Cancer as a genetic disease chapter 21 pp & lecture notes

Cancer is abnormal cell growth. TUMORS Skin Cancer

TUMORS MalignantBenign

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

osteoclastsneutrophils 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 Oncogene virus mutated in virusControl by viral promotermutated by virus In 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 angiogenesis

5. Telomerase activity 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 Normal Loss of functionGain of function Cancer Many mutations Multiple mutations

Cancer : Multi-step process  Initiation  Clonal expansion  Progression  Expansion

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

Human Papilloma Virus & Cervical Cancer  GARDASIL Vaccine  Caused by HPV  Types 16 and 18: Cause 70% of cervical cancer  HPV Types 6 and 11: cause 90% of genital warts  Risk Factors: smoking, having many children, and human immunodeficiency virus (HIV) infection.

The relationship of p53 and Rb to the cell cycle

Cancer Prevention Pap Smear for Cervical CA detectionHPV & genital warts

Part II of lecture: Examples of miscommunication and cancer

First a brief overview: The cell cycle

Mitosis prophase metaphase anaphase telophase

Interphase

Cyclins are the control proteins that keep the cell cycle moving. But how??

Overview of how cyclin regulation

(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 p21 inhibits phosphorylation step by Preventing cyclin/Cdk complex 4