7.Cancer Genetics.Oct.09

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  • 1. Cancer genetics
  • 2. Cancer genetics
    • “ all cancer is genetic, but some cancers are more genetic than others”
    • “ cancer runs in families”
  • 3. Cancer genetics
    • acquired somatic genetic diseases
    • 95% of all cases
    • somatic mutation mostly caused by environmental factors
    • hereditary cancer
    • 5% of all cases
    • susceptibility/major genes
    • germline mutation
  • 4. Differentiation between genetic and environmental factors in cancer
    • 1. epidemiological study:
    • breast cancer
    • association with reproduction and menstruation
    • having children vs. nulliparous
    • first menstrual age: early vs. late
    • indicative in genetic vs. environment
    • incidence
    • highest in European origin populations
    • 8 times lower in Chinese, Japanese
    • indicating genetic component
    • migration
    • migration from low to high incidence areas:
    • increased incidence
    • indicating environmental factors
  • 5. Differentiation between genetic and environmental factors in cancer
    • 2. family study
    • breast cancer incidence
    • risk 1.5-3 folds than general population ,
    • if having one 1st degree relative patient
    • gastric cancer
    • risk 2-3 folds than general population
    • if one 1st degree relative patient
    • liability curve
    • 3. twin study
    • concordance rates for breast cancer
    • monozygotic twins: 17%
    • dizygotic twins: 13%
    • indicating importance of environment
  • 6.  
  • 7. Differentiation between genetic and environmental factors in cancer
    • 4 . association study
    • blood group A people have an 20% increased risk for gastric cancer over the general population
    • 5. animal models
    • 6. viral factors
    • DNA viruses: table 14.1, p198
    • retroviruses:
    • RNA – DNA (reverse transcriptase)
    • – integration into host genome
  • 8.  
  • 9. Oncogenes
    • concept
    • proto - oncogen
    • normal cellular genes
    • have key roles in cell growth and differentiation
    • have the potential to be tumorogenic
    • oncogene
    • converted from proto – oncogene
    • has tumorogenic (carcinogenic) effects
    • cellular oncogene (C-oncogene)
    • cellular origin
    • has tumorogenic (carcinogenic) function
    • viral oncogene (V-oncogene)
    • viral origin
    • has tumorogenic (carcinogenic) property
  • 10. Oncogenes
    • identification of oncogenes
    • 1. at chromosomal translocation breakpoints
    • Philadelphia chromosome:
    • Fig in Li Pu’s book
    • Burketts lymphoma chromosome:
    • Fig in Li Pu’s book
    • 2. amplification of oncogenes
    • 10,000, or 1,000 folds of increased gene copies
    • ERBB2 gene copy number increased 20% in breast cancer cases
    • MYC gene copy number increased 30% neuroblastoma cases
  • 11. Philadelphia chromosome
  • 12. Burketts lymphoma gene
  • 13. Oncogenes
    • Types of oncogens
    • growth factor:
    • v-SIS gene: codes for part of platelet-derived growth factor
    • HST : homologous of fibroblast growth factor
    • growth factor receptors:
    • ERB-B : epidermal growth factor receptor
    • intracellular signal transduction factors:
    • proteins with GTPase activities
    • RAS genes
    • cytoplasmic serine threonine kinases RAF gene
    • DNA-binding nuclear proteins:
    • transcription factors
    • FOS, JUN
    • cell cycle genes:
    • loss of cell cycle inhibitory genes
    • cyclin-dependent kinases
    • cyclin D1
    • loss of genes lead to apoptosis
  • 14. Tumor suppressor genes
    • RB1 and retinoblastoma
    • retinoblastoma
    • phenotype: Fig
    • hereditary
    • non-hereditary
    • two-hint theory:
    • Fig
    • loss of heterozygosity (LOH)
    • Fig 14.7, p204
    • table 14.2, p205
  • 15.  
  • 16.  
  • 17.  
  • 18.  
  • 19.
    • TP53 and Li-Fraumeini syndrome
    • TP53 : the most mutated tumor suppressor genes
    • in cancer
    • checkpoint control of G1-> S
    • Li-Fraumeini syndrome:
    • phenotype: familial cancer multiple organ cancers
    • TP53 somatic and germ-line mutations
    • familial cancer due to tumor suppressor gene mutation
    • table 14.3, p208
  • 20. Tumor suppressor genes
  • 21. Epigenetics and cancer
    • epigenetics
    • 1. concept
    • heritable changes to gene expression that are not due to difference in gene code (DNA sequence), transmitted either through mitosis or meiosis
    • 2. roles
    • imprinting
    • the phenomenon of a gene or a region of a chromosome showing differential expression depending on the parent of origin.
    • Fig 7.22
    • X-inactivation
    • regulation of gene expression
  • 22. Prader-Willi and Angelman syndrome genes
  • 23. Epigenetics and cancer
    • 3. mechanisms of epigenetics
    • re-imprinting in gamatogenesis
    • methylation of DNA sequences
    • reduced expression
    • maintain genome stability
    • chromatin remodeling (histone modification)
    • condensed or loosened super-coil structures
    • changes in transcriptional activity of sex genes during development
    • 4. epigenetics in cancers
    • hypomethylation of oncogenes
    • hypermethylation of tumor suppressor genes
  • 24. Telomere length and cancer
    • telomere: chromosomal ends
    • tandem repeats: TTAGGG for 10-15 Kb
    • length maintained by telomerase
    • shortened telomere in cancer
    • aging
    • Fig 14.9
  • 25. Telomere length and cancer
  • 26. Genetics of common cancers colorectal cancer
    • 1. multistage hypothesis of carcinogenesis
    • Fig 14.10
  • 27. multistage hypothesis of carcinogenesis
  • 28. Multistage (multistep) theory
  • 29. Genetics of common cancers colorectal cancer
    • 2. familial adenomatous polypsis (FAP)
    • phenotype: Figs x 2
    • genetics: autosomal dominant
    • APC gene
    • treatment: prophylactic colectomy
  • 30.
    • hereditary familial adenomatous polyposis
  • 31.  
  • 32. Colorectal cancer
    • 3. hereditary non-polypsis colorectal cancer (HNPCC)
    • phenotype: less polyps site specific: proximal
    • right
    • genetics: autosomal dominant
    • gene: DNA mismatch repair genes
    • table 14.4
    • microsatellite instability (MSI)
    • (replication error)
    • somatic or germline
  • 33.  
  • 34. Breast cancer
    • 1. incidence in west:
    • 1 in 12 women aged 40-55
    • 1 in 3 will be metastatic
    • 2. genetics (somatic form):
    • cumulative changes
    • amplification: ERB-B1 ERB-B2
    • LOH: 7q, 16q, 13q, 17p, etc
    • Fig 14.7
  • 35.  
  • 36. Breast cancer
    • 3. familial breast cancer
    • (1) autosomal dominant
    • (2) BRCA1 : chr 17
    • mutations in 40-50% early onset families
    • lifetime risk for family members:
    • 60-85%
    • if having the mutation
    • increased risk for : ovarian cancer in female prostate cancer in male
  • 37. Breast cancer
    • (3) BRCA2 , chr 13
    • 30-40% early onset autosomal dominant families
    • female mutations carriers
    • lifetime risk for family member as BRCA1
    • heterozygotes: increased risk of ovarian cancer
    • male mutations carriers
    • 6% lifetime risk for breast cancer, which is
    • 100 - fold increased risk in comparison with the general population
  • 38. Genetic counseling in familial cancer
    • inherited cancer-predisposing syndrome
    • individual has more than one site cancers or at
    • different sites in various individuals of a family
    • than would be expected
    • box 4.1
    • risk estimation
    • table 14.6, 14.7
  • 39.  
  • 40. Risk estimation
  • 41.  
  • 42. Genetic counseling in familial cancer
    • screening for familial cancer
    • phenotype screening
    • genotype screening
    • treatment
    • prophylactic medications: Asprin in FAP
    • tamoxifen for breast cancer
    • (anti - estrogen)
    • life style change
    • prophylactic surgery: table 14.9
  • 43.  
  • 44.  
  • 45.  
  • 46.  
  • 47.