Cancer as a genetic chapter 23 select topics and lecture 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 gland Hidradenoma: fluid filled benight Some benign tumors may be enlargements without abnormal growth eg. 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, Men 292,540 Women 269,800  26%Lung & bronchus  15%Breast  9%Colon & rectum  6%Pancreas  5%Ovary  4%Non-Hodgkin lymphoma  3%Leukemia  3%Uterine corpus  2% Liver & intrahepatic bile duct  2%Brain/ONS  25% All other sites Lung & bronchus30% Prostate9% Colon & rectum 9% Pancreas6% Leukemia4% Liver & intrahepatic4% bile duct Esophagus4% Urinary bladder3% Non-Hodgkin 3% lymphoma Kidney & renal pelvis3% 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

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 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 p21 inhibits phosphorylation step by Preventing cyclin/Cdk complex 4

Cancer : Multi-step process Normal Loss of functionGain of function Cancer Many mutations Multiple mutations