Table Of ContentKevin M. Haigis Editor
Molecular
Pathogenesis
of Colorectal
Cancer
Molecular Pathogenesis of Colorectal Cancer
Kevin M. Haigis
Editor
Molecular Pathogenesis
of Colorectal Cancer
Editor
Kevin M. Haigis, Ph.D.
Molecular Pathology Unit
Harvard Medical School
Charlestown , MA , USA
ISBN 978-1-4614-8411-0 ISBN 978-1-4614-8412-7 (eBook)
DOI 10.1007/978-1-4614-8412-7
Springer New York Heidelberg Dordrecht London
Library of Congress Control Number: 2013949281
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Pref ace
Colorectal cancer (CRC) represents a major healthcare burden worldwide for two
simple reasons: it is common and it is deadly. And while improvements in early
detection have helped to reduce the incidence of CRC-related death over the past
several decades, the overall frequency of the disease is likely to increase steadily
due to its connection to western style diet, which is spreading across the globe, and
to obesity and chronic infl ammation (i.e., infl ammatory bowel disease), which are
also rapidly increasing in incidence. As a result, a new generation of effective CRC
therapies is greatly needed. The search for new therapies to treat CRC is intertwined
with the identifi cation of the molecular etiology of the disease.
Even prior to the advent of whole genome sequencing, many of the mutant genes
that contribute to CRC ( APC , KRAS , TP53 ) were known from targeted sequencing
efforts. As a result, CRC has become the paradigm for multistage tumorigenesis,
where the histologically defi ned transition states from normal tissue to malignancy
can be associated with mutations in specifi c genes or pathways. As we enter the
post-genomic era, it is possible that most, if not all, of the genes that contribute to
CRC in a meaningful way have been identifi ed. Now it is time to leverage the exten-
sive mutational information to establish new therapeutic strategies. This will require
a combination of functional genomics (i.e., genetics), medicinal chemistry, and pre-
clinical and clinical efforts.
The goal of this book is to provide a broad overview of the state of understanding
of the molecular pathogenesis of CRC. This book is organized as a timeline of the
study of CRC. Chapters 1 and 2 provide a general and historical viewpoint of the
role for genetic changes and genomic instability in CRC. Chapters 3 – 8 discuss the
roles of specifi c pathways (RAS, PI3K, TGF-β) or environmental conditions
(infl ammation). And Chaps. 9 – 12 look toward the future, focusing on the potential
for genome-wide analyses to fi nd new genes/pathways that contribute to CRC.
I hope that the reader will get an appreciation for the rich history of CRC research
and a fresh perspective on the possibilities for emerging therapeutic options.
Charlestown , MA Kevin M. Haigis , Ph.D.
v
Contents
1 The Genetics of Colorectal Cancer ........................................................ 1
William Hankey and Joanna Groden
2 Molecular Mechanisms of Colorectal Carcinogenesis ......................... 25
Jatin Roper and Kenneth E. Hung
3 The Association Between Infl ammation and Colorectal Cancer ........ 67
Maria José Oliveira and Sérgia Velho
4 Importance of the Niche: Wnt Signaling
and Stem Cell Plasticity in Intestinal Homeostasis and Disease ......... 107
Owen J. Sansom and Inke Näthke
5 Mutational Activation of K RAS and BRAF
in Colorectal Cancer ............................................................................... 121
Katherine H. Pedone, Jennifer L. Sells, and Channing J. Der
6 The PI3K Pathway in Colorectal Cancers ............................................ 157
Jihye Yun, George Poulogiannis, Evan T. Brower, Samuel Klempner,
and Lewis L. Cantley
7 TGF-ß Signaling Pathway and Colorectal Cancer .............................. 201
William M. Grady
8 The Clinical Signifi cance of Mutations in Colorectal Cancer ............. 231
Franklin W. Huang, Laura B. Kleiman, and Theodore S. Hong
9 Colorectal Cancer Genome and Its Implications ................................. 247
Nickolas Papadopoulos
10 Copy-Number Alterations in the Colorectal Cancer Genome ............ 267
Jihun Kim and Adam J. Bas s
vii
viii Contents
11 Genome-Wide Association Studies in Colorectal Cancer ................... 289
Ian Tomlinson
12 Future Prospects for Leveraging Molecular Information
in the Fight Against Colorectal Cancer................................................. 303
Laura B. Kleiman and Kevin M. Haigis
Index ................................................................................................................. 309
Chapter 1
The Genetics of Colorectal Cancer
William Hankey and Joanna Groden
Abstract Colorectal cancer (CRC) develops over a period of years through a
defi ned progression from a single aberrant crypt to a benign adenoma and ulti-
mately to an invasive malignancy. These phenotypic steps parallel a series of under-
lying changes at the DNA level. Many of the critical tumor suppressor loci have
been identifi ed through cytogenetic or genetic linkage studies of inherited disorders
that predispose affected family members to the development of benign or malignant
lesions in the colorectal epithelium. Inactivating mutations in the A PC gene not only
were fi rst identifi ed in the germline of individuals with familial adenomatous pol-
yposis coli but also are present in most sporadic CRCs. Germline mutations in
MSH2 , MLH1 , MSH6 , or P MS2 predispose individuals with Lynch syndrome to
CRCs with DNA mismatch repair defects; these genes can be mutated or silenced in
sporadic CRCs as well. Other inherited mutations are responsible for benign
colorectal lesions that rarely progress to malignancy, including those found in the
SMAD4 , BMPR1A , and PTEN genes. Sporadic changes in these genes are found in
malignant rather than premalignant lesions, suggesting that these mutations pro-
mote rather than initiate tumorigenesis. Genetic analysis of CRCs will permit strati-
fi cation for improved prognosis and treatment.
1.1 Introduction
Colorectal carcinoma has been observed in humans as far back in history as the time
of the ancient Egyptians (Zimmerman 2 003 ) while the term carcinoma has been
used to describe the broader classifi cation of solid tumors since the time of
W. Hankey • J. Groden (*)
Department of Molecular Immunology, Virology & Medical Genetics ,
The Ohio State University College of Medicine , 460 West 12th Avenue,
986 Biomedical Research Tower , Columbus , OH , USA
e-mail: [email protected]
K.M. Haigis (ed.), Molecular Pathogenesis of Colorectal Cancer, 1
DOI 10.1007/978-1-4614-8412-7_1, © Springer Science+Business Media New York 2013
