Imad Fadl-ElmulaImad Fadl-ElmulaAl Neelain UniversityAl Neelain University

The Biology and The Biology and Genetic Base of Genetic Base of

CancerCancer

The oldest known cases (Osteosarcomas) have been

verified in Egyptian mummies that died 4000

Cancer ........an old........ new problem Cancer ........an old........ new problem

KarkinosKarkinos

Uroepithelial cancerUroepithelial cancer

54,000 new cases 12,500 deaths Three times more frequently in € than in

7th most common cancer in 4th most common cancer in €

In areas where Schistosoma haematobium is endemic

The most common cancer (25%) in €

Rarely occur before the age of 40 years

One in three persons develops One in three persons develops cancer at some time during their cancer at some time during their lives, and one in four dies from lives, and one in four dies from

his diseasehis disease

In Sudan?National Cancer registry (1968)

Steps on the wrong direction

The only available dataThe only available dataThe radiation and isotopes Center Khartoum and Madani

حاالت حاالت السرطان السرطان

فى فى !!!!السودانالسودان

My personal adviceMy personal advice

عليا دراسات طالب

ست الودع

Geographical distribution of cancer cases seen at the Radiation and Isotope centre at

31%

13%26%

7%

12%

9% 2%Khartoum

Gazira

Northern

Western

Kordofan

Darfor

Southern

Commonest cancer for Sudanese Males

1997-2000

24%

17%

13%10%

10%

7%6%

5% 4% 4%

C.M. Leukemia

Lymphosarcoma

Oesophagus

Testis

Hypopharynx

Bladder

Bone

H.D

Thyroid gland

Rectum

Commonest cancer for Sudanese females 1997-2000

30%

19%14%

12%

10%

4%3% 3% 3% 2%

Breast

Cervix

C.M. Leukemia

Oesophagus

Ovary

Lymphosarcoma

Bone

Thyroid gland

Hypopharynx

Bladder

What is Cancer Genetics?

Molecular pathology.Molecular pathology. Tumor biology.Tumor biology. Molecular genetics.Molecular genetics. Cytogenetics.Cytogenetics. Epidemiology.Epidemiology. Others. Others.

Tumor GrowthTumor Growth

By the time a tumor is By the time a tumor is detected, it already detected, it already contains about a contains about a billion cells.billion cells.

Does a tumor Does a tumor originate from a single originate from a single abnormal cell?abnormal cell?

What is Cancer?What is Cancer?

Aging process!Aging process!

Uncontrolled cell division Uncontrolled cell division

Loss of Normal Growth ControlLoss of Normal Growth Control

Mutation

The whole scenario

Mutation Mutation

☻Immortal cells!

☻Deranged growth control

☻Continuous cell proliferation

Disturbed apoptosis weeding

☻Deranged growth control

What is Cancer?What is Cancer?

The somatic mutation theory of cancer

Theodor Boveri (1862-1915)

AAcquired genetic changes are cquired genetic changes are

the main causes of malignant the main causes of malignant

transformation oftransformation of target cells target cells

NowellNowell && HungerfordHungerford, 1960, 1960

C-bands

G-bands R-bands

Q-bands

Caspersson Caspersson et alet al., 1970., 1970

Rowley, 1973

SummarySummary

Heredity

Biological

PhysicalChemicals

Carcinogens Carcinogens Diet

Cancer & Ethnicity

• Anglo men – higher rates of bladder cancer.

• Hispanics – lowest rates of lung cancer but

women have highest rates of cervix cancer.

• Blacks – highest rates of prostate cancer.

• Japanese – highest rates of stomach cancer.

• Chinese- Americans lowest rates of liver cancer.

• Northern Europeans – high rates of breast cancer.

Polymorphisms • Polymorphism in CYP1A1 found in 10% of

Caucasians associated with increased inducibility produces heightened activation of carcinogens in tobacco smoke.

• CYP genes also play a role in the metabolism of estrogens making them relevant to breast cancer.

• N-acetyltransferases (NATs) play a role in detyoxifying aromatic amines in tobacco smoke. Individuals with 2 mutant NAT2 alleles exhibit “slow acetylator phenotype”with reduced detoxification of aromatic amines and an association with bladder cancer.

0

1

2

3

4

5

6

7

Japan Japaneseimigrants to

California

Sons ofJapaneseImigrants

California whites

Stomach Liver

Colon Prostate

Style of live and cancer Style of live and cancer

Large number of dividing cells

Large variable shaped nuclei

Small cytoplasmic volume relative to nuclei

Variation in cell size and shape

Loss of normal specialized cell features

Disorganized arrangment of cells

Poorly defined tumor boundary

Cancer cell characteristics

Histology

The development of Carcinomas

MutationMutation HyperplasiaHyperplasia DysplasiaDysplasiaIn situ CancerIn situ Cancer

Invasive CancerInvasive Cancer

Natural history of cancerNatural history of cancer

ProgressionProgression

Genetic

(Oncogenes/ tr suppressor genes)

Mitogenesis

Immune surveillance

Angiogenesis

Epigenetic

(clonal expansion)

Biology of Cancer!Biology of Cancer!

Promotion

Initiation

Ist Hit Normal Cell

Apoptosis

Rep

air

2nd Hit

Apoptosi

s

Apoptosi

s

Severe Dysplasia

Cancer

Mild Dysplasia

3rd Hit

Genetic alterations

Normal PIA PIN PCA

inflammation

30 year 80 year

Gene defects

Proliferation

GSTP expression

Oxidative stress

0

100

Well differentiated

?

Moderately differentiated Moderately differentiated Undifferentiated Undifferentiated

?

Poorly differentiated Poorly differentiated

Multistep Carcinogenesis in Prostate CancerMultistep Carcinogenesis in Prostate Cancer

Hit 1Hit 1 Hit 2Hit 2 Hit 3Hit 3 Hit 4Hit 4 Hit 5Hit 5

Ist oncogeneactivated

(e.g c-Erb) (e.g RB gene)

2nd oncogeneactivated

(e.g c-myc)

2nd TSGdeleted

(e.g p53)

Locally invasiveLocally invasiveCA prostateCA prostate

Loss of Invasion

suppressor gene

E-cadherin)

Normal Prostate cells

PIN (prostatic intraepithelial

neoplasia)

Ist TSG deleted

Microscopic latentMicroscopic latentCA prostateCA prostate Metastatic Metastatic

CA prostateCA prostate

Multistep Carcinogenesis of Prostate CancerMultistep Carcinogenesis of Prostate Cancer

The Big PictureThe Big PictureMultihit ± SynergismMultihit ± Synergism

"MUTATOR""MUTATOR"

ACTIVATEDACTIVATED ONCOGENE 1ONCOGENE 1 ACTIVATEDACTIVATED ONCOGENE 2ONCOGENE 2

INACTIVATED TSGINACTIVATED TSG

CANCERCANCER

Activation of Oncogenes by Chromosomal Translocations

70%

19%

4% 1% 1%0%

10%

20%

30%

40%

50%

60%

70%

80%

CRC

SporadicFamily historyHNPCCFAPRare syndromes

CRC

Cancer Cells Contain Multiple Mutations

Normal Epithelium

Abnormal Proliferation

Early Adenoma

Late Adenoma

Carcinoma

loss of APC

activation of RAS

loss of DPC4

loss of p53

The The Good,Good, the the BadBad, and the , and the UglyUgly

Tumor suppressor genes prevent Tumor suppressor genes prevent

transformation of cells transformation of cells [good][good]

Oncogenes cause transformation Oncogenes cause transformation [Bad][Bad] Loss of genomic integrity Loss of genomic integrity [Ugly][Ugly]

Inactivation of tumor suppressor genes. Inactivation of tumor suppressor genes. Activation of oncogenes.Activation of oncogenes.

Genetic changes contribute to carcinogenesisGenetic changes contribute to carcinogenesis

Oncogenes

Tumor suppressor genes DNA repair genes

Retroviralinsertion

Point mutation

Chromosome translocation

Gene amplification

Point mutation

DNA tumor virus

Imprinting(methylation)Deletion (LOH),

partial or whole chromosome loss

Normal cell

Tumor cell

DNA Repair

Oncogenes

Activation

Tumor Suppressor Genes

Inactivation

Differentiation Apoptosis/Proliferation

CANCER

Alterations of Specific Cellular Alterations of Specific Cellular Functions in CancerFunctions in Cancer

Gene groupGene group ExampleExample Chromosomal locationChromosomal location

Oncogenes MYC, ABL 8q24,

Tumor suppressor genes TP53, RB1 17p13, 13q14

DNA repair genes MSH2, PMS2 2p21, 3p21

Apoptosis regulating genes BCL2 18q21

Cell cycle regulator genes CDKN2A, MDM2

9p21, 12q14

Genes involved in tumorigenesis Genes involved in tumorigenesis

Familial Cancer Syndromes RetinoblastomaKnudson’s “Two Hit” Hypothesis

Normal

Occasional mutation of one allele - no tumor

Hereditary Retinoblastoma

Germaine mutation

Retinoblastoma

Retinoblastoma

Rare second mutation

Sporadic Retinoblastoma

Somatic mutation

Mutation

Gene

Chemical bases

DNA Molecule

Chromosome

DefinitionDefinition

Germinal Germinal and/or and/or acquiredacquired,,

stablestable alteration in alteration in DNADNA

sequencesequence or or amountamount

causing causing

harmful, beneficial, harmful, beneficial, oror

neutral neutral effects. effects.

Mutation …Bad ….Good

It is good, it is bad also!!• Mutation in the long term it is essential to our

existence. • Without mutation there Could be no change and

without change life cannot evolve.

Ex. Adaptive mutation

Definition of mutation

A change in DNAA change in DNA

1. Arrangement.

2. Context.

3. Dosage.

4. Sequence.

Size of mutation• Point mutation.

• Submicroscopic mutation.

• Microscopically visible

mutation.

• Loss of a whole chromosome.

Types of mutationsTypes of mutationsSomatic or germinal?

Normal 1st event 2nd event

Born with mutation 2nd event

Familiar.Familiar. Sporadic.Sporadic.

Type of MutationsType of Mutations

ApoptosisApoptosis

Death Receptor-ligand interactionsApaf-1Cytochrome C

Regulated bycytokines and

hormones

Mitochondria

Cell Injury

Nucleus

DNAFragmentation

Initiator Caspases

Execution Caspases

Keeping apoptosis under control.

ced-9 and bcl-2 family proteins

Negative regulatorActivation mechanism

autoactivated protease cascade

InvasiveInvasivecarcinomacarcinoma

Telomeres and Telomeres and Chromosomal AnomaliesChromosomal Anomalies

Tumorgrowth

Hypoxia

Growth factors

Vessels sprouting

Tumor growth

Tumor angiogenesisTumor angiogenesis

Primary Tumor Shed of tumor cells

Intraluminal Seeding

Development of Multifocal Tumors

Intraluminalseeding

Development ofmultifocal tumors

Normal epithelium

MonoclonalityMonoclonality

Intraluminal seeding

Intraluminal seedingShedding of cancer cells

Primary tumor

2

Tumor 3

Carcinogenic effect

Field disease

Polychronotopicity

Carcinogenic effect

Tumor 1

Tumor 2

Tumor 3

PolyclonalityPolyclonality

Development ofmultifocal tumors

Normal epithelium Field cancerization Multifocal tumors

Take home massage

Cancer arises from damage to DNA.

The damage to DNA is acquired.

The damage typically occurs in multiple steps.

The damage affects protooncogenes and/or

tumor suppressor genes.