Cancer as a genetic disease

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Cancer as a genetic disease
chapter 21pp 627-637 lecture notes
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Cancer is abnormal cell growth.
TUMORS
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TUMORS
Malignant
Benign
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Most cancers fall into one of these groups

• Carcinomas
• Sarcomas
• Leukemias
• Lymphomas

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Scientists have also defined characteristics of a
cancer cell.
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Normal Fibroblasts
Transformed Fibroblasts
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Characteristics of Cancer

• Loss of contact inhibition
• Loss of apoptosis
• Growth in soft agar
• Tumor growth in vivo

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2 broad groups of cancer causing genes

• 1. Tumor suppressor genes
• 2. Oncogenes

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1. Tumor Suppressors

• Mutations cause loss of function
• Normally requires 2 hits
• Haploinsufficiency

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1.
Loss of Heterozygosity
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Examples of tumor suppressors

• Retinoblastoma gene (rb)
• p53 gene

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Retinoblastoma Retinal tumor
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Alfred Knudson 2 hit model of cancer
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Breast cancer and p53
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Example
osteoclasts
neutrophils
P53 and the bax gene
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Nobel Prize in 2002 for their discovery of
apoptosis
Brenner
Horvitz
Sulston
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2. Oncogenes
Second group of cancer causing genes
Mutations cause a gain of activity
Requires only one hit
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2.
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Where do Oncogenes originate?
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Hypothesis of origin of oncogenes

• Viruses recombine with proto-oncogenes

Michael Bishop and Harold Varmus
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Possible outcomes of recombination
virus
Oncogene

• Proto-oncogenes

mutated in virus
Control by viral promoter
mutated by virus In host cell DNA
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Here are some examples of how tumor suppressors
and oncogenes stimulate cell growth.
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1. Genes controlling the cell cycle
For example cyclic dependent kinases
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2. Genes controlling DNA repair
Colon cancer
For example HNPCC colon cancer and DNA repair
mutations
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Breast cancer susceptibility genes (BRCA1 and
BRCA2) DNA repair
Breast Cancer Tumors
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3.Genes affecting chromosome segregation
metaphase
apc gene and p53 gene required for proper
chromosomal separation
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4. GENES that promote vascularization
Van Hippel-Landau disease ? Extensive
vascularization ? Dominant mutation
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5. Telomerase may with cancer
Genes that regulate telomerase
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6. Genomic Instability
Hypomethylation (?)
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Hypermethylation

• Gene repression

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Lets summarize some key points
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These Cancer Causing Genes may affect

• The cell cycle
• DNA repair
• Chromosome segregation
• Changes in chromosome number
• Telomerase regulation
• Vascularization
• Genomic Instability
• DNA hypomethylation (?)

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

• Initiation
• Clonal expansion
• Progression
• Expansion

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Now, Lets look more closely at 2 cancers their
multi-step progression
Colon Cancer
Retinoblastoma
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The relationship of p53 and Rb to the cell cycle
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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.

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Cancer Prevention
Pap Smear for Cervical CA detection HPV
genital warts
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First a brief overview The cell cycle
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Mitosis
metaphase
prophase
telophase
anaphase
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Interphase
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Cyclins are the control proteins that keep the
cell cycle moving.
But how??
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Overview of how cyclin regulation
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Cell cycle cyclins
I get it!
(and late G1)
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Wt Rb protein are changed by cyclins.
Release of
Rb mutations prevent E2F binding
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Another look at the cell cycle
Requires E2F
(and late G1)
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But you said p53 is also involved in the cell
cycle. Where is it in the picture?!
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Under normal (wt) conditions P53 and Rb
communicate
p21 inhibits phosphorylation step by Preventing
cyclin/Cdk complex
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