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Single Genes and Susceptibility Genes—and Cancer Risk
Definition
Example
Gene prevalence
Gene type
Study setting
Strength of association
Absolute risk
Population attributable risk
Gene-environment interaction/exposure
Single genes
Necessary and sufficient for disease causation
BRCA
APC
RB
(breast/ovary)
(polyposis coli)
(retinoblastoma)
Low
Susceptibility genes
Alter risk—but is neither necessary or sufficient for disease causation
CYP1A1 (lung)
CYP2D6 (lung)
GST-M1 (lung, bladder)
DNA repair genes
Often high
Mutation
Family
Mutation
General population/ epidemiological studies
Low to moderate Very high
High Low
Low High (because mutation common)
Secondary and variable Primary and crucial
39


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


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
Genes
Src ras
Selected Examples*
Functions
Cytoplasmic Tyrosine Kinase
G-protein; Signal transduction
rasH
rasK
rasN
Associated Cancers
Sarcomas
Bladder
Lung, Ovarian, Bladder
Breast
Myc
EGF Family
Erb-2/
Her2/neu
Cell Proliferation and DNA Synthesis
mycN
mycC
Membrane Receptor the stimulates DNA
Synthesis – a Tyrosine Kinase
Neuroblastoma, Retinoblastoma
Breast, leukemia, Lung, Cervical, Colon
Breast, Salivary Gland, Ovarian
*Adapted from Cancer Quest – Tumor Suppressors,
Emory University, 2008; accessed Aug, 2011
42

Muller, W. et al. Cell 49: 465-475, 1987
43

erB2/neu
44

Suppressor Genes
Selected Examples with Function & Location
Contribute to tumor formation when expression/function lost or inactivated
Tumor Suppressor genes – Selected Examples
Genes Functions
P53 - Transcription factor regulating genes
Associated Cancers
Bladder, Breast, Liver,
Colorectal, Lung, Prostate controlling cell division and cell death
- Sensor of DNA damage
- Aids in decision between repair and activation
of programmed cell death
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 & non-
inherited 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
11 colorectal cancers
11 breast cancers
24 pancreas cancers
22 gliomas
22 meduloblastomas
Washington
University
2 leukemias
1 breast cancer
British Columbia 1 breast cancer
Cancer Research 4 granulosa cell tumors
Centre
Sanger Institute
1 lung cancer Sanger
1 melanoma
3142 mutated genes
286 tumor suppressors
33 oncogenes
*Vogelstein B AACR Annual Meeting (2010) – Slide provided by W. Nelson


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


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