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7.Cancer Genetics.Oct.09
 

7.Cancer Genetics.Oct.09

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    7.Cancer Genetics.Oct.09 7.Cancer Genetics.Oct.09 Presentation Transcript

    • Cancer genetics
    • Cancer genetics
      • “ all cancer is genetic, but some cancers are more genetic than others”
      • “ cancer runs in families”
    • 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
    • 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
    • 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
    •  
    • 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
    •  
    • 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
    • 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
    • Philadelphia chromosome
    • Burketts lymphoma gene
    • 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
    • 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
    •  
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    •  
      • 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
    • Tumor suppressor genes
    • 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
    • Prader-Willi and Angelman syndrome genes
    • 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
    • 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
    • Telomere length and cancer
    • Genetics of common cancers colorectal cancer
      • 1. multistage hypothesis of carcinogenesis
      • Fig 14.10
    • multistage hypothesis of carcinogenesis
    • Multistage (multistep) theory
    • Genetics of common cancers colorectal cancer
      • 2. familial adenomatous polypsis (FAP)
      • phenotype: Figs x 2
      • genetics: autosomal dominant
      • APC gene
      • treatment: prophylactic colectomy
      • hereditary familial adenomatous polyposis
    •  
    • 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
    •  
    • 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
    •  
    • 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
    • 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
    • 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
    •  
    • Risk estimation
    •  
    • 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
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