Example: Breast CancerExample: Breast Cancer
SporadicSporadic
Family clustersFamily clusters
HereditaryHereditary
5%–10%5%–10%
15%15%20%20%
An inherited predisposition underlies only a fraction of
adult cancers
Relative Proportion and Case Loadof ‘Hereditary Cancers’ in the US
Breast 10% 18,000Ovarian 5% 6,000Colon 10% 15,000Prostate 10% 25,000Melanoma 10% 3,000Medullary thyroid 25% 125Retinoblastoma 40% 70
Estimate of Hereditary Hereditary
Cancer type Proportion Cases/Yr
Genes Involved in Carcinogenesis
• Oncogenes– Cancer results when inappropriately activated– dominant acting
• Tumor Suppressor Genes– Cancer can arise when function is lost or blocked– More likely (than oncogenes) to be involved in
inherited predispositions to cancer
• Metabolism/detoxification Genes
Oncogenes
Normal genes Normal genes (regulate cell (regulate cell
growth)growth)
1st mutation1st mutation(leads to accelerated (leads to accelerated
cell division)cell division)
1 mutation sufficient for role in cancer development1 mutation sufficient for role in cancer development
Tumor Suppressor Genes
Normal geneNormal gene
1st mutation1st mutation(susceptible carrier)(susceptible carrier)
2nd mutation or loss 2nd mutation or loss (leads to cancer)(leads to cancer)
Genes Involved in Carcinogenesis
• Oncogenes– Cancer results when inappropriately activated– dominant acting
• Tumor Suppressor Genes– Cancer can arise when function is lost or blocked– More likely (than oncogenes) to be involved in
inherited predispositions to cancer
• Metabolism/detoxification Genes
Risk of oral cancer from alcoholThe influence of polymorphisms in
alcohol dehydrogenase (ADH)
Homozygous for thefast-metabolizing allele
Homozygous for theslow-metabolizing allele
Heterozygotes
Number of alcoholic drinks per week
OddsRatio(log)
100 200
1
10
Tobacco-derivedprocarcinogen
Metabolite A(nonreactive)
Metabolite B
Enz A
Carcinogen
Excreted in urine
Bladder Cancer
Enz B(in bladder wall)
Sewer
Years of smoking
Odd
s R
ati
o
Increase in Bladder Cancer Risk in Smokers -as a function of an individual’s genotype
Slow A, Fast B
Slow A, Slow B
Fast A, Slow B
Fast/Fast
The Accumulation of Genetic Changes The Accumulation of Genetic Changes Underlies the Development and Underlies the Development and
Progression of CancerProgression of Cancer
Genetic pathways involved in tumorigenesis Acquisition of invasive, metastatic, drug-resistant
phenotypes Somatic vs. germline
The Accumulation of Genetic Changes The Accumulation of Genetic Changes Underlies the Development and Underlies the Development and
Progression of CancerProgression of CancerGenetic pathways involved in tumorigenesis
Regulation of proliferationRegulation of cell death (apoptosis)Maintenance of DNA integrity
chromosomal stability repair of damaged DNA correction of errors in DNA replication
Acquisition of invasive, metastatic, drug-resistant phenotypes
Somatic vs germline
The Accumulation of Genetic Changes The Accumulation of Genetic Changes Underlies the Development and Underlies the Development and
Progression of CancerProgression of Cancer
Genetic pathways involved in tumorigenesisAcquisition of invasive, metastatic, drug-
resistant phenotypesSomatic vs germline
The Accumulation of Genetic Changes The Accumulation of Genetic Changes Underlies the Development and Underlies the Development and
Progression of CancerProgression of Cancer
Genetic pathways involved in tumorigenesisAcquisition of invasive, metastatic, drug-resistant
phenotypesSomatic vs. germline
–Somatic: only in the affected tissue–germline: aka constitutional, heritable DNA
Tumor Suppressor Genes
Normal genes Normal genes (prevent cancer)(prevent cancer)
1st mutation1st mutation(susceptible carrier)(susceptible carrier)
2nd mutation or loss 2nd mutation or loss (leads to cancer)(leads to cancer)
The Two-Hit Hypothesis
First hit First hit
First hit in First hit in germline of germline of
childchild
Second hitSecond hit(tumor)(tumor)
Human Genome Project1990-2003
• Determine the complete nucleotide sequence of the human genome (3 X 109).
• Advances in DNA sequencing methodology and the sequencing of model organisms– C. elegans, E. coli, D. melanogaster
• Ethical, Legal, and Social Implications (ELSI)• 1994: Comprehensive human genetic linkage
map with an average marker density of 0.7 cM, based primarily on microsatellite markers.
DA1B3
dA2B2
dA3B2
dA4B4
DA1B3
dA4B4
dA2B2
dA3B2
dA3B2
dA1B2
dA4B3
DA1B3
dA1B2
dA4B4
dA1B2
DA1B3
Linkage AnalysisWhere is gene ‘D’
DA1B3
dA2B2
dA3B2
dA4B4
DA1B3
dA4B4
dA2B2
dA3B2
dA3B2
dA1B2
dA4B3
DA1B4
dA1B2
dA4B4
dA1B2
DA1B3
Crossover tells us thatlocus A is closer to “D”
than is locus B
Breast Cancer Susceptibility Genes
• BRCA1• BRCA2
– Also associated with male breast cancer– Not associated with ovarian cancer
• ATM (Ataxia Telangectasia)– Heterozygotes (0.5-1.5% of the general population) may
be at increased risk of breast cancer (≥5-fold)– Could account for as much as 8% of all cases of breast
cancer in the USA
• Others (including p53)
BreastCancer
Risk(%)
20
40
60
80
100
30 50 70
AGE (years)
BRCA1-mutation carriers
General population
Risk of a second cancer after breast Risk of a second cancer after breast cancer in cancer in BRCA1BRCA1 mutation carriers mutation carriers
AGE (years)
Ovarian CA
Breast CA
40 50 60 70
Cu
mu
lati
ve R
isk
0.8
0.6
0.4
0.2
0
Causes of Hereditary Susceptibility to CRC
Sporadic Sporadic (65(65%–%–85%)85%)
Familial Familial (10(10%–%–30%)30%)
Hereditary nonpolyposis Hereditary nonpolyposis colorectal cancer colorectal cancer (HNPCC) (5%)(HNPCC) (5%)Familial adenomatous Familial adenomatous
polyposis (FAP) (1%)polyposis (FAP) (1%)
Rare CRC Rare CRC syndromes syndromes
(<0.1%)(<0.1%)
Age-Specific Penetrance for Colon Cancer in Hereditary Nonpolyposis Colon Cancer (‘HNPCC’)
Percentage of individuals with an altered disease Percentage of individuals with an altered disease gene who develop the diseasegene who develop the disease
00 2020 4040 6060 808000
2020
4040
6060
8080
100100
HNPCC HNPCC mutation mutation carrierscarriers
General General populationpopulation
Affected Affected with with
colorectal colorectal cancer (%)cancer (%)
Risk of Colorectal Cancer (CRC)
0 20 40 60 80 100
General populationGeneral population
Personal history of Personal history of colorectal neoplasiacolorectal neoplasia
Inflammatory Inflammatory bowel diseasebowel disease
HNPCC mutationHNPCC mutation
FAPFAP
5%5%
15%–15%–20%20%
15%–40%15%–40%
70%–80%70%–80%
>95%>95%
Lifetime risk (%)Lifetime risk (%)
Cancer Risks in HNPCC
Aarnio M et al. Aarnio M et al. Int J CancerInt J Cancer 64:430, 1995 64:430, 1995
% % with with
cancercancer
100100
8080
6060
4040
2020
002020 4040 6060 808000
Age (years)Age (years)
Colorectal 78%Colorectal 78%
Endometrial 43% Endometrial 43%
Stomach 19%Stomach 19%Biliary tract 18%Biliary tract 18%
Ovarian 9%Ovarian 9%
The Potential of Genetic Testing
Knowledge is Power
• Appropriate prophylaxis and screening• Reduction of uncertainty• “Sometimes the coin comes up heads”• Genotype-directed therapy• Informative for other family members
Caveats in Genetic Testing• Multiple suspect genes for a given tumor type
– especially a problem for the first member of a family to be tested
• Multiple cancers from a given germline mutation– ?influence of the environment or modifier genes
• Multiple mechanisms of gene inactivation• Mutation or polymorphism?
– functional assays, once developed, will help
• Estimates of penetrance are difficult to apply– current estimates are derived from the most
severely affected families
From DNA sequence to protein -- From DNA sequence to protein -- the effect of nucleotide changesthe effect of nucleotide changes
...ATG GAT AGT TGC CAA... ...ATG GAA AGT TGC CAA...
...Met Asp Ser Cys Gln... ...Met Glu Ser Cys Gln...
Missense mutations
Nonsense mutations...ATG GAT AGT TGC CAA... ...ATG GAT AGT TGA CAA......Met Asp Ser Cys Gln... ...Met Asp Ser STOP
Frameshift mutations...ATG GAT AGT TGC CAA... ...ATG GAT ACG TTG CCA A......Met Asp Ser Cys Gln... ...Met Asp Thr Leu Pro...
Benign Polymorphisms (beware)
OtherPromoter function or RNA splicing altered
The Challenge of Genetic TestingThe Challenge of Genetic Testing
-- -- not like other testsnot like other tests -- --
Probabalistic, not diagnostic Can affect other family members Uninformative results Uncertain effectiveness of preventive measures Fear of insurance loss Unanticipated psychological reactions Integration of genetic testing into decisions
regarding primary therapy of a new cancer in a possible mutation carrier
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