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Section D
Genes whose Mutation can lead to
Initiation
Single Genes and Susceptibility Genes—and Cancer Risk
Single genes
Susceptibility genes
Definition
Necessary and sufficient Alter risk—but is neither
for disease causation
necessary or sufficient for
disease causation
Example
BRCA (breast/ovary)
APC (polyposis coli)
RB (retinoblastoma)
CYP1A1 (lung)
CYP2D6 (lung)
GST-M1 (lung, bladder)
DNA repair genes
Gene prevalence
Low
Often high
Gene type
Mutation
Mutation
Study setting
Family
General population/
epidemiological studies
Strength of association
Very high
Low to moderate
Absolute risk
High
Low
Population attributable risk
Low
High (because mutation
common)
Gene-environment
interaction/exposure
Secondary and variable
Primary and crucial
39
Two Categories of Genes in which
“Mutation” is Associated with Cancer
  Gain of function:
–  Proto-oncogenes become oncogenes
•  Point mutation – change in amino acid sequence
•  Translocation – gene or part of gene moved to
another location
•  Amplification – multiple copies of gene created
  Loss of Function
–  Tumor suppressor genes lose function
•  Deletion
•  Translocation
•  Mutation
40
Oncogenes
  Presence of proto-oncogenes
in normal cells
  Detection of activated protooncogenes (oncogenes) in
tumor cells
–  Ras gene – one of the
first discovered using
transfection
41
Oncogenes Genes
Selected Examples with Function & Location
Contribute to tumor formation when expression/function enhanced
Selected Examples*
Genes
Src
ras
Myc
EGF Family
Erb-2/
Her2/neu
Functions
Cytoplasmic Tyrosine Kinase
G-protein; Signal transduction
rasH
rasK
rasN
Cell Proliferation and DNA Synthesis
mycN
mycC
Membrane Receptor the stimulates DNA
Synthesis – a Tyrosine Kinase
Associated Cancers
Sarcomas
Bladder
Lung, Ovarian, Bladder
Breast
Neuroblastoma, Retinoblastoma
Breast, leukemia, Lung, Cervical, Colon
Breast, Salivary Gland, Ovarian
*Adapted from Cancer Quest – Tumor Suppressors,
Emory University, 2008; accessed Aug, 2011
42
Oncogenes Drive Tumorigenesis
Muller, W. et al. Cell 49: 465-475, 1987
43
Impact of erB2/neu Amplification
on Breast Cancer
44
Suppressor Genes
Selected Examples with Function & Location
Contribute to tumor formation when expression/function lost or inactivated
Tumor Suppressor genes – Selected Examples
Genes
P53
Functions
- Transcription factor regulating genes
controlling cell division and cell death
- Sensor of DNA damage
- Aids in decision between repair and activation
of programmed cell death
Associated Cancers
Bladder, Breast, Liver,
Colorectal, Lung, Prostate
Rb
- Signal integrator related to cell cycle progression Retinoblastoma, Sarcomas,
- Transduces growth inhibitory signals
Bladder, Breast, Lung
BRCA
- Involvement in DNA repair
- Regulation of gene expression
Inherited Breast and Ovarian
APC
- Controls activity of certain transcription
factors
Familial adenomatous & noninherited colorectal cancers
Adapted from Cancer Quest – Tumor Suppressors, Emory University, 2008; accessed Aug, 2011
45
Slide 8 (split)
Genetic Model for
Colorectal Tumorigenesis
50
Whole Exome Sequences of 100 Human Cancers*
SKCCC
Washington
University
11 colorectal cancers
11 breast cancers
24 pancreas cancers
22 gliomas
22 meduloblastomas
2 leukemias
1 breast cancer
British Columbia 1 breast cancer
Cancer Research 4 granulosa cell tumors
Centre
1 lung cancer Sanger
Sanger Institute
1 melanoma
3142 mutated genes
286 tumor suppressors
33 oncogenes
*Vogelstein B AACR Annual Meeting (2010) – Slide provided by W. Nelson
Key points – Section D
  Inherited genetic susceptibility can increase
risk
–  Mutations in key genes can lead to high
individual risk, but low attributable population
risk
–  Mutations in certain genes lead to lower
individual risk but high attributable population
risk
  Oncogenes and tumor suppressor genes are key
molecular/biological targets
  Tumors contain hundreds of mutations and
contain a few common mutations
56
Key Points – Section D cont’d
  Mutations accumulate as as progression occurs
  Different carcinogens cause different mutations –
“finger print”
–  Adducts of chemicals with DNA bases can
serve a biomarkers of biologically effective
dose
57