Cancer as a genetic

chapter 23 select topics andlecture notes

What is cancer? Epidemiology statistics Phenotype of the cancer cell

Cancer genes Tumor suppressor genes oncogenes

How cancer genes do alter a cell’s phenotype?

Molecular multi-step process and cancer

P53 and Rb genes: specific example

Cancer is abnormal cell growth.

Lead to

TUMOR is NOT = CANCER

TUMORS= Neoplasms

Cancers however are malignant

tumors

Benign

A photo of a sweat glandHidradenoma: fluid filled benight

Some benign tumors may be enlargements without abnormal

growtheg. CF

Most cancers fall into one of these groups

Carcinomas

Sarcomas

Leukemias

Lymphomas

2009 Estimated US Cancer Deaths*

ONS=Other nervous system.Source: American Cancer Society, 2009.

Men292,540

Women269,800

26% Lung & bronchus

15% Breast

9% Colon & rectum

6% Pancreas

5% Ovary

4% Non-Hodgkin lymphoma

3% Leukemia

3% Uterine corpus

2% Liver & intrahepaticbile duct

2% Brain/ONS

25% All other sites

Lung & bronchus 30%

Prostate 9%

Colon & rectum 9%

Pancreas 6%

Leukemia 4%

Liver & intrahepatic 4%bile duct

Esophagus 4%

Urinary bladder 3%

Non-Hodgkin 3% lymphoma

Kidney & renal pelvis 3%

All other sites 25%

Characteristics of Cancer

Loss of contact inhibition

Loss of apoptosis

Growth in soft agar

Tumor growth “in vivo”

2 broad groups of cancer causing genes

1. Tumor suppressor genes

2. Oncogenes

1. Tumor Suppressors

Normally requires 2 “hits”

Mutations cause loss of function

haploinsufficiency

Alfred Knudson: 2 hit model of cancer

1.

Loss of Heterozygosity

Examples of tumor suppressors

Retinoblastoma gene (rb)

p53 gene

Retinoblastoma: Rb gene and Retinal tumor

P53 gene and breast cancer

bilateral retinoblastoma autosomal dominant

Li-Fraumeni Syndrome autosomal dominant

osteoclasts neutrophils

P53 and the bax gene

Example

Nobel Prize in 2002 for their discovery of apoptosis

Brenner

Horvitz

Sulston

2. Oncogenes

■ Second group of cancer causing genes

■ Mutations cause a gain of activity

■ Requires only one “hit”

2.

Where do Oncogenes originate?

Hypothesis of origin of oncogenes

Viruses recombine with proto-oncogenes

Michael Bishop and Harold Varmus

Proto-oncogenes Oncogenevirus

mutated in virusControl by viral promoter mutated by virusIn host cell DNA

Possible outcomes of recombination

Here are some examples of how tumor suppressors and oncogenes stimulate cell

growth.

1. Genes controlling the cell cycle

For example: cyclic dependent kinases

2. Genes controlling DNA repair

Colon cancer

For example: HNPCC: colon cancer and DNA repair mutations

Breast cancer susceptibility genes (BRCA1 and BRCA2) & DNA repair

Breast Cancer Tumors

3.Genes affecting chromosome segregation

apc gene and p53 gene required for proper chromosomal separation

metaphase

Van Hippel-Landau disease

▪ Extensive vascularization

▪ Dominant mutation

4. GENES that promote vascularization

5. Telomerase may with cancer

Genes that regulate telomerase

6. Genomic Instability

Hypomethylation (?)

Hypermethylation

Gene repression

Let’s summarize some key points

These Cancer Causing Genes may affect

The cell cycle

DNA repair

Chromosome segregation Changes in chromosome number

Telomerase regulation

Vascularization

Genomic Instability DNA hypomethylation (?)

The relationship of p53 and Rb to the cell cycle

Cyclins are the control proteins that keep the cell cycle moving.

But how??

(and late G1)

Cell cycle & cyclins

I get it!

(and late G1)

Requires E2F

Another look at the cell cycle

But you said p53 is also involved in

the cell cycle. Where is it in the

picture?!

Release of

Wt Rb protein are changed by cyclins.

Rb mutations prevent E2F binding

Under normal (wt) conditions P53 and Rb communicate

1 2 3

p21 inhibits phosphorylation step byPreventing cyclin/Cdk complex

4

Cancer : Multi-step process

No

rmal

Loss of functionGain of function

Can

cerMany mutationsMultiple mutations