneraDame Roma Mitchell Cancer Research Laboratories, AdelaideUniversity/Hanson Institute, Adelaide, South Australia

DuyKhanh P. Ceppa, MDDivision of Thoracic Surgery, Indiana University School ofMedicine, Indianapolis, IN, USA

Timothy A. ChanMemorial Sloan Kettering Cancer Center, New York, NY, USA

Zhong Chen, MD, PhDHead and Neck Surgery Branch, National Institute onDeafness and Other Communication Disorders, NIH,Bethesda, MD, USA

Derek Y. Chiang, PhDNovartis Institutes for Biomedical Research, Cambridge, MA,USA

Michael D. ColeDepartments of Pharmacology and Genetics, DartmouthMedical School, Norris Cotton Cancer Center, Lebanon, NH,USA

Kevin D. Courtney, MD, PhDDivision of Hematology/Oncology, UT Southwestern MedicalCenter, Dallas, TX, USA

Adrienne D. Cox, PhDDepartments of Radiation Oncology and Pharmacology,Lineberger Comprehensive Cancer Center, University ofNorth Carolina at Chapel Hill, Chapel Hill, NC, USA

Nicholas C. P. CrossWessex Regional Genetics Laboratory, University ofSouthampton, Salisbury District Hospital, Salisbury, UK

Thomas A. D’Amico, MDDivision of Thoracic Surgery, Duke University Health System,Durham, NC, USA

Alan D. D’AndreaDepartment of Radiation Oncology, Dana-FarberCancer Institute, Harvard Medical School, Boston,MA, USA

Michele Dal-BoClinical and Experimental Onco-Hematology Unit,Centro di Riferimento Oncologico, I.R.C.C.S., Aviano,Pordenone, Italy

Riccardo Dalla-Favera, MDDepartment of Genetics and Development, Department ofPathology and Cell Biology, and Department of Microbiologyand Immunology, Institute for Cancer Genetics and HerbertIrving Comprehensive Cancer Center, Columbia University,New York, NY, USA

Altaf A. DarCalifornia Pacific Medical Center Research Institute, SanFrancisco, CA, USA

Rachel S. DarkenDepartment of Neurology, Washington University School ofMedicine, St. Louis, MO, USA

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Kaustubh DattaDepartment of Urologic Research, Biochemistry andMolecular Biology, Mayo Clinic Cancer Center, Mayo ClinicFoundation, Rochester, MN, USA

Hugues de TheCNRS 7212, Universite Paris Diderot, Paris, France

Jeffry L. DeanKimmel Cancer Center, Department of Cancer Biology,Thomas Jefferson University, Philadelphia, PA, USA

Molly J. DeCristoDepartment of Biology, University of North Carolina atChapel Hill, Chapel Hill, NC, USA

Giovanni Del PoetaDepartment of Hematology, S. Eugenio Hospital andUniversity of Tor Vergata, Rome, Italy

Rebecca J. Deyell MDCenter for Childhood Cancer Research, Department ofPediatrics, Childrens Hospital of Philadelphia, Philadelphia,PA, USA

Colin P. Dinney MDDepartment of Urology, The University of Texas M. D.Anderson Cancer Center, Houston, TX, USA

John DoorbarDivision of Virology, National Institute for Medical Research,London, UK

Wael El-Rifai, MD, PhDDepartment of Surgery and Vanderbilt-Ingram Cancer Center,Vanderbilt University Medical Center, Nashville, TN, USA

Ervin H. Epstein, JrChildren’s Hospital Oakland Research Institute, Oakland, CA,USA

Shereen EzzatDepartment of Medicine, University of Toronto andthe Princess Margaret Cancer Center, University HealthNetwork, Toronto, Ontario, Canada

James A. Fagin, MDDepartment of Medicine and Human Oncology andPathogenesis Program, Memorial Sloan-Kettering CancerCenter, New York, NY, USA

Jian-Bing FanIllumina, Inc., San Diego, CA, USA

Ping FanVincent T. Lombardi Comprehensive Cancer Center,Georgetown University, DC, USA

Julio C. Ricarte FilhoDepartment of Medicine and Human Oncology andPathogenesis Program, Memorial Sloan-Kettering CancerCenter, New York, NY, USA

Jeffrey FisherIllumina, Inc., San Diego, CA, USA

Antonio Tito Fojo, MD, PhDMedical Oncology Branch and Affiliates Head, ExperimentalTherapeutics Section, Center for Cancer Research, NationalCancer Institute, Bethesda, MD, USA

Francesco ForconiDivision of Hematology and Transplant, Department ofClinical Medicine and Immunological Sciences, University ofSiena, Italy

Errol C. FriedbergLaboratory of Molecular Pathology, Department of Pathology,University of Texas Southwestern Medical Center, Dallas, TX,USA

Alan D. Friedman, MDDepartments of Oncology and Pediatrics, Division of PediatricOncology, Johns Hopkins University, Baltimore, MD, USA

Kyle A. Furge, PhDLaboratory of Computational Biology, Van Andel ResearchInstitute, Grand Rapids, MI, USA

Alexandra K. GardinoDavid H. Koch Institute for Integrative Cancer Research,Massachusetts Institute of Technology, Cambridge, MA,USA

Valter GatteiClinical and Experimental Onco-Hematology Unit, Centro diRiferimento Oncologico, I.R.C.C.S., Aviano, Pordenone, Italy

Edward P. Gelmann, MDDepartments of Medicine and Pathology, Herbert IrvingComprehensive Cancer Center, Columbia University, NewYork, NY, USA

Paramita GhoshDepartments of Biochemistry and Molecular Medicine, andUrology, University of California David School of Medicine,Sacramento, and VA Northern Health Care System, Mather,CA, USA

Elizabeth L. GosnellKimmel Cancer Center, Department of Cancer Biology,Thomas Jefferson University, Philadelphia, PA, USA

Marco M. GottardisOncology Drug Discovery, Bristol-Myers Squibb, Co.,Princeton, NJ, USA

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Jennifer GrandisUniversity of Pittsburgh Medical Center, Pittsburgh, PA,USA

Joanna GrodenDepartment of Molecular Virology, Immunology, and MedicalGenetics, The Ohio State University College of Medicine,Columbus, OH, USA

Antonio Gualberto MD PhDDepartment of Pathology and Laboratory Medicine, TheAlpert Medical School of Brown University, Providence, RI,USA

David H. Gutmann, MD, PhDDepartment of Neurology, Washington University School ofMedicine, St. Louis, MO, USA

Samir HanashFred Hutchinson Cancer Research Center, Seattle, WA, USA

J. Marie HardwickFeinstone Department of Molecular Microbiology andImmunology, Johns Hopkins University, Bloomberg School ofPublic Health, Baltimore, MD, USA

Ruth HeLombardi Comprehensive Cancer Center, GeorgetownUniversity, Washington DC, USA

Carl-Henrik HeldinLudwig Institute for Cancer Research, Uppsala University,Uppsala, Sweden

Lee J. Helman, MDCenter for Cancer Research, National Cancer Institute,Bethesda, MD, USA

Bryan T. Hennessy, MDDepartments of Experimental Therapeutics, GynecologicMedical Oncology, Bioinformatics and ComputationalBiology, and Systems Biology, University of Texas M.D.Anderson Cancer Center, Houston, TX, USA

Susan M. Henshall, PhDCancer Research Program, Garvan Institute of MedicalResearch, Darlinghurst, Sydney, NSW, Australia

Roy S. Herbst, MD, PhDYale University School of Medicine, New Haven, CT

Meenhard HerlynTheWistar Institute Melanoma Research Center, Philadelphia,PA, USA

Theresa E. HickeyDame Roma Mitchell Cancer Research Laboratories,Adelaide University/Hanson Institute, Adelaide, SouthAustralia

Timothy HlaCenter of Vascular Biology, Department of Pathology andLaboratory Medicine, Weill Medical College of CornellUniversity, New York, NY, USA

Jo W. M. HoppenerDepartment of Molecular Cancer Research, UniversityMedical Center Utrecht, University Hospital, the Netherlands

Yujin Hoshida, MD, PhDLiver Cancer Program, Tisch Cancer Institute, Division ofLiver Diseases, Icahn School of Medicine at Mount Sinai, NewYork, NY, USA

Nancy E. HynesFriedrich Miescher Institute for Biomedical Research, Basel,Switzerland

Rosalyn B. IrbyPenn State Hershey Cancer Institute H046, Penn StateUniversity College of Medicine, Hershey, PA, USA

Jean-Pierre IssaFels Institute for Cancer Research, Temple University Schoolof Medicine, Philadelphia, PA, USA

Yoshiaki Ito, MD PhDCancer Science Institute, National University of Singapore,Center for Translational Medicine, Singapore

V. Craig JordanVincent T. Lombardi Comprehensive Cancer Center,Georgetown University, DC, USA

Richard Jove, PhDBeckham Research Institute, City of Hope, Duarte, CA,USA

Michael KarinLaboratory of Gene Regulation and Signal Transduction,Department of Pharmacology and Pathology, MooresCancer Center, UCSD School of Medicine, La Jolla,CA, USA

Masaru Katoh, MD, PhDGenetics and Cell Biology Section, National Cancer Center,Tokyo, Japan

Aerang KimDepartment of Pediatrics, Children’s National Medical Center,George Washington University, Washington, DC, USA

Erik S. KnudsenDepartment of Pathology, UT Southwestern Medical Center,Dallas, TX, USA

Chuay-Yeng KooDepartment of Surgery and Cancer, Imperial College London,Hammersmith Hospital Campus, London, UK

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Wolfgang J. KostlerDepartment of Biological Regulation, TheWeizmann Instituteof Science, Rehovot, Israel

W.Michael Kuehl, MDCancer Genetics Branch, Center for Cancer Research, NationalCancer Institute, Bethesda, MD, USA

Hsing-Jien KungDepartments of Biochemistry and Molecular Medicine, andUrology, University of California David School of Medicine,Sacramento, CA, USA

Chang-Hyuk KwonDepartment of Developmental Biology, University of TexasSouthwestern Medical Center, Dallas, TX, USA; Solid TumorProgram and Department of Neurological Surgery, JamesComprehensive Cancer Center, The Ohio State UniversityWexner Medical Center, Columbus, OH, USA

Abizar LakdawallaIllumina, Inc., San Diego, CA, USA

Valerie Lallemand-BreittenbachCNRS 7212, Universite Paris Diderot, Paris, France

Eric W.-F. LamDepartment of Surgery and Cancer, Imperial College London,Hammersmith Hospital Campus, London, UK

Jill E. Larsen, PhDHamon Center for Therapeutic Oncology Research, SimmonsCancer Center, University of Texas Southwestern MedicalCenter, Dallas, TX, USA

Shun J. LeeDivision of Hematology-Oncology, Department of Medicine,Moores Cancer Center, University of California, San Diego, LaJolla, CA, USA

Young H. LeeUrologic Oncology Branch, Center for Cancer Research,National Cancer Institute, National Institutes of Health,Bethesda, MD, USA

Ross L. Levine, MDHuman Oncology and Pathogenesis Program, LeukemiaService, Department of Medicine, Memorial Sloan-KetteringCancer Center, New York, NY, USA

Ying LiThe University of Texas, M.D. Anderson Cancer Center,Houston, TX, USA

Siong-Seng Liau, MD, FRCSHepatopancreatobiliary Surgery Unit, Department of Surgery,Addenbrooke’s Hospital, and Medical Research CouncilCancer Cell Unit, Hutchison-MRC Research Center,University of Cambridge, Cambridge, UK

Jonathan D. Licht, MDDivision of Hematology/Oncology, Robert H. LurieComprehensive Cancer Center, Northwestern UniversityFeinberg School of Medicine, Chicago, IL, USA

C. J. M. LipsDepartment of Internal Medicine, University Medical CenterUtrecht, Utrecht, the Netherlands

Josep M. Llovet, MDLiver Cancer Program, Division of Liver Diseases, IcahnSchool of Medicine at Mount Sinai, New York, NY, USA; andBCLC Group, IDIBAPS, CIBEREHD, Liver Unit, HospitalClınic, Barcelona, Spain

Leendert H. J. LooijengaDepartment of Pathology, Erasmus MC – University MedicalCenter Rotterdam, Daniel den Hoed Cancer Center, JosephineNefkens Institute, Rotterdam, the Netherlands

Matthew V. LorenziOncology Drug Discovery, Bristol-Myers Squibb, Co.,Princeton, NJ, USA

Yongde LuoCenter for Cancer and Stem Cell Biology, Institute ofBiosciences and Technology, Texas A&MHealth ScienceCenter, Houston, TX, USA

Donald H. C. MacdonaldDepartment of Haematology, Imperial College, London,UK

GwenMacDonaldFriedrich Miescher Institute for Biomedical Research, Basel,Switzerland

A. Robert MacLeodDepartment of Antisense Drug Discovery, IsisPharmaceuticals, Inc., Carlsbad, CA, USA

A. Kathleen McClendonKimmel Cancer Center, Department of Cancer Biology,Thomas Jefferson University, Philadelphia, PA, USA

Wallace L. McKeehanCenter for Cancer and Stem Cell Biology, Institute ofBiosciences and Technology, Texas A&MHealth ScienceCenter, Houston, TX, USA

John M. Maris MDCenter for Childhood Cancer Research, Department ofPediatrics, Childrens Hospital of Philadelphia, Philadelphia,PA, USA

Paul A. MarksCell Biology and Genetics Program, Sloan-Kettering Institutefor Cancer Research, Memorial Sloan-Kettering CancerCenter, New York, NY, USA

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Soheil MeshinchiClinical Research Division, Fred Hutchinson Cancer ResearchCenter, Seattle, WA, USA

Gordon B. Mills, MD, PhDDepartments of Experimental Therapeutics, GynecologicMedical Oncology, Bioinformatics and ComputationalBiology, and Systems Biology, University of Texas M.D.Anderson Cancer Center, Houston, TX, USA

John D. Minna, MDHamon Center for Therapeutic Oncology Research, SimmonsCancer Center University of Texas Southwestern MedicalCenter, Dallas, TX, USA

Lopa MishraThe University of Texas, M.D. Anderson Cancer Center,Houston, TX, USA

Vivek MittalDepartment of Cardiothoracic Surgery and NeubergerBerman Lung Cancer Research Center, and Department ofCell and Developmental Biology, Weill Medical College ofCornell University, New York, NY, USA

Nicole L. MooreDame Roma Mitchell Cancer Research Laboratories, AdelaideUniversity/Hanson Institute, Adelaide, South Australia

John C. Morris, MDMetabolism Branch, National Cancer Institute, NIH, Bethesda,MD, USA

Kyle W. MuirDepartment of Surgery and Cancer, Imperial College London,Hammersmith Hospital Campus, London, UK

Karl MungerBrigham andWomen’s Hospital, Harvard Medical School,Boston, MA, USA

Willscott E. NauglerOregon Health and Sciences University, Department ofMedicine, Division of GI and Hepatology, Portland, OR,USA

Milena S. NicolosoRNA Interference and Non-coding RNA Center and theDepartment of Experimental Therapeutics, Universityof Texas, M.D. Anderson Cancer Center, Houston, TX,USA

Moriah H. NissanHuman Oncology and Pathogenesis Program, and Louis V.Gerstner Jr. Graduate School of Biomedical Sciences,Memorial Sloan-Kettering Cancer Center, New York, NY,USA

Benjamin F. O’ConnorDivision of Hematology-Oncology, Department of Medicine,Moores Cancer Center, University of California, San Diego, LaJolla, CA, USA

Kenneth OffitDepartment of Medicine, Clinical Genetics Service, MemorialSloan-Kettering Cancer Center, New York, NY, USA

J. Wolter OosterhuisDepartment of Pathology, Erasmus MC – University MedicalCenter Rotterdam, Daniel den Hoed Cancer Center, JosephineNefkens Institute, Rotterdam, the Netherlands

Arne OstmanCancer Center Karolinska, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

Vassiliki PapadimitrakopoulouUniversity of Texas M.D. Anderson Cancer Center, Houston,TX, USA

Luis F. ParadaDepartment of Developmental Biology, University ofTexas Southwestern Medical Center, Dallas, TX, USA

Laura Pasqualucci, MDInstitute for Cancer Genetics and Herbert IrvingComprehensive Cancer Center, Columbia University, NewYork, NY, USA

Ido Paz-Priel, MDDepartments of Oncology and Pediatrics, Division ofPediatric Oncology, Johns Hopkins University, Baltimore,MD, USA

Erin M. PerchiniakDepartment of Molecular Virology, Immunology, and MedicalGenetics, The Ohio State University College of Medicine,Columbus, OH, USA

Richard G. PestellDepartment of Cancer Biology, Kimmel Cancer Center,Thomas Jefferson University, Philadelphia, PA, USA

Daniel PinkelHelen Diller Family Comprehensive Cancer Center,University of California San Francisco, San Francisco,CA, USA

Michael Pollak, MDDepartment of Oncology, McGill University, Montreal,Quebec, Canada

Marshall R. PosnerMount Sinai Medical Center, Tisch Cancer Institute, IcahnSchool of Medicine, New York, NY, USA

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Karen PulfordNuffield Division of Clinical Laboratory Sciences, RadcliffeDepartment of Medicine, University of Oxford, Oxford, UK

Yun QiuDepartment of Pharmacology and Experimental Therapeutics,University of Maryland School of Medicine, Baltimore, MD,USA

Kelly QuesnelleUniversity of Pittsburgh Medical Center, Pittsburgh, PA, USA

Andreas ReiterMedizinische Klinik, Universatsmedizin Mannheim, Germany

Marsha ReyngoldMemorial Sloan-Kettering Cancer Center, New York, NY, USA

Kim L. RiceDivision of Hematology/Oncology, Robert H. LurieComprehensive Cancer Center, Northwestern UniversityFeinberg School of Medicine, Chicago, IL, USA

Thomas Ried, MDSection of Cancer Genomics, Genetics Branch, Center forCancer Research /NCI/NIH, Bethesda, MD, USA

David L. RimmMD, PhDDepartment of Pathology, Yale University School of Medicine,New Haven, CT, USA

Mostafa RonaghiIllumina, Inc., San Diego, CA, USA

Charles L. Sawyers, MDHoward Hughes Medical Institute, Chevy Chase, MD, andHuman Oncology and Pathogenesis Program, MemorialSloan-Kettering Cancer Center, New York, NY, USA

Christof Schneider, MDInstitute for Cancer Genetics and Herbert IrvingComprehensive Cancer Center, Columbia University, NewYork, NY, USA

Roger A. SchultzSignature Genomics, Spokane, WA, USA

Vikas SehdevDepartment of Surgery and Vanderbilt-Ingram Cancer Center,Vanderbilt University Medical Center, Nashville, TN, USA

Sohela ShahDepartment of Medicine, Clinical Genetics Service, MemorialSloan-Kettering Cancer Center, New York, NY, USA

Eitan ShaulianDepartment of Biochemistry and Molecular Biology, IMRIC,The Hebrew University – Hadassah Medical School, Jerusalem,Israel

Jerry W. ShayUniversity of Texas Southwestern Medical Center, Departmentof Cell Biology, Dallas, TX, USA

Yosef ShilohThe David and Inez Myers Laboratory for Genetic Research,Department of Human Molecular Genetics and Biochemistry,Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Keiran SmalleyDepartment of Molecular Oncology, H. Lee Moffitt CancerCenter and Research Institute, Tampa, FL, USA

David B. Solit, MDHuman Oncology and Pathogenesis Program, Department ofMedicine, Memorial Sloan-Kettering Cancer Center, NewYork, NY, USA

Allan D. SpigelmanUNSW St Vincent’s Clinical School, Cancer Services, StVincent’s & Mater Health, Sydney, Hereditary Cancer Clinic,St Vincent’s Hospital, The Kinghorn Cancer Centre, Sydney,NSW, Australia

Zsofia K. StadlerDepartment of Medicine, Clinical Genetics Service, MemorialSloan-Kettering Cancer Center, New York, NY, USA

Tinna StevnsnerDanish Centre for Molecular Gerontology and Danish AgingResearch Center, University of Aarhus, Department ofMolecular Biology, Denmark

Derek L. StirewaltClinical Research Division, Fred Hutchinson Cancer ResearchCenter, Seattle, WA, USA

Scott A. StuartDivision of Hematology-Oncology, Department of Medicine,Moores Cancer Center, University of California, San Diego, LaJolla, CA, USA

Grace K. Suh, MDDepartments of Experimental Therapeutics, GynecologicMedical Oncology, Bioinformatics and ComputationalBiology, and Systems Biology, University of Texas M.D.Anderson Cancer Center, Houston, TX, USA

Robert S. SvatekDepartment of Urology, the University of Texas M. D.Anderson Cancer Center, Houston, TX, USA

Ayumu TaguchiFred Hutchinson Cancer Research Center, Seattle, WA, USA

Bin T. Teh, MD, PhDNational Cancer Centre of Singapore, Duke-NUS GraduateMedical School, Singapore, and Cancer Science Institute ofSingapore

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Xinchen TengFeinstone Department of Molecular Microbiology andImmunology, Johns Hopkins University, Bloomberg School ofPublic Health, Baltimore, MD, USA

Lifeng TianDepartment of Cancer Biology, Kimmel Cancer Center,Thomas Jefferson University, Philadelphia, PA, USA

Wayne D. TilleyDame Roma Mitchell Cancer Research Laboratories, AdelaideUniversity/Hanson Institute, Adelaide, South Australia

Donald J. TindallDepartment of Urologic Research, Biochemistry andMolecular Biology, Mayo Clinic Cancer Center, Mayo ClinicFoundation, Rochester, MN, USA

Jeffrey A. ToretskyDepartments of Oncology and Pediatrics, GeorgetownUniversity, Washington, DC, USA

Anne S. TsaoUniversity of Texas M.D. Anderson Cancer Center, Houston,TX, USA

David A. Tuveson, MD, PhDDepartment of Oncology, Addenbrooke’s Hospital, Universityof Cambridge, Cambridge, UK

Robert C. A. M. vanWaardenburgDepartment of Pharmacology and Toxicology, University ofAlabama at Birmingham, Birmingham, AL, USA

Carter VanWaes, MD, PhDHead and Neck Surgery Branch, National Institute onDeafness and Other Communication Disorders, NIH,Bethesda, MD, USA

Roeland Verhaak, PhDDepartments of Experimental Therapeutics, GynecologicMedical Oncology, Bioinformatics and ComputationalBiology, and Systems Biology, University of Texas M.D.Anderson Cancer Center, Houston, TX, USA

Augusto Villanueva, MDInstitute of Liver Studies, Division of TransplantationImmunology andMucosal Biology, King’s College London, UK

Adina VulturTheWistar Institute Melanoma Research Center, Philadelphia,PA, USA

ChenguangWangDepartment of Stem Cell Biology and Regenerative Medicine,Kimmel Cancer Center, Thomas Jefferson University,Philadelphia, PA, USA

FenWangCenter for Cancer and Stem Cell Biology, Institute ofBiosciences and Technology, Texas A&MHealth ScienceCenter, Houston, TX, USA

Jean Y. J. WangDivision of Hematology-Oncology, Department of Medicine,Moores Cancer Center, University of California, San Diego, LaJolla, CA, USA

Ling-YuWangDepartments of Biochemistry and Molecular Medicine,University of California David School of Medicine,Sacramento, CA, USA

Janindra WarusavitarneDepartment of Surgery, St Mark’s Hospital, Harrow,Middlesex, UK

JodyWhiteFrank Reidy Research Center for Bioelectrics, Old DominionUniversity, Norfolk, VA, USA

Woodring E. WrightUniversity of Texas Southwestern Medical Center, Departmentof Cell Biology, Dallas, TX, USA

Michael B. YaffeDavid H. Koch Institute for Integrative Cancer Research andDepartment of Biological Engineering, Massachusetts Instituteof Technology, Cambridge, MA, USA

Ji-Yeon Yang, PhDDepartments of Experimental Therapeutics, GynecologicMedical Oncology, Bioinformatics and ComputationalBiology, and Systems Biology, University of Texas M.D.Anderson Cancer Center, Houston, TX, USA

Yosef YardenDepartment of Biological Regulation, TheWeizmann Instituteof Science, Rehovot, Israel

Timothy J. Yeatman, MDGibbs Cancer Center and Research Institute, Spartanburg, SC,USA

Khay Guan Yeoh, MBBS, FRCP, FRCP (Glasg)Department of Medicine, Yong Loo Lin School of Medicine,National University of Singapore and National UniversityHealth System, Singapore

Dihua Yu, MD, PhDUniversity of Texas, M.D. Anderson Cancer Center, Houston,TX, USA

Hua Yu, PhDBeckham Research Institute, City of Hope, Duarte, CA, USA

Siyuan Zhang, MD PhDUniversity of Texas, M.D. Anderson Cancer Center, Houston,TX, USA

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Xuemin ZhangState Key Laboratory of Proteomics, Institute of Basic MedicalSciences, National Center of Biomedical Analysis, Beijing,China

Antonella ZucchettoClinical and Experimental Onco-Hematology Unit, Centro diRiferimento Oncologico, I.R.C.C.S., Aviano, Pordenone,Italy

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Preface

This bookwas conceivedmore than five years before its publica-tion date. It was intended to provide a resource that summarizedtechnology, biochemistry, molecular pathophysiology, and tar-geted therapeutics. As contributors were being recruited andchapters written the field that was being described changed atan accelerating pace. It is a tribute to scientific progress that vol-umes like this are out-of-date as they are published, but bookslike this are not meant to contain the most current laboratorydiscovery or report the most recent FDA approval.

While this book was being written there have been majoradvances in molecular oncology. The Cancer Genome Atlas(cancergenome.nih.gov) has demonstrated the broad spectrumof mutations in an expanding list of cancers. DNA sequenceanalysis alone has demonstrated that as cancers grow, metas-tasize, and develop treatment resistance, individual tumor siteswithin a single patient evolve differently and demonstrateincreasingly complex spectra of driver and passenger muta-tions.These findings alone strongly support theDarwinian viewof tumor progression.The complexities of cellular dysregulationin cancer may arise fromDNA sequence changes, but extend toother levels of gene regulation. During the writing of this bookthe role of micro-RNAs (miRNAs) in cancer was elucidated.Aberrations in epigenetics such as DNA methylation and his-tone acetylation were demonstrated. Cancer drug developmenthas also proceeded at increasing rates. In the period 2008–2012there were 51 approvals of new drugs for cancer treatment bytheUSFood andDrugAdministration.Many of these approvals

resulted from impressive data in Phase II trials that clearlydemonstrated efficacy where no agents have worked before.

As we have assembled the contributions for this volume wehave watched as more and more information is provided andaccessed in electronic format, replacing the printed word. It isnot hard to predict that younger generations of investigatorswill dispense entirely with books and access all information onelectronic screens. Clearly a volume like this ismeant to providerapid reference when accessed from a shelf in someone’s office.

We the editors took on the task of assembling this volumeto provide background for active researchers, to provide mean-ingful lists of important citations that form the foundation ofthemolecular pathophysiology of cancer, and to define the con-text in which current investigation is pursued. This book isintended for students and professionals in academia and indus-try. Where electronic databases are non-discriminatory andweb-based searches can be overwhelming in their downloadlists, volumes like this provide the perspective and judgmentof experts who have spent a very long time in a path of studyand therefore share their understanding and viewpoints that aremissed in database or electronic literature searches. Volumeslike this collect the experience and wisdom of the contributorsand therefore provide value and perspective. As journal titlesproliferate and the scientific literature expands, it is books likethis that guide knowledge and help organize the work in a fieldinto a comprehensible narrative. We hope you find these pagesuseful.

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