Robert A.

Weinberg

The Biology of Cancer

First Edition

Chapter 12:
Maintenance of Genomic Integrity
and the Development of Cancer
Copyright Garland Science 2007

 normal cells / senescence

immortalize/ transformation

Colon cancer
multisteps process

How many mutations are

required for cancer formation?

3 to 7 mutations

Solid tumors requires a greater number

of mutations for their development than
liquid tumors.

What genes are mutated in

cancers?

Table 11.2 The Biology of Cancer ( Garland Science 2007)

 The genes that directly

control cellular proliferation
The genes control the rate of
mutation

Genetic instability:
Sequence level: mutation, deletion,
insertion, translocation
Chromosomal level:
aneuploid() cells

Single base pair substitutions

account for the majority of gene defect

How does these happened?

genetic instability is dependent on :

rate of error accumulation
efficiency of DNA repair

How does mutations happened?

Polymerase error
Spontaneously depurinaition, depyrimidination,
deamination
Mutagene

proofreading
Pol-

Figure 12.6 The Biology of Cancer ( Garland Science 2007)

Pol- mutant
Proofreading domain

Figure 12.7 The Biology of Cancer ( Garland Science 2007)

Mismatch repair (MMR)

MutS:mismatch
MutL:single strand nick

Figure 12.8c The Biology of Cancer ( Garland Science 2007)

Microsatellites instability (MIN)

Figure 12.8a The Biology of Cancer ( Garland Science 2007)

Figure 12.28 The Biology of Cancer ( Garland Science 2007)

 Pol- error: 10-5

Proofreading error: 10-2
MMR error: 10-2
DNA replication error

10-9

How does mutations happened?

Polymerase error
Spontaneously depurinaition,
depyrimidination, deamination, oxidation
Mutagene

depurination: 10,000/cell/day
(under low concentration ~10-7M)

Figure 12.11a The Biology of Cancer ( Garland Science 2007)

deamination
T

repaired

C
T
Major source point mutation
Figure 12.11b The Biology of Cancer ( Garland Science 2007)

Oxidation
O2+e-

O2 .- +e-

H2O2+e-

Superoxide
ion

H2O

ROS: reactive oxygen species

.OH+eHydroxy
radical

Figure 12.12a The Biology of Cancer ( Garland Science 2007)

G:T transversion

Figure 12.12b The Biology of Cancer ( Garland Science 2007)

inflammation
Phagocytosis release
NO, O2 .- , H2O2, OCl-

Induce oxidation of DNA

How does mutations happened?

Polymerase error
Spontaneously depurinaition,
depyrimidination, deamination, oxidation
Mutagene

 enviromental factor: responsible for up to 80% of all cancers

*smoking
*alcohol
*diet
*radiation: radiation, UV
*occupational expose
*drug

infection
genetic factor

UV radiation

CPD
Figure 12.14a The Biology of Cancer ( Garland Science 2007)

UV radiation

Figure 12.14b The Biology of Cancer ( Garland Science 2007)

A
The genetic basis of human cancer; K. W. kinzler 2nd edition 2002

Alkylated agents

Figure 12.14c The Biology of Cancer ( Garland Science 2007)

Figure 12.15b The Biology of Cancer ( Garland Science 2007)

DNA adduct
Figure 12.16 The Biology of Cancer ( Garland Science 2007)

Figure 12.18b The Biology of Cancer ( Garland Science 2007)

Mutations caused by DNA-damaging agents.

Base pairing
Modifying agent

Example

Recognised as

Old

New

Small adduct

GMe.G

G:C

A:T

Large adduct

GG.BP

G:C

T:A

Pyrimidine dimers

G:C

A:T

Oxidations

G8-OH.G

G:C

T:A

Oxidations

Strand breaks

Deletions

Ionising radiations

Strand breaks

Deletions

Ultraviolet light

A, G, C, T, DNA bases; Me, methyl; BP, benzopyrene.

Cancer Biology, Roger J. B. KING, Longman; Table 7.7., p.99

Common heterocyclic amines: from cooked food

Induce colon and breast cancer

in rats; lymphomas in mice
Figure 12.19a The Biology of Cancer ( Garland Science 2007)

2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine

Figure 12.19b The Biology of Cancer ( Garland Science 2007)

Mutations caused by DNA-damaging agents.

Base pairing
Modifying agent

Example

Recognised as

Old

New

Small adduct

GMe.G

G:C

A:T

Large adduct

GG.BP

G:C

T:A

Pyrimidine dimers

G:C

A:T

Oxidations

G8-OH.G

G:C

T:A

Oxidations

Strand breaks

Deletions

Ionising radiations

Strand breaks

Deletions

Ultraviolet light

A, G, C, T, DNA bases; Me, methyl; BP, benzopyrene.

Cancer Biology, Roger J. B. KING, Longman; Table 7.7., p.99

Figure 12.17 The Biology of Cancer ( Garland Science 2007)

Protect DNA from attack

Physically shields: melanin
Chemical protection:
ROS detoxify
GST

Figure 12.20 The Biology of Cancer ( Garland Science 2007)

ROS detoxify
Catalase, superoxide dismutase
Free radical scavengers: Vit. C, Vit.E etc.

Figure 12.21a The Biology of Cancer ( Garland Science 2007)

epoxide

Tumor cells lack GST

Figure 12.21b The Biology of Cancer ( Garland Science 2007)

genetic instability is dependent on :

rate of error accumulation
efficiency of DNA repair

DNA repaired system

DNA alkyltransferase: reverse the Rx

Figure 12.22a The Biology of Cancer ( Garland Science 2007)

MGMT transgenic mice

Figure 12.22c The Biology of Cancer ( Garland Science 2007)

MGMT was down regulated by methylation in

some tumors

Repair system
Nucleotide excision repair (NER)

Mismatch repair (MMR)

Base-excision repair (BER)

Recombinational repair

Nature 411, 366 - 374

Figure 12.23a The Biology of Cancer ( Garland Science 2007)

Figure 12.23b The Biology of Cancer ( Garland Science 2007)

XPB, XPD

>25 protein involved in

Xeroderma pigmentosum (XP)

NER complex protein
XPA------XPG

Figure 12.25 The Biology of Cancer ( Garland Science 2007)

Skin cancer

Figure 12.26 The Biology of Cancer ( Garland Science 2007)

error-prone repair

Figure 12.24 The Biology of Cancer ( Garland Science 2007)

Mismatch repair (MMR): microsatellite instability (MIN)

e.g. Poly (CA) repeats
hereditary non-polyposis colorectal cancer (HNPCC):hMLH1

Mutation in 6 MMR genes has been identified: MSH2, MLH1,

PMS1, PMS2, MSH6
colon cancer, gastric cancer, endometrial cancer~~ 13%
others < 2%

Table 12.2 The Biology of Cancer ( Garland Science 2007)

Homology directed repair

Figure 12.32 The Biology of Cancer ( Garland Science 2007)

Nonhomologous end joining

Figure 12.33 The Biology of Cancer ( Garland Science 2007)

Brca2 mutation: chromosome translocation or unrepaired

Figure 12.31a The Biology of Cancer ( Garland Science 2007)

Figure 12.34a The Biology of Cancer ( Garland Science 2007)

Figure 12.34b The Biology of Cancer ( Garland Science 2007)

Table 12.1 The Biology of Cancer ( Garland Science 2007)

Chromosome instability
mis-segregation: checkpoint control

Colorectal cancer

Figure 12.36a The Biology of Cancer ( Garland Science 2007)

Figure 12.39 The Biology of Cancer ( Garland Science 2007)

Table 12.3 The Biology of Cancer ( Garland Science 2007)

Figure 10.14a The Biology of Cancer ( Garland Science 2007)

Figure 10.14b The Biology of Cancer ( Garland Science 2007)

Figure 10.14c The Biology of Cancer ( Garland Science 2007)

Types of genetic alternations

1.Subtle sequence changes
2.Chromosome translocations
3. Alterations in chromosome number (CIN)
4.Gene amplification
5. Exogenous sequences