台大農藝系 遺傳學 601

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Chapter 22 slide 1

Tumor Genetics

MGL-12

July 21st 2013

Mohammed El-Khateeb

2

Cellular Basis of Cancer

• Cancer is a collection of diseases characterized

by abnormal and uncontrolled growth

• Cancer arises from a loss of normal growth

control

• In normal tissues, the rates of new cell growth

and old cell death are kept in balance

• In cancer, this balance is disrupted

• This disruption can result from

1) uncontrolled cell growth or

2) loss of a cell's ability to undergo apoptosis

3

Cancer Cell Do Not Grow Faster

Than Normal Cells

Rather, Their Growth is Just

Uncontrolled

4

Proliferation Differentiation Death

Transit

Proliferating

Exiting

Renewing

Cellular equilibrium

5Proliferation Differentiation Death

Cancer: disruption of

cellular equilibrium

6

Post mitoticStem cell

DifferentiatedNormal

senescent

differentiated

cell

Benign tumor

Grade 2

malignancy

Grade 3 or 4

malignancy

Stem cells as the target of carcinogens

CELL GROWTH

• Cells in the body are "programmed" to:

To develop

To grow

To differentiate

To die

• in response to a complex system

of biochemical signals.

Cancer results from the emergence of a clone of cells

freed of these developmental programming constraints

and capable of inappropriate proliferation

Cancer is a Disease of the Cell Cycle

Response to the

Environmental Signals

• SIGNALS RESPONSE

Growth Factors Differentiation

Steroids

Cell to Cell Interaction

Growth and Death

Mitosis

Fig. 18.2, Regulation of cell division by signal transduction.

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Class I: Growth Factors

Class II: Receptors for Growth Factors and Hormones

Class III: Intracellular Signal Transducers

Class IV: Nuclear Transcription Factors

Class V: Cell-Cycle Control Proteins

Five types of proteins encoded by proto-oncogenes participate in control

of cell growth:

Types of Growth Factors

for Differentiation

1.Growth Factors

2.TM GF R (TKase)

3. Integral MR

4. Ras GTPase

5. Cytoplasmic

Oncogenes

6. Nuclear Oncogene

Oncogenes and Proto-Oncogenes

Products

Cancer cells have acquired the ability to

proliferate in the absence of appropriate

signals

Cancer: General Etiology

and Pathogenesis

• Etiologic agents: Environmental (chemical, physical, and biological)

Hereditary (familial cancer syndromes)

• General mechanisms: Acquired capabilities (Self-maintained replication,

longer survival, genetic instability, neoangiogenesis, invasion and metastasis)

Activation of oncogenes, inactivation of TSG, non-effective DNA repair

Caretaker and gatekeeper pathways

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Cause Damage Cancer Risk Signals

Physical

UVSkin Ca,

MelanomaP53 (CC-TT)

RadiationThyroid Ca.,

LeucemiaTranslokation

Chemical

Benzopren Lung Ca. p53 (G-T)

Aflatoxin Liver Ca. p53 (249 G-T)

Oxidative

StressGeriatric Ca P53 (C-T)

Biological HBV Liver Ca.Virus DNA

Integration

THE CAUSES OF GENOMIC CHANGES

IN CANCER : Somatic Changes

Chemical Signals that Control the Cell

Cycle

1. Cyclin and Kinase

proteins that initiate mitosis

requires buildup of cyclin to pair with kinase

2. Hormones

chemical signals from specialized glands that stimulate mitosis

3. Growth Factors

chemical factors produced locally that stimulate mitosis

Cell cycle and cancer:

Cell differentiation occurs as cells proliferate to form

tissues.

• Cell differentiation correlates with loss of ability to

proliferate; highly specialized cells are terminally

differentiated.

• Terminally differentiated cells have a finite life

span, and are replaced with new cells produced

from stem cells.

• Stem cells are capable of self-renewal; cells

divide without undergoing terminal differentiation.

Cell Cycle Checkpoints

G1S

G2

cytoplasm

doubles

chromosomes

replicate

assembly of

components

for divisioncytokinesis

PM

A

T

Mitosis

DNA Damage

Checkpoints

DNA Damage

Checkpoint

Apoptosis

Checkpoint

Spindle

Assembly

Checkpoint

The Cell CycleThe Cell Cycle

MM

(mitosis)(mitosis)

GG11

(cell growth)(cell growth)

REPAIRS

AHEAD

S (synthesis)S (synthesis)

GG00 (resting) (resting)

OncogenesOncogenes

Tumor suppressor genesTumor suppressor genes

GG22

DNA repairDNA repair

genesgenes

ASCO

Normal cell cycle is controlled by

signal transduction:

• Growth factors bind to surface receptors on the cell;

transmembrane proteins relay signals into the cell.

• Two types of growth factors:

1. Growth factors stimulate cell division.

2. Growth-inhibiting factors inhibit cell division

• Healthy cells divide only when growth factor and growth-

inhibiting factor balance favors cell division.

• Cancer cells divide without constraint

(e.g., mutations in growth and growth-inhibiting factor

genes).

Genetic Mechanisms of

Tumors• Gene deletions / amplifications

• Mutations

Inserstional

Point Mutations

• Genetic Instability

Microsatellite Instability (MSI)

Chromosomal Instability (CIN)

EXAMPLES

Environmental vs.

Hereditary Cancer

Familial Clustering of Cancer

• Epidemiological studies show an

increased relative risk of cancer in

individuals with a family history of cancer

• This is probably due to a mixture of rare

highly penetrant genes, commoner lower

penetrance genes and environmental

effects

Cancer Inheritance

MULTIPLE HITS PROCESS

• The first hit it could be embryonic as in Retinoplastoma

• The others could be due to: Point mutation

Loss of reduplication

Deletion

Mutation of normal gene

Somatic recombination

Inherited Cancer Genes

• Neurofibromatosis type-1

• P53 gene

• Familial Polyposis Gene (APC)

• Hereditary nonpolyposis colon cancer (HNCC)

• Breast Cancer Genes (BRCAI, BRCA2)

• P16 Familial Melanoma

• RET proto-oncogene and multiple endocrine neoplasia

SOLID TUMORS SARCOMAS

• In addition to leukemias and lymphomas

some sarcomas also have specific

chromosomal abnormalities

•One example is t(11;22) seen in Ewing’s

sarcoma in which the DNA binding domain

of a transcription factor FLI1 is fused with

the transactivation domain of EWSR1

gene

RECURRENT ABNORMALITIES

EPITHELIAL TUMORS

• Small cell ca of the lung del(3)(p14-

p24)

• Wilm’s tumor del(11)(p13)

• Breast Her-2/neu amplification

• Mostly multiple abnormalities

Ovarian Cancer• > 400 cases karyotyped

• 2 cytogenetic pathways 1: +7,+8q and +12 2: 6q- and 1q-

• 3 phases of karyotypic evolution 1. step wise changes 2. Increased chromosome instability 3. Triploidization with 6q- and 1q-

• CGH reveal multiple changes in the malignant and fewer changes in borderline tumors

Uterine leiomyomas and

leiomyosarcomas• Benign tumors such as leiomyomas also

show recurrent chromosomal abnormalities such as t(12;14) and deletion of 7q

• 40% of leiomyomas show abnormal karyotypes

• Leiomyosarcomas show complex chromosomal rearrangements

COPY NUMBER CHANGES IN

LEIOMYOSARCOMA

LOSS

• 13q (59%)

• 10q(59%)

• 2q(35%)

• 16q(29%)

GAIN

• 5p(35%)

• 6p amplification

• 17p amplification

The Familial Polyposis Gene (A PC),

• The familial polyposis gene (APC), which strikingly predisposes to colon cancer, was ultimately identified by mutations in patients.

• The inherited gene is also involved in the great majority of sporadic cases of colon polyps and colon cancer.

• This tumor suppressor gene has been shown to function as a major regulator of the Wntpathway, a signaling system that is well characterized both biochemically and developmentally

Moderate Colorectal Cancer

Risk

• Two first-degree relatives affected

(0.4% population)

• One first-degree relative

diagnosed <45y (0.2% population)

• Suggest colonoscopy at 35y (2%

risk of polyp) and 55y (17-21% risk

of polyp)

Morphological and Molecular Changes in Adenoma and Carcinoma Sequence

The Hereditary Nonpolyposis Colon

Cancer Genes

• HNPCC is an inherited form of

colorectal cancer that is caused by

mutations in any of several genes

involved in DNA mismatch repair.

• It represents an example of a cancer

syndrome caused by genomic

instability

Hereditary Non-Polyposis

Colon Cancer

• 80% lifetime risk of colorectal cancer (males)

• 60% lifetime risk of endometrial cancer

• 10% risk of ovarian cancer

• Surveillance 1-2 yearly colonoscopies from 25y

• Consider endometrial screening by ultrasound and endometrial pipelle biopsy

• Consider ovarian screening by transvaginal ultrasound

Cancer and repair: HNPCC

Normal epithelium

Adenoma Carcinoma Metastasis

Accumulation of mutations in multiple genes

Oncogenes:(gain of function)=increased proli-feration, etc.

Tumor supressors:(loss of function)=loss of control: apoptosis, etc.

Mismatch repair defects

Retinoblastoma

• Deletions 13q14 or mutations of the RB1

gene

• Cell cycle regulatory protein that inhibits G1

to S phase transition

• 80% de novo mutations

• High rate of loss of heterozygosity in tumor

tissue

Retinoplastoma Inheritance

• Inheritance of RB1 heterozygous

• Second hit occurs during embryonic life due to Point mutation

Loss of reduplication

Deletion

Mutation of normal gene

Somatic recombination

The Development of Hereditary Cancer

1 damaged gene

1 normal gene

Tumordevelops

2 normal genes 2 damaged genes

In hereditary cancer, one damaged gene is inherited.

1 damaged gene1 normal gene

Tumordevelops2 damaged genes

Sporadic and Familial (Mendelian) forms

of Cancer Knudson’s Two-Hit Hypothesis

SporadicNormal

tumor

suppressor

gene

Single tumors,

unilateral,

later-onset

Somatic

mutation

in one allele

Somatic

mutation

in other allele

• two mutations (two hits) are required for loss of tumor suppressor function

Sporadic and Familial (Mendelian) Forms of Cancer

Knudson’s two-hit hypothesis

Familial

Tumor suppressor gene

containing a germline

mutation in one allele -

heterozygous for the

mutation

Multiple tumors,

bilateral,

early-onset

Somatic

mutation

in other allele

• two mutations (two hits) are required for loss of tumor suppressor function

• the first “hit” is inherited and the second “hit” is somatic

Neurofibromatosis Type 1

• The gene responsible for NFl chro. 17q

• GAP Protein, and a similar role in signal transduction.

BRCA1 and BRCA2

• High (60-80%) lifetime risk of breast

cancer, both genes.

• Increased ovarian cancer risk

(BRCA1>BRCA2)

• Surveillance for both indicated;

mammography, MRI, TV ultrasound

• Consider prophylactic surgery

The Inherited Breast Cancer Genes:

BRCA 1 and BRCA2

• Mutations in BRCA 1 and BRCA2 are responsible for a large proportion of inherited breast cancer cases.

• These mutations usually result in a truncated protein product and loss of function.

• The protein products of both of these genes interact with RAD51, a DNA repair protein.

BRCA1-Linked Hereditary

Breast and Ovarian Cancer

Noncarrier

BRCA1-mutation carrier

Affected with cancer

Breast, dx

45

d. 89

92 86

73 68 Ovary, dx 59

d. 62

Breast

, dx

59

Breast,

dx 36

36

71

p16 and Familial Melanoma

• Can be aused by loss-of-function

mutations in the p 16 tumor

suppressor gene or by gain-of-

function mutations in the target of

p16, the CDK4 proto-oncogene.

• Both mutations result in a loss of cell

cycle control via the pRI pathway.

7/21/2013 MSK/UJ/GL2 52

CHROMOSOMAL

ABNORMALITIES

IN MALIGNANCIES

Three classes of error lead to

aneuploidy in tumor cells

Chronic Myelogenous Leukemia

• Invariably fatal

• The Philadelphia Chromosome

– Reciprocal Translocation

– long arm of HAS 22 < > small part of HSA 9

• 2 chromosomal changes

– Translocation causes oncogene activation

MOST FREQUENT CLONAL CHROMOSOME

ABNORMALITIES IN HEMATOLOGIC

MALIGNANCIES

DIAGNOSIS: ABNORMALITY:

CML, ALL t(9;22)(q34;q11.2)

AML t(8;21)(q22;q22)

APL t(15;17)(q22;q12~21)

AML with EO inv(16)(p13q22)

MDS /AML 5q-, -7, 7q-,+8, 20q-

CLL del(13q), +12

ALL t(1;19)(q23;p13)

t(4;11)(q21;q23)

Burkitt’s Lymphoma t(8;14)(q24;q32)

Follicular Lymphoma t(14;18)(q32;q21)

Mantle Cell Lymphoma t(11;14)(q13;q32)

Chromosomal Rearrangements

or Translocations

Neoplasm Translocation Proto-oncogene

Burkitt lymphoma t(8;14) 80% of cases c-myc1

t(8;22) 15% of cases

t(2;8) 5% of cases

Chronic myelogenous t(9;22) 90-95% of cases bcr-abl2

leukemia

Acute lymphocytic t(9;22) 10-15% of cases bcr-abl2

leukemia

1c-myc is translocated to the IgG locus, which results in its activated expression2bcr-abl fusion protein is produced, which results in a constitutively active abl kinase

Examples of Chromosomal Regions That

Show Loss of Heterozygosity in Tumors

Chormosome

Region Disorder(s) Associated TSG

lq Breast carcinoma Unknown

3p Small~celllung carcinoma Unknown

5q Familial polyposis coli;

colorectal carcinoma MCC

11 p Wilms tumor; rhabdomyosarcoma WTl

13q Retinoblastoma; breast carcinoma;

osteosarcomas RB 1

17p Colorectal carcinoma; breast cancer TP53

18q Colorectal carcinoma DCC

22 Neurofibromatosis, type 2 Unknown

Cancer: General Etiology and Pathogenesis