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Mechanisms of

Mutagenesis &
Carcinogenesis
Jamil Momand, Ph.D.
California State University at Los
Angeles

Outline (in brief)


Introduction
Carcinogenesis - a definition
Pathways to cancer: overview
Oncogenes
Tumor suppressor genes
Apoptosis
Telomerase
Angiogenesis
Summary

Maintenance of
homeostasis
Adult human maintains ~1015 cells
Stem cells undergo ~1012 divisions
per day
There is a balance between cell
birth and cell death
Random mutations disrupt
homeostasis

Molecular basis for cancer


progression
DNA damage
Failure to repair damage
Failure to destroy cells with DNA damage
Mutation
Selection advantage

Example of DNA damage

From Bertram, Molecular Aspects of Medicine 21, 2001, 161-223

List of carcinogens
Chemical
Physical
Asbestos
Gamma radiation
Arsenic
UV light
Chromium
Radon
Polyaromatic
X-rays
hydocarbons
Viruses*
dichlorodiphenyltrichloroethane (DDT)

http://www.eur.nl/fgg/ch1/gen_research/dbr-man.html

Hereditary form of colon


cancer
Case 1:
Beth M.'s father died of colon cancer, as did her grandmother.
Now
two of her brothers, both in their 40's, have been diagnosed
with colon
cancer. Beth, age 37, feels a curse is hanging over her family
and is
worried about her future and that of her children.
Case 2:
Paul C. was 35 when his doctor told him the grim news: he had
advanced colon cancer. As far as he knew, Paul had no family
history
of the disease. But after checking, Paul learned that several
aunts
and uncles had died of colon cancer at an early age.
Diagnosis:

hereditary nonpolyposis colorectal cancer


(HNPCC)

From Bertram, Molecular Aspects of Medicine 21, 2001, 161-223

Clonal Nature of Cancer


Cancers are composed of cells that
descended from a single cell.
Evidence 1: X-chromosome inactivation
Evidence 2: Ig genes in lymphomas and
leukemias are identically rearranged.
Multistage theory of cancer development
(Armitage and Doll, 1954)

http://www.hhmi.org/communic/annrep/research/regulate

Viruses and cancer


Viruses account for 15% of all cancers
DNA viruses

Epstein-Barr virus
Human papilloma virus
Hepatitis B virus

RNA viruses

HIV-1
HTLV-1
HTLV-2

Protection

DNA Damage

Progression
Normal
Cell

Repair

Mutation

Cell cycle arrest

Proliferation

Initiatied
Cell
Apoptosis

Immortality

Chemotherapy
Radiation therapy

Mutator phenotype

Cancer
Cell
Angiogenesis

Mutations

Proliferation

Necrosis

Metastasis

Adapted from Bertram, Molecular Aspects of Medicine 21, 2001, 1

Definitions of terms
Amplification
Immortal
Oncogene
Point mutation
Proto-oncogene
Transformation
Translocation

DNA Amplification

c-myc translocation

DNA Methylation and


Demethylation-ways to
control expression of
genes

Point mutation activation of


Ras

Oncoprotein pathways

http://www.biocarta.com/pathfiles/pdgfPathway.asp

Her2/neu/erbB-2
This gene was discovered by three
different groups. That is why it has three
different names.
Its oncogene counterpart is v-erbB-2
Dr. Slamon (UCLA) described the role of
Her2/neu in breast cancer and ovarian
cancer.
Overexpression, amplification, rare
translocations
No ligand is known

The Philadelphia Chromosome

BCR-ABL translocation and


expression

http://www.kent.k12.wa.us/staff/vhoward/apbio/oncogenes/brc-ablcartoon.gif

STI-571--an inhibitor of
BCR-ABL function

http://www.blc.arizona.edu/courses/181gh/Lectures_WJG.01/cell_signaling.01/Applications.html

PET scanning to show efficacy of STI571 on tumor metastasis

http://www.blc.arizona.edu/courses/181gh/Lectures_WJG.01/cell_signaling.01/Applications.html

Design of experiment to clone the


first human cellular oncogene (Shi et al.,
1979)

What we have learned


Human cellular oncogenes are dominantacting genes that transform cells and
cause tumors in mice.
Activation-abnormality that results in
higher than normal level of biochemical
activity.

Point mutation
Overexpression

Proto-oncogenes-The wild-type noncancerous form of the oncogene

How are oncogenes


activated?
Point mutation-Eg. K-ras,
Amplification-Eg. N-myc, MDM2,
Her2/neu/ErbB2
Chromosome translocation-Eg. cmyc, bcr-abl
Overexpression due to DNA
demethylation

Tumor suppressor genes


Somatic cell hybrids
Knudsens hypothesis
Mutations and mechanisms that
lead to tumor suppressor gene
loss of function
RB
p53

Somatic cell hybrids

Transformed

Cell fusion

Normal

Harris et al., 1969

Normal

Genetics of
Retinoblastoma

Pedigree of Rb-prone
family

Alfred Knudson

Knudsons hypothesis

Mechanisms of tumor
suppressor gene
inactivation
Deletion
Point mutation
Mutation followed by duplication
Loss of heterozygosity
DNA methylation
Post-translational mechanismbinding to DNA viral oncoproteins

Genetic mapping of Rb
susceptibility gene

RB function

http://p53.curie.fr/p53%20site%20version%202.0/p53%20in%20cancer/p53_databaseANAL.htm

p53 mutation spectrum

p53 structure

p53 signal
transduction pathway
[MDM2/p53] complex
(transient)

degradation

p53 Latent

p53
Stabilization

Transcription

DNA damage
Other p53 functions

1. MDM2
2. GADD45
3. WAF1/CIP1
4.
5.

synthesis
n

DNA Repair
Cell cycle
arrest
Cell Death

Functional domains of
BRCA1

Transcriptional
activation

Dimerization
Ring finger

NLS

BRCA1 C-Term. domains

Proteins that bind BRCA1:


BARD1
Rb
BRCA2
p3
BAP1
p53
RHA
E2F1
Rad51
RNA PolII
cMyc
Rad50
CREB binding protei

BRCA1
Mapped to chromosome 17q by Mary Clair King in
1990
Linkage was also found in ovarian cancer families.
More than 90% of women with germline BRCA1
mutations lose the wild-type allele in breast tumor.
The gene encodes a nuclear phosphoprotein of 220
kD (1863 aas)
The mRNA is 5711 bases long
24 exons, 22 of which is coding

BRCA1 (cont. 1)
BRCA1-deficient ES cells are hypersensitive to
oxidative reagents
BRCA1-deficient ES cells are defective in
transcription-coupled repair
Expression of BRCA1 leads to p21CIP1/WAF1
upregulation and G1-S cell cycle arrest (is this
through p53?)
BRCA1del11 maintain G1-S cell cycle arrest but
not G2-M arrest.

http://www.biocarta.com/pathfiles/atmPathway.asp

What have we learned


about tumor suppressor
proteins?
Both alleles are deleted in the cancer
If one allele is mutated at birth then
patients have increased susceptibility
to cancer at an early age
They often serve as cell cycle
checkpoints or DNA repair activities

Apoptosis-programmed
cell death

BCL-2 is a protooncogene that gets overexpressed in


some B-cell leukemias

Other processes that


affect tumor formation
and
growthexpression
Telomerase
Angiogenesis

The BIG picture-a


molecular analysis of
mutations in colorectal
cancers

Correlation of tumor morphology to


specific allelic deletion
(Vogelstein et al., 1988)

Future studies-profiling
cancers with DNA arrays

http://cmgm.stanford.edu/pbrown/

http://www.pnas.org/cgi/content/full/241500798

Dilbert by Scott Adams


San Gabriel Valley Tribune, Sept. 10, 2000

References
Bertram, J.S. (2001) The molecular biology of cancer.
Molecular Aspects of Medicine 21, 167-223.
Gelehrter et al. Principles of Medical Genetics, 2nd ed.
pp 245-272, Williams & Wilkins, Baltimore, 1998.
Levine and Lane, (2000) Surfing the p53 network.
Nature 408, 307-310
Angier, N., Natural Obsessions: Striving to Unlock the
Deepest Secrets of the Cancer Cell, Mariner
Books/Houghton Mifflin Co, 1999.
Bazell,R., Her-2: The Making of Herceptin, a
Revolutionary Treatment for Breast Cancer, Crown
Publishing Group, 1998.