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Cancer genetics
Cancer genetics <ul><li>“ all cancer is genetic, but some cancers are more genetic than others” </li></ul><ul><li>“ cancer...
Cancer genetics <ul><li>  acquired somatic   genetic diseases </li></ul><ul><li>95% of all cases </li></ul><ul><li>somatic...
Differentiation between genetic and environmental factors in cancer <ul><li>1. epidemiological study: </li></ul><ul><li>br...
Differentiation between genetic and environmental factors in cancer <ul><li>2. family study </li></ul><ul><li>breast cance...
 
Differentiation between genetic and environmental factors in cancer <ul><li>4 . association study </li></ul><ul><li>blood ...
 
Oncogenes <ul><li>concept </li></ul><ul><li>  proto - oncogen </li></ul><ul><li>normal  cellular genes </li></ul><ul><li>h...
Oncogenes   <ul><li>identification of oncogenes  </li></ul><ul><li>1. at chromosomal translocation breakpoints </li></ul><...
Philadelphia chromosome
Burketts lymphoma gene
Oncogenes <ul><li>Types of oncogens </li></ul><ul><li>growth factor:   </li></ul><ul><li>v-SIS  gene: codes for part of pl...
Tumor suppressor genes   <ul><li>RB1  and retinoblastoma </li></ul><ul><li>  retinoblastoma </li></ul><ul><li>    phenotyp...
 
 
 
 
<ul><li>TP53  and Li-Fraumeini syndrome </li></ul><ul><li>  TP53 :  the most mutated tumor suppressor genes  </li></ul><ul...
Tumor suppressor genes
Epigenetics and cancer <ul><li>epigenetics  </li></ul><ul><li>1. concept </li></ul><ul><li>heritable changes to gene expre...
Prader-Willi and Angelman syndrome genes
Epigenetics and cancer <ul><li>3. mechanisms of epigenetics </li></ul><ul><li>re-imprinting in gamatogenesis </li></ul><ul...
  Telomere length and cancer <ul><li>telomere:   chromosomal ends </li></ul><ul><li>tandem repeats: TTAGGG for 10-15 Kb </...
  Telomere length and cancer
    Genetics of common cancers colorectal cancer <ul><li>1. multistage hypothesis of carcinogenesis </li></ul><ul><li>Fig ...
multistage hypothesis of carcinogenesis
Multistage (multistep) theory
    Genetics of common cancers colorectal cancer <ul><li>2. familial adenomatous polypsis (FAP) </li></ul><ul><li>phenotyp...
<ul><li>hereditary familial adenomatous polyposis </li></ul>
 
Colorectal cancer <ul><li>3. hereditary non-polypsis colorectal cancer  (HNPCC) </li></ul><ul><li>phenotype:  less polyps ...
 
Breast cancer <ul><li>1. incidence in west:   </li></ul><ul><li>1 in 12 women aged 40-55  </li></ul><ul><li>1 in 3 will be...
 
Breast cancer <ul><li>3.   familial breast cancer </li></ul><ul><li>  (1)   autosomal dominant </li></ul><ul><li>  (2)  BR...
Breast cancer <ul><li>(3)  BRCA2 ,  chr 13 </li></ul><ul><li>  30-40% early onset autosomal dominant families </li></ul><u...
Genetic counseling in familial cancer <ul><li>inherited cancer-predisposing syndrome </li></ul><ul><li>individual has more...
 
Risk estimation
 
Genetic counseling in familial cancer <ul><li>screening for familial cancer </li></ul><ul><li>  phenotype screening </li><...
 
 
 
 
 
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7.Cancer Genetics.Oct.09

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Transcript of "7.Cancer Genetics.Oct.09"

  1. 1. Cancer genetics
  2. 2. Cancer genetics <ul><li>“ all cancer is genetic, but some cancers are more genetic than others” </li></ul><ul><li>“ cancer runs in families” </li></ul>
  3. 3. Cancer genetics <ul><li> acquired somatic genetic diseases </li></ul><ul><li>95% of all cases </li></ul><ul><li>somatic mutation mostly caused by environmental factors </li></ul><ul><li> hereditary cancer </li></ul><ul><li>5% of all cases </li></ul><ul><li>susceptibility/major genes </li></ul><ul><li>germline mutation </li></ul>
  4. 4. Differentiation between genetic and environmental factors in cancer <ul><li>1. epidemiological study: </li></ul><ul><li>breast cancer </li></ul><ul><li>association with reproduction and menstruation </li></ul><ul><li> having children vs. nulliparous </li></ul><ul><li> first menstrual age: early vs. late </li></ul><ul><li> indicative in genetic vs. environment </li></ul><ul><li>incidence </li></ul><ul><li>highest in European origin populations </li></ul><ul><li> 8 times lower in Chinese, Japanese </li></ul><ul><li> indicating genetic component </li></ul><ul><li> migration </li></ul><ul><li> migration from low to high incidence areas: </li></ul><ul><li>increased incidence </li></ul><ul><li> indicating environmental factors </li></ul>
  5. 5. Differentiation between genetic and environmental factors in cancer <ul><li>2. family study </li></ul><ul><li>breast cancer incidence </li></ul><ul><li>risk 1.5-3 folds than general population , </li></ul><ul><li> if having one 1st degree relative patient </li></ul><ul><li>gastric cancer </li></ul><ul><li>risk 2-3 folds than general population </li></ul><ul><li> if one 1st degree relative patient </li></ul><ul><li> liability curve </li></ul><ul><li>3. twin study </li></ul><ul><li>concordance rates for breast cancer </li></ul><ul><li>monozygotic twins: 17% </li></ul><ul><li>dizygotic twins: 13% </li></ul><ul><li>indicating importance of environment </li></ul>
  6. 7. Differentiation between genetic and environmental factors in cancer <ul><li>4 . association study </li></ul><ul><li>blood group A people have an 20% increased risk for gastric cancer over the general population </li></ul><ul><li>5. animal models </li></ul><ul><li>6. viral factors </li></ul><ul><li>DNA viruses: table 14.1, p198 </li></ul><ul><li>retroviruses: </li></ul><ul><li>RNA – DNA (reverse transcriptase) </li></ul><ul><li>– integration into host genome </li></ul>
  7. 9. Oncogenes <ul><li>concept </li></ul><ul><li> proto - oncogen </li></ul><ul><li>normal cellular genes </li></ul><ul><li>have key roles in cell growth and differentiation </li></ul><ul><li>have the potential to be tumorogenic </li></ul><ul><li> oncogene </li></ul><ul><li>converted from proto – oncogene </li></ul><ul><li>has tumorogenic (carcinogenic) effects </li></ul><ul><li> cellular oncogene (C-oncogene) </li></ul><ul><li>cellular origin </li></ul><ul><li>has tumorogenic (carcinogenic) function </li></ul><ul><li> viral oncogene (V-oncogene) </li></ul><ul><li>viral origin </li></ul><ul><li>has tumorogenic (carcinogenic) property </li></ul>
  8. 10. Oncogenes <ul><li>identification of oncogenes </li></ul><ul><li>1. at chromosomal translocation breakpoints </li></ul><ul><li> Philadelphia chromosome: </li></ul><ul><li>Fig in Li Pu’s book </li></ul><ul><li> Burketts lymphoma chromosome: </li></ul><ul><li>Fig in Li Pu’s book </li></ul><ul><li>2. amplification of oncogenes </li></ul><ul><li> 10,000, or 1,000 folds of increased gene copies </li></ul><ul><li> ERBB2 gene copy number increased 20% in breast cancer cases </li></ul><ul><li> MYC gene copy number increased 30% neuroblastoma cases </li></ul>
  9. 11. Philadelphia chromosome
  10. 12. Burketts lymphoma gene
  11. 13. Oncogenes <ul><li>Types of oncogens </li></ul><ul><li>growth factor: </li></ul><ul><li>v-SIS gene: codes for part of platelet-derived growth factor </li></ul><ul><li>HST : homologous of fibroblast growth factor </li></ul><ul><li>growth factor receptors: </li></ul><ul><li>ERB-B : epidermal growth factor receptor </li></ul><ul><li>intracellular signal transduction factors: </li></ul><ul><li>proteins with GTPase activities </li></ul><ul><li> RAS genes </li></ul><ul><li>cytoplasmic serine threonine kinases RAF gene </li></ul><ul><li>DNA-binding nuclear proteins: </li></ul><ul><li>transcription factors </li></ul><ul><li> FOS, JUN </li></ul><ul><li>cell cycle genes: </li></ul><ul><li>loss of cell cycle inhibitory genes </li></ul><ul><li> cyclin-dependent kinases </li></ul><ul><li> cyclin D1 </li></ul><ul><li>loss of genes lead to apoptosis </li></ul>
  12. 14. Tumor suppressor genes <ul><li>RB1 and retinoblastoma </li></ul><ul><li> retinoblastoma </li></ul><ul><li> phenotype: Fig </li></ul><ul><li> hereditary </li></ul><ul><li> non-hereditary </li></ul><ul><li> two-hint theory: </li></ul><ul><li>Fig </li></ul><ul><li> loss of heterozygosity (LOH) </li></ul><ul><li>Fig 14.7, p204 </li></ul><ul><li>table 14.2, p205 </li></ul>
  13. 19. <ul><li>TP53 and Li-Fraumeini syndrome </li></ul><ul><li> TP53 : the most mutated tumor suppressor genes </li></ul><ul><li>in cancer </li></ul><ul><li> checkpoint control of G1-> S </li></ul><ul><li> Li-Fraumeini syndrome: </li></ul><ul><li> phenotype: familial cancer multiple organ cancers </li></ul><ul><li> TP53 somatic and germ-line mutations </li></ul><ul><li>familial cancer due to tumor suppressor gene mutation </li></ul><ul><li> table 14.3, p208 </li></ul>
  14. 20. Tumor suppressor genes
  15. 21. Epigenetics and cancer <ul><li>epigenetics </li></ul><ul><li>1. concept </li></ul><ul><li>heritable changes to gene expression that are not due to difference in gene code (DNA sequence), transmitted either through mitosis or meiosis </li></ul><ul><li>2. roles </li></ul><ul><li>imprinting </li></ul><ul><li> the phenomenon of a gene or a region of a chromosome showing differential expression depending on the parent of origin. </li></ul><ul><li>Fig 7.22 </li></ul><ul><li>X-inactivation </li></ul><ul><li>regulation of gene expression </li></ul>
  16. 22. Prader-Willi and Angelman syndrome genes
  17. 23. Epigenetics and cancer <ul><li>3. mechanisms of epigenetics </li></ul><ul><li>re-imprinting in gamatogenesis </li></ul><ul><li>methylation of DNA sequences </li></ul><ul><li>reduced expression </li></ul><ul><li>maintain genome stability </li></ul><ul><li>chromatin remodeling (histone modification) </li></ul><ul><li>condensed or loosened super-coil structures </li></ul><ul><li> changes in transcriptional activity of sex genes during development </li></ul><ul><li>4. epigenetics in cancers </li></ul><ul><li>hypomethylation of oncogenes </li></ul><ul><li>hypermethylation of tumor suppressor genes </li></ul>
  18. 24. Telomere length and cancer <ul><li>telomere: chromosomal ends </li></ul><ul><li>tandem repeats: TTAGGG for 10-15 Kb </li></ul><ul><li>length maintained by telomerase </li></ul><ul><li>shortened telomere in cancer </li></ul><ul><li>aging </li></ul><ul><li>Fig 14.9 </li></ul>
  19. 25. Telomere length and cancer
  20. 26. Genetics of common cancers colorectal cancer <ul><li>1. multistage hypothesis of carcinogenesis </li></ul><ul><li>Fig 14.10 </li></ul>
  21. 27. multistage hypothesis of carcinogenesis
  22. 28. Multistage (multistep) theory
  23. 29. Genetics of common cancers colorectal cancer <ul><li>2. familial adenomatous polypsis (FAP) </li></ul><ul><li>phenotype: Figs x 2 </li></ul><ul><li>genetics: autosomal dominant </li></ul><ul><li> APC gene </li></ul><ul><li>treatment: prophylactic colectomy </li></ul>
  24. 30. <ul><li>hereditary familial adenomatous polyposis </li></ul>
  25. 32. Colorectal cancer <ul><li>3. hereditary non-polypsis colorectal cancer (HNPCC) </li></ul><ul><li>phenotype: less polyps site specific: proximal </li></ul><ul><li>right </li></ul><ul><li>genetics: autosomal dominant </li></ul><ul><li> gene: DNA mismatch repair genes </li></ul><ul><li>table 14.4 </li></ul><ul><li> microsatellite instability (MSI) </li></ul><ul><li>(replication error) </li></ul><ul><li> somatic or germline </li></ul><ul><li> </li></ul>
  26. 34. Breast cancer <ul><li>1. incidence in west: </li></ul><ul><li>1 in 12 women aged 40-55 </li></ul><ul><li>1 in 3 will be metastatic </li></ul><ul><li> 2. genetics (somatic form): </li></ul><ul><li>cumulative changes </li></ul><ul><li> amplification: ERB-B1 ERB-B2 </li></ul><ul><li> LOH: 7q, 16q, 13q, 17p, etc </li></ul><ul><li>Fig 14.7 </li></ul>
  27. 36. Breast cancer <ul><li>3. familial breast cancer </li></ul><ul><li> (1) autosomal dominant </li></ul><ul><li> (2) BRCA1 : chr 17 </li></ul><ul><li> mutations in 40-50% early onset families </li></ul><ul><li> lifetime risk for family members: </li></ul><ul><li>60-85% </li></ul><ul><li>if having the mutation </li></ul><ul><li> increased risk for : ovarian cancer in female prostate cancer in male </li></ul><ul><li> </li></ul>
  28. 37. Breast cancer <ul><li>(3) BRCA2 , chr 13 </li></ul><ul><li> 30-40% early onset autosomal dominant families </li></ul><ul><li> female mutations carriers </li></ul><ul><li>lifetime risk for family member as BRCA1 </li></ul><ul><li>heterozygotes: increased risk of ovarian cancer </li></ul><ul><li> male mutations carriers </li></ul><ul><li>6% lifetime risk for breast cancer, which is </li></ul><ul><li> 100 - fold increased risk in comparison with the general population </li></ul>
  29. 38. Genetic counseling in familial cancer <ul><li>inherited cancer-predisposing syndrome </li></ul><ul><li>individual has more than one site cancers or at </li></ul><ul><li>different sites in various individuals of a family </li></ul><ul><li>than would be expected </li></ul><ul><li>box 4.1 </li></ul><ul><li> risk estimation </li></ul><ul><li>table 14.6, 14.7 </li></ul>
  30. 40. Risk estimation
  31. 42. Genetic counseling in familial cancer <ul><li>screening for familial cancer </li></ul><ul><li> phenotype screening </li></ul><ul><li> genotype screening </li></ul><ul><li> treatment </li></ul><ul><li> prophylactic medications: Asprin in FAP </li></ul><ul><li> tamoxifen for breast cancer </li></ul><ul><li>(anti - estrogen) </li></ul><ul><li> life style change </li></ul><ul><li> prophylactic surgery: table 14.9 </li></ul>
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