Cancer as a genetic

chapter 21pp 627-637 &lecture notes

Cancer is abnormal cell growth.

TUMORS

TUMORS

Malignant Benign

Most cancers fall into one of these groups

Carcinomas

Sarcomas

Leukemias

Lymphomas

Scientists have also defined characteristics of a cancer cell.

Normal Fibroblasts Transformed Fibroblasts

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

Mutations cause loss of function

Normally requires 2 “hits”

Haploinsufficiency

1.

Loss of Heterozygosity

Examples of tumor suppressors

Retinoblastoma gene (rb)

p53 gene

Retinoblastoma: Retinal tumor

Alfred Knudson: 2 hit model of cancer

Breast cancer and p53

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 (?)

Cancer : Multi-step process

No

rmal

Loss of functionGain of function

Can

cerMany mutationsMultiple mutations

Cancer : Multi-step process

Initiation

Clonal expansion

Progression

Expansion

Now, Let’s look more closely at 2 cancers & their multi-step progression

Colon Cancer Retinoblastoma

The relationship of p53 and Rb to the cell cycle

Brief overview: The cell cycle

Mitosis

prophase metaphase

anaphase telophase

Interphase

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

But how??

(and late G1)

Cell cycle & cyclins

I get it!

Release of

Wt Rb protein are changed by cyclins.

Rb mutations prevent E2F binding

(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?!

Under normal (wt) conditions P53 and Rb communicate

1 2 3

p21 inhibits phosphorylation step byPreventing cyclin/Cdk complex

4