? BrCA at 44 BrCA at 51 BrCA at 58 Tom 43 72 Example: Breast Cancer Sporadic Family clusters...

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? BrCA at 44 BrCA at 51 BrCA at 58 Tom 43 72

Transcript of ? BrCA at 44 BrCA at 51 BrCA at 58 Tom 43 72 Example: Breast Cancer Sporadic Family clusters...

Page 1: ? BrCA at 44 BrCA at 51 BrCA at 58 Tom 43 72 Example: Breast Cancer Sporadic Family clusters Hereditary 5%–10% 15% 20% An inherited predisposition.

?

BrCAat44

BrCAat51

BrCAat58

Tom43

72

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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

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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

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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

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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

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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)

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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

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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

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Tobacco-derivedprocarcinogen

Metabolite A(nonreactive)

Metabolite B

Enz A

Carcinogen

Excreted in urine

Bladder Cancer

Enz B(in bladder wall)

Sewer

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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

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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

Page 12: ? BrCA at 44 BrCA at 51 BrCA at 58 Tom 43 72 Example: Breast Cancer Sporadic Family clusters Hereditary 5%–10% 15% 20% An inherited predisposition.

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

Page 13: ? BrCA at 44 BrCA at 51 BrCA at 58 Tom 43 72 Example: Breast Cancer Sporadic Family clusters Hereditary 5%–10% 15% 20% An inherited predisposition.

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

Page 14: ? BrCA at 44 BrCA at 51 BrCA at 58 Tom 43 72 Example: Breast Cancer Sporadic Family clusters Hereditary 5%–10% 15% 20% An inherited predisposition.

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

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http://www.ncbi.nlm.nih.gov/ncicgap/

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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)

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The Two-Hit Hypothesis

First hit First hit

First hit in First hit in germline of germline of

childchild

Second hitSecond hit(tumor)(tumor)

Page 23: ? BrCA at 44 BrCA at 51 BrCA at 58 Tom 43 72 Example: Breast Cancer Sporadic Family clusters Hereditary 5%–10% 15% 20% An inherited predisposition.
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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.

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DA1B3

dA2B2

dA3B2

dA4B4

DA1B3

dA4B4

dA2B2

dA3B2

dA3B2

dA1B2

dA4B3

DA1B3

dA1B2

dA4B4

dA1B2

DA1B3

Linkage AnalysisWhere is gene ‘D’

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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

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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)

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BreastCancer

Risk(%)

20

40

60

80

100

30 50 70

AGE (years)

BRCA1-mutation carriers

General population

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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

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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%)

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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 (%)

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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 (%)

Page 39: ? BrCA at 44 BrCA at 51 BrCA at 58 Tom 43 72 Example: Breast Cancer Sporadic Family clusters Hereditary 5%–10% 15% 20% An inherited predisposition.

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%

Page 40: ? BrCA at 44 BrCA at 51 BrCA at 58 Tom 43 72 Example: Breast Cancer Sporadic Family clusters Hereditary 5%–10% 15% 20% An inherited predisposition.

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

Page 41: ? BrCA at 44 BrCA at 51 BrCA at 58 Tom 43 72 Example: Breast Cancer Sporadic Family clusters Hereditary 5%–10% 15% 20% An inherited predisposition.

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

Page 42: ? BrCA at 44 BrCA at 51 BrCA at 58 Tom 43 72 Example: Breast Cancer Sporadic Family clusters Hereditary 5%–10% 15% 20% An inherited predisposition.

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

Page 43: ? BrCA at 44 BrCA at 51 BrCA at 58 Tom 43 72 Example: Breast Cancer Sporadic Family clusters Hereditary 5%–10% 15% 20% An inherited predisposition.

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

Page 44: ? BrCA at 44 BrCA at 51 BrCA at 58 Tom 43 72 Example: Breast Cancer Sporadic Family clusters Hereditary 5%–10% 15% 20% An inherited predisposition.

?

BrCAat44

BrCAat51

BrCAat58

Tom43

72

Page 45: ? BrCA at 44 BrCA at 51 BrCA at 58 Tom 43 72 Example: Breast Cancer Sporadic Family clusters Hereditary 5%–10% 15% 20% An inherited predisposition.

CARCINOMA OVARICO BRCA MUTATO - AIOM

CARCINOMA OVARICO BRCA MUTATO - AIOM

Cultural Predisposition

Cultural Predisposition

Investigating Complex Oak Decline-Diseases: Predisposition ...

Investigating Complex Oak Decline-Diseases: Predisposition ...

evaluarea riscului de purtator BRCA

evaluarea riscului de purtator BRCA

TFCP2 Genetic Polymorphism Is Associated with Predisposition …downloads.hindawi.com/journals/grp/2017/6353248.pdf · TFCP2 Genetic Polymorphism Is Associated with Predisposition

TFCP2 Genetic Polymorphism Is Associated with Predisposition …downloads.hindawi.com/journals/grp/2017/6353248.pdf · TFCP2 Genetic Polymorphism Is Associated with Predisposition

Breast cancer and the BRCA genes

Breast cancer and the BRCA genes

Brochure BRCA Packers Plus MFG Sept 2015

Brochure BRCA Packers Plus MFG Sept 2015

Clinical Policy Bulletin: BRCA Testing, Prophylactic ......BRCA Testing, Prophylactic Mastectomy, and Prophylactic Oophorectomy Page 1 of 30 ... Clinical Policy Bulletin: BRCA Testing,

Clinical Policy Bulletin: BRCA Testing, Prophylactic ......BRCA Testing, Prophylactic Mastectomy, and Prophylactic Oophorectomy Page 1 of 30 ... Clinical Policy Bulletin: BRCA Testing,

20150602 BRCA Review Final

20150602 BRCA Review Final

TYPES OF BRCA

TYPES OF BRCA

Breast Cancer: A focus on BRCA Mutations.

Breast Cancer: A focus on BRCA Mutations.

Aging: a predisposition to dry eye

Aging: a predisposition to dry eye

BRCA Mutations and Breast Cancer

BRCA Mutations and Breast Cancer

Brca brac 1 & 2 cluttered scotus

Brca brac 1 & 2 cluttered scotus

Predisposition and Positivism: The Forgotten Foundations ...

Predisposition and Positivism: The Forgotten Foundations ...

BRCA Challenge...Bartha Knoppers, McGill University, Montreal, Canada genomicsandhealth.org BRCA Challenge – Ins5tu5ons across the globe John Burn, Newcastle University, Newcastle

BRCA Challenge...Bartha Knoppers, McGill University, Montreal, Canada genomicsandhealth.org BRCA Challenge – Ins5tu5ons across the globe John Burn, Newcastle University, Newcastle

Ovarian Cancer Genetics and Risk Reducing Surgery · •14% had BRCA mutation •17% of patients with HGSOC had germline BRCA mutation •44% of those with BRCA mutation had no reported

Ovarian Cancer Genetics and Risk Reducing Surgery · •14% had BRCA mutation •17% of patients with HGSOC had germline BRCA mutation •44% of those with BRCA mutation had no reported

The Cancer Pedigree BRCA What?. Outline Introduction: Understanding the weight of genetics in Ovarian Breast Cancer BRCA 1 and BRCA 2 Genes – Function.

The Cancer Pedigree BRCA What?. Outline Introduction: Understanding the weight of genetics in Ovarian Breast Cancer BRCA 1 and BRCA 2 Genes – Function.

Platinum Predisposition for Trade

Platinum Predisposition for Trade

Identification of new Wilms tumour predisposition genes ... · supporting the role of KDM3B as a childhood cancer predisposition gene. Interpretation The four new Wilms tumour predisposition

Identification of new Wilms tumour predisposition genes ... · supporting the role of KDM3B as a childhood cancer predisposition gene. Interpretation The four new Wilms tumour predisposition