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BrCA at 51. BrCA at 58. 72. BrCA at 44. 43. Tom. ?. 15%  20%. 5%–10%. Sporadic Family clusters Hereditary. An inherited predisposition underlies only a fraction of adult cancers. Example: Breast Cancer. Estimate of Hereditary Hereditary

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slide1

BrCA

at

51

BrCA

at

58

72

BrCA

at

44

43

Tom

?

slide2

15%20%

5%–10%

Sporadic

Family clusters

Hereditary

An inherited predisposition underlies only a fraction of adult cancers

Example: Breast Cancer

relative proportion and case load of hereditary cancers in the us

Estimate of

Hereditary Hereditary

Cancer type Proportion Cases/Yr

Breast 10% 18,000

Ovarian 5% 6,000

Colon 10% 15,000

Prostate 10% 25,000

Melanoma 10% 3,000

Medullary thyroid 25% 125

Retinoblastoma 40% 70

Relative Proportion and Case Loadof ‘Hereditary Cancers’ in the US
genes involved in carcinogenesis
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
Oncogenes

Normal genes (regulate cell growth)

1st mutation

(leads to accelerated cell division)

1 mutation sufficient for role in cancer development

tumor suppressor genes
Tumor Suppressor Genes

Normal gene

1st mutation

(susceptible carrier)

2nd mutation or loss (leads to cancer)

genes involved in carcinogenesis1
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 alcohol the influence of polymorphisms in alcohol dehydrogenase adh

Homozygous for the

fast-metabolizing allele

Odds

Ratio

(log)

Homozygous for the

slow-metabolizing allele

10

Heterozygotes

1

200

100

Number of alcoholic drinks per week

Risk of oral cancer from alcoholThe influence of polymorphisms in alcohol dehydrogenase (ADH)
slide9

Metabolite B

Enz A

Excreted in urine

Sewer

Metabolite A

(nonreactive)

Enz B

(in bladder wall)

Carcinogen

Bladder Cancer

Tobacco-derived

procarcinogen

slide10

Increase in Bladder Cancer Risk in Smokers

-as a function of an individual’s genotype

Slow A, Fast B

Odds Ratio

Slow A, Slow B

Fast/Fast

Fast A, Slow B

Years of smoking

the accumulation of genetic changes underlies the development and progression of cancer

The Accumulation of Genetic Changes Underlies the Development and Progression of Cancer

Genetic pathways involved in tumorigenesis

Acquisition of invasive, metastatic, drug-resistant phenotypes

Somatic vs. germline

the accumulation of genetic changes underlies the development and progression of cancer1

The Accumulation of Genetic Changes Underlies the Development and Progression of Cancer

Genetic pathways involved in tumorigenesis

Regulation of proliferation

Regulation 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 underlies the development and progression of cancer2

The Accumulation of Genetic Changes Underlies the Development and Progression of Cancer

Genetic pathways involved in tumorigenesis

Acquisition of invasive, metastatic, drug-resistant phenotypes

Somatic vs germline

the accumulation of genetic changes underlies the development and progression of cancer3

The Accumulation of Genetic Changes Underlies the Development and Progression of Cancer

Genetic pathways involved in tumorigenesis

Acquisition of invasive, metastatic, drug-resistant phenotypes

Somatic vs. germline

Somatic: only in the affected tissue

germline: aka constitutional, heritable DNA

tumor suppressor genes1
Tumor Suppressor Genes

Normal genes (prevent cancer)

1st mutation

(susceptible carrier)

2nd mutation or loss (leads to cancer)

slide22

The Two-Hit Hypothesis

First hit

First hit in germline of child

Second hit

(tumor)

human genome project 1990 2003
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.
slide31

Linkage Analysis

Where is gene ‘D’

D

A1

B3

d

A2

B2

d

A3

B2

d

A4

B4

D

A1

B3

d

A3

B2

d

A1

B2

d

A4

B3

d

A2

B2

d

A3

B2

D

A1

B3

d

A4

B4

D

A1

B3

d

A1

B2

d

A4

B4

d

A1

B2

slide32

Crossover tells us that

locus A is closer to “D”

than is locus B

D

A1

B3

d

A2

B2

d

A3

B2

d

A4

B4

D

A1

B3

d

A3

B2

d

A1

B2

d

A4

B3

d

A2

B2

d

A3

B2

D

A1

B3

d

A4

B4

D

A1

B4

d

A1

B2

d

A4

B4

d

A1

B2

breast cancer susceptibility genes
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)
slide34

100

BRCA1-mutation carriers

80

Breast

Cancer

Risk

(%)

60

40

20

General population

30

50

70

AGE (years)

slide35

Risk of a second cancer after breast cancer in BRCA1 mutation carriers

0.8

0.6

Breast CA

Cumulative Risk

0.4

Ovarian CA

0.2

0

40

70

50

60

AGE (years)

causes of hereditary susceptibility to crc
Causes of Hereditary Susceptibility to CRC

Sporadic (65%–85%)

Familial (10%–30%)

Rare CRC syndromes (<0.1%)

Hereditary nonpolyposis colorectal cancer (HNPCC) (5%)

Familial adenomatous polyposis (FAP) (1%)

age specific penetrance for colon cancer in h ereditary n on p olyposis c olon c ancer hnpcc
Age-Specific Penetrance for Colon Cancer in Hereditary Nonpolyposis Colon Cancer (‘HNPCC’)

Percentage of individuals with an altered disease gene who develop the disease

100

Affected with colorectal cancer (%)

HNPCC mutation carriers

80

60

40

20

General population

0

0

20

40

60

80

risk of colorectal cancer crc
Risk of Colorectal Cancer (CRC)

5%

General population

Personal history of colorectal neoplasia

15%–20%

Inflammatory bowel disease

15%–40%

70%–80%

HNPCC mutation

>95%

FAP

0

20

40

60

80

100

Lifetime risk (%)

cancer risks in hnpcc
Cancer Risks in HNPCC

100

80

% with cancer

Colorectal 78%

60

Endometrial 43%

40

Stomach 19%

20

Biliary tract 18%

Ovarian 9%

0

0

20

40

60

80

Age (years)

Aarnio M et al. Int J Cancer 64:430, 1995

the potential of genetic testing knowledge is power
The Potential of Genetic TestingKnowledge 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
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
slide42

Missense mutations

...ATG GAT AGT TGC CAA...  ...ATGGAA AGT TGC CAA...

...MetAsp SerCys Gln... ...Met Glu Ser Cys Gln...

Nonsense mutations

...ATG GAT AGT TGC CAA...  ...ATG GAT AGT TGA CAA...

...MetAsp Ser Cys Gln... ...MetAsp SerSTOP

Frameshift mutations

...ATG GAT AGT TGC CAA... ...ATG GAT ACG TTG CCA A...

...Met AspSer Cys Gln... ...Met Asp Thr Leu Pro...

Other

Promoter function or RNA splicing altered

Benign Polymorphisms (beware)

From DNA sequence to protein -- the effect of nucleotide changes

slide43

The Challenge of Genetic Testing -- not 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
slide44

BrCA

at

51

BrCA

at

58

72

BrCA

at

44

43

Tom

?