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BrCA at 44

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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BrCA at 44

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

  2. 15%20% 5%–10% Sporadic Family clusters Hereditary An inherited predisposition underlies only a fraction of adult cancers Example: Breast Cancer

  3. 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

  4. 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

  5. Oncogenes Normal genes (regulate cell growth) 1st mutation (leads to accelerated cell division) 1 mutation sufficient for role in cancer development

  6. Tumor Suppressor Genes Normal gene 1st mutation (susceptible carrier) 2nd mutation or loss (leads to cancer)

  7. 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

  8. 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)

  9. Metabolite B Enz A Excreted in urine Sewer Metabolite A (nonreactive) Enz B (in bladder wall) Carcinogen Bladder Cancer Tobacco-derived procarcinogen

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

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

  16. Tumor Suppressor Genes Normal genes (prevent cancer) 1st mutation (susceptible carrier) 2nd mutation or loss (leads to cancer)

  17. The Two-Hit Hypothesis First hit First hit in germline of child Second hit (tumor)

  18. 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.

  19. 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

  20. 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

  21. 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)

  22. 100 BRCA1-mutation carriers 80 Breast Cancer Risk (%) 60 40 20 General population 30 50 70 AGE (years)

  23. 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)

  24. 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%)

  25. 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

  26. 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 (%)

  27. 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

  28. 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

  29. 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

  30. 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

  31. 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

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

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