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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 diseases95% of all casessomatic mutation mostly caused by environmental factors
hereditary cancer5% of all cases
susceptibility/major genesgermline 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 studybreast cancer incidence
risk 1.5-3 folds than general population, if having one 1st degree relative patientgastric cancer
risk 2-3 folds than general population if one 1st degree relative patient liability curve
3. twin studyconcordance rates for breast cancer
monozygotic twins: 17%dizygotic twins: 13%indicating importance of environment
Differentiation between genetic and environmental factors in cancer
4. association studyblood group A people have an 20% increased
risk for gastric cancer over the general population
5. animal models
6. viral factorsDNA viruses: table 14.1, p198retroviruses:
RNA – DNA (reverse transcriptase) – integration into host genome
Oncogenes
concept proto - oncogen
normal cellular geneshave key roles in cell growth and differentiationhave the potential to be tumorogenic
oncogeneconverted from proto – oncogenehas 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
OncogenesTypes of oncogens
growth factor: v-SIS gene: codes for part of platelet-derived growth factorHST: homologous of fibroblast growth factor
growth factor receptors:ERB-B: epidermal growth factor receptor
intracellular signal transduction factors:proteins with GTPase activities RAS genescytoplasmic 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 D1loss 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, p204table 14.2, p205
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. rolesimprinting
• the phenomenon of a gene or a region of a chromosome showing differential expression depending on the parent of origin.Fig 7.22
X-inactivationregulation 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 expressionmaintain 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 oncogeneshypermethylation 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: proximalright
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-B1ERB-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 carrierslifetime 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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