Principles of Cancer Genetics

Fred Bunz, M.D., Ph.D is a native of Long Beach, New York. He attended Stony Brook University and graduated from its Medical Scientist Training Program. His doctoral research in the enzymology of human DNA replication was conducted at Cold Spring Harbor Laboratory. Dr. Bunz completed a postdoctoral fellowship in Cancer Genetics at The Johns Hopkins University and the Howard Hughes Medical Institute, and now heads a laboratory at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins that is focused on understanding the effects of DNA damage on cancer cells and normal cells. He lives in Baltimore with his wife, two children, a cat, and an Old English Sheepdog. 

 

Preface

Chapter 1: The Genetic Basis of Cancer

The cancer gene theory

Cancers are invasive tumors

Cancer is a unique type of genetic disease

What are cancer genes and how are they acquired?

Mutations alter the human genome

Genes and mutations



Single nucleotide substitutions

Gene silencing is marked by cytosine methylation: epigenetics

Environmental mutagens, mutations and cancer

Inflammation promotes the propagation of cancer genes

Stem cells, Darwinian selection and the clonal evolution of cancers

Selective pressure and adaptation:  hypoxia and altered metabolism

Multiple somatic mutations punctuate clonal evolution

Tumor growth leads to cellular heterogeneity

Tumors are distinguished by their spectrum of driver gene mutations and passenger gene mutations

Colorectal cancer: a model for understanding the process of tumorigenesis

Do cancer cells divide more rapidly than normal cells?

Germline cancer genes allow neoplasia to bypass steps in clonal evolution

Cancer syndromes reveal rate-limiting steps in tumorigenesis

The etiolog

ic triad: heredity, the environment, and stem cell division

Understanding cancer genetics

 

Chapter 2:  Oncogenes

What is an oncogene?

The discovery of transmissible cancer genes

Viral oncogenes are derived from the host genome

The search for activated oncogene











s:  the RAS gene family

Complex genomic rearrangements: the MYC gene family

Proto-oncogene activation by gene amplification

Proto-oncogenes can be activated by chromosomal translocation

 

Chromosomal translocations in liquid tumors

Chronic myeloid leukemia and the Philadelphia chromosome

Oncogenic activation of transcription factors in Prostate cancer and Ewing’s sarcoma

Oncogene discovery in the genomic era: mutations in PIK3CA

Selection of tumor-associated mutations

Multiple modes of proto-oncogene activation

Oncogenes are dominant cancer genes

Germline mutations in RET and MET confer cancer predisposition

Proto-oncogene activation and tumorigenesis

 



Chapter 3:  Tumor Suppressor Genes

What is a tumor suppressor gene?

The discovery of recessive cancer phenotypes

Retinoblastoma and Knudson’s two-hit hypothesis

Chromosomal localization of the retinoblastoma gene

The mapping and cloning of the retinoblastoma gene

Tumor suppressor gene inactivation: the second ‘hit’ and loss of heterozygosity

Recessive genes, dominant traits

APC inactivation in inherited and sporadic colorectal cancers

TP53 inactivation: a frequent event in tumorigenesis

Functional inactivation of p53: tumor suppressor genes and oncogenes interact

Mutant TP53 in the germl

ine:  L

i Fraum

eni syn

drome

Ga

ins-of-function caused by cancer-associated mutations in TP53

Cancer predisposition: allelic penetrance, relative risk and the odds ratio

Breast cancer susceptibility:  BRCA1 and BRCA2

Genetic losses on chromosome 9:  CDKN2A

Complexity at CDKN2A:  neighboring and overlapping genes

Genetic losses on chromosome 10:  PTEN

SMAD4 and the maintenance of stromal architecture

Two distinct genes cause neurofibromatosis

From flies to humans, Patched proteins regulate developmental morphogenesis

von Hippel-Lindau disease

NOTCH1: tumor suppressor gene or oncogene?

Multiple endocrine neoplasia type 1

Most tumor suppressor genes are tissue-specific

Modeling cancer syndromes in mice



Genetic variation and germline cancer genes

Tumor suppressor gene inactivation during colorectal tumorigenesis

Inherited tumor suppressor gene mutations: gatekeepers and landscapers

Maintaining the genome: caretakers

 

Chapter 4:  Genetic Instability and Cancer

What is genetic instability?



The majority of cancer cells are aneuploid

Aneuploid cancer cells exhibit chromosome instability

Chromosome instability arises early in colorectal tumorigenesis

Chromosomal instability accelerates clonal evolution

Aneuploidy can result from mutations th

at directly im

pact mitosis

STAG2

and

the cohesion

of sister chromatids

Other genetic and epigenetic causes of aneuploidy

Transition from tetraploidy to aneuploidy during tumorigenesis 

Multiple forms of genetic instability in cancer

Defects in mismatch repair cause hereditary nonpolyposis colorectal cancer

Mismatch repair-deficient cancers have a distinct spectrum of mutations

Defects in nucleotide excision repair cause xeroderma pigmentosum

NER syndromes: clinical heterogeneity and pleiotropy



DNA repair defects and mutagens define two steps towards genetic instability

Defects in DNA crosslink repair cause Fanconi anemia

A defect in DNA double strand break responses causes ataxia-telangiectasia

A unique form of genetic instability underlies Bloom syndrome

Aging and cancer:  insights from the progeroid syndromes

Instability at the end: telomeres and telomerase

Overview: genes and genetic stability



 

Chapter 5:  Cancer Genomes

Discovering the genetic basis of cancer: from genes to genomes

What types of genetic alterations are found in tumor cells?

How many genes are mutated in the various types of cancer?

What is the significance of the mutations that are found in cancers?

When do cancer-associated mutations occur?



How many different cancer genes are there?

How many cancer genes are required for th

e development

of cancer?

Cance

r genetics sha

pes our understanding

of metastasis

Tumors are genetically heterogenous

Beyond the exome: the ‘dark matter’ of the cancer genome

A summary:  the genome of a cancer cell

 



Chapter 6:  Cancer Gene Pathways

What are cancer gene pathways?

Cellular pathways are defined by protein-protein interactions

Individual biochemical reactions, multistep pathways, and networks

Protein phosphorylation is a common regulatory mechanism

Signals from the cell surface:  protein tyrosine kinases

Membrane-associated GTPases:  the RAS pathway



An intracellular kinase cascade: the MAPK pathway

Genetic alterations of the RAS pathway in cancer

Membrane-associated lipid phosphorylation: the PI3K/AKT pathway

Control of cell growth and energetics:  the mTOR pathway

Genetic alterations in the PI3K/AKT and mTOR pathways define roles in cell survival

The STAT pathway transmits cytokine signals to the cell nucleus

Morphogenesis and cancer:  the WNT/APC pathway

Dysregulation of the WNT/APC pathway in cancers

Notch signaling mediates cell-to-cell communication

Morphogenesis and cancer:  the Hedgehog pathway

TGF-/ SMAD signaling maintains adult tissue homeostasis

MYC is a downstream effector of multiple cancer gene pathways

activation is triggered by damaged or incompletely

replicated chromosom

es

p53 is controlled b

y protein kinases enc

oded by

tumor suppressor genes

p53 induces the transcription of genes that suppress cancer phenotypes

Feedback loops dynamically control p53 abundance

The DNA damage signaling network activates interconnected repair pathways

Inactivation of the pathways to apoptosis in cancer

RB1 and the regulation of the cell cycle

Several cancer gene pathways converge on cell cycle regulators



Many cancer cells are cell cycle checkpoint-deficient

Chromatin modification is recurrently altered in many types of cancer

Summary: putting together the puzzle 

 

Chapter 7:  Genetic Alternations in Common Cancers

Cancer genes cause diverse diseases

Cancer incidence and prevalence

Lung cancer



Prostate cancer

Breast cancer

Colorectal cancer

Endometrial cancer

Melanoma of the skin

Bladder cancer

Lymphoma

Cancers in the kidney

Thyroid cancer

Leukemia

Cancer in the pancreas

Ovarian cancer

Cancers of the oral cavity and pharynx

Liver cancer

Cancer of the uterine cervix

Stomach cancer



Brain tumors

 

Chapter 8: Cancer Genetics in the Clinic

The uses of genetic information

Elements of cancer risk:  carcinogens and genes

Identifying carriers o

f germline cancer genes

Cance

r genes as biomarkers of ear

ly stage malignancies

Cancer

genes as biomarkers f

or diagnosis, prognosis and recurrence

Conventional anticancer therapies inhibit cell growth

Exploiting the loss of DNA repair pathways: synthetic lethality

On the horizon: achieving synthetic lethality in TP53-mutant cancers

Molecularly targeted therapy:  BCR-ABL and imatinib

Clonal evolution of therapeutic resistance

Targeting EGFR mutations



Antibody-mediated inhibition of receptor tyrosine kinases

Inhibiting Hedgehog signaling

A pipeline from genetically-defined targets to targeted therapies

Neoantigens are recognized by the immune system

The future of oncology

Index