Professional Documents
Culture Documents
Cancer Genetics
Cancer Genetics
Edyta Borkowska
Department of Clinical Genetics
Medical University of Lodz
3 Sterling Street 91-425 Lodz Poland
Materials from:
National Cancer Institute
Biology of the Cancer Robert Weinberg
Centromer
6
10
q
11
12
13
14
15
Chromosom 5
16
17
18
21
22
X Y
19
20
Geny
Start site
Promoter
Exon 1
Splice sites
Intron
Exon 2
Stop site
Intron
Exon 3
5 end
3 end
Exon 1
Exon 2
mRNA
Exon 3
Regiony niekodujce
Gen 1
Biako 1
Region niekodujcy
Biako 2
Gen 2
Exon
Noncoding
intron
Region niekodujacy
Biako
C
G
G
A
mRNA
G
C
C
U
G
C
C
T
switched-on
DNA
Exon
Intron
Exon
Intron
Transkrypcja
Primary
mRNA
Processing
Mature
mRNA
Translacja
Biako
Exon
Kod trjkowy
Kodony s zbudowane z 3 nukleotydw
64 moliwe kodony
61 kodonw kodujcych
20 aminokwasw
(kod zdegenerowany)
AUG
GCA
Methionina
Alanina
3 ckodony stop
Zatrzymuj translacj biaek
UAA
UAG
UGA
Mutacje
Mutacje somatyczne
Mutacje germline
Nie dziedzicza si
Dziedzicz si
niedziedziczne
Somatic mutation
(e.g., breast)
Malignant cells
2N
Nuclear
membrane
2N
2N
4N
Centromere
Microtubules
4N
Ova (or sperm)
N
N
N
Nuclear
membrane
Homologous
chromosomes form
a bivalent
2N
Crossing over has
occurred
Synapsis
Crossing over
De Novo Mutations
No family history of hereditary cancer
New mutation in
germ cell
Affected offspring
30%
50%
50%
Point Mutations
GU UC G AU UGA
DNA
Normal
mRNA
C A AG C T A A C T
GU U C G C U U GA
Missense
CAAG C GAA C T
GU U C C G C G A U U G A
Frameshift insertion
CA A G G C G C T A A C T
GU UC UUG A
Frameshift deletion
CA A G AA C T
GUU UA G
Nonsense
CAAAC T
C
T
Frameshift Mutations
Normal
AUG
A AG
UUU
GG C
GCA
UUG
GAA
Methionine
Lysine
Phenylalanine
Glycine
Alanine
Leucine
Glutamine
C AU
UG G
tRNA
Protein
Frameshift
AUG
A AG
UUG
GCG
Methionine
Lysine
Leucine
Alanine
tRNA
Protein
AA
Splice-Site Mutations
DNA Exon 1
Altered
mRNA
Intron
Exon 1
Exon 2
Intron
Exon 2
Exon 3
Exon 3
DNA Exon 1
Altered
mRNA
Intron
Exon 2
Exon 1
Intron
Exon 3
Exon 3
Regulatory Mutations
Normal expression
Overexpression
Her2 protein
Her2 protein
Messenger
RNA
Chromosome 17
Her2 gene
SNP site
Common
sequence
Variant
sequence
Functional protein
Functional protein
9
(q+)
Ph
22
bcr
(22q)
bcr-abl
abl
Fusion protein
with tyrosine
kinase activity
Cancer-Associated Mutations
Oncogenes
Tumor suppressor genes
DNA repair genes
Carcinogen
activating genes
deactivating genes
Cell cycle genes
Cell cycle checkpoint genes
Cell death genes
Cell signaling genes
Cellular differentiation genes
Cellular senescence genes
Metastasis/invasion genes
Alleles
Dominant
allele
Normal
allele
Recessive
allele
Aa
aa
Aa
aa
Damaged
allele
Aa
aa
Cysteine-rich domain
Transmembrane domain
Tyrosine kinase 1
Tyrosine kinase 2
Activating mutations: MEN 2A/B
3
Chromosome 13
Allele
(gene)
Locus (spot
on gene)
Allele
(gene)
Locus (spot
on gene)
BRCA1
BRCA2
Penetrance
Genotype and phenotype
present
Genotype and
phenotype absent
Genotype present,
phenotype (disease) absent
Modifier genes
Carcinogens
Estrogen
Repair enzyme
Response to DNA
damage
Hormonal/
reproductive
factors
Age-Related Penetrance
100
80
HNPCC
mutation
carriers
Affected 60
with
colorectal
cancer (%) 40
20
General
population
20
40
60
80
Age
Percentage of individuals with altered
mismatch repair gene who develop cancer
Primary RNA
transcript
Translational control
mRNA
RNA transport
control
Transcriptional control
DNA
Translational control
mRNA
ribosome
Active mRNA
Inactive
protein
Protein activity
control
Protein
Phosphorylation
Active
protein
Epigenetic Example:
Methylation Alters Gene Expression
CpG island
Me
Gene
Me
HDAC
CpG island
becomes
methylated
Methyl-binding
proteins
Me
Me
Gene inactivated
Gene 1
Me
Gene 1
Me
Me
Gene 2
Me
Paternal chromosome
II
Gene 2
Maternal
chromosome II
Active gene
Imprinted gene
Carrier Frequency
Example: carrier frequency=20%
Founder
Original population
Marked population
decrease, migration, or
isolation
Generations later
BRCA1
185delAG
Prevalence = ~1%
5382insC
Prevalence = ~0.15%
BRCA2
6174delT
Prevalence = ~1.5%
Mutations in
Cancer Susceptibility Genes: BRCA1
On chromosome 17
Autosomal dominant
transmission
Nonsense/Frameshift
Missense
Splice-site
Mutations in
Cancer Susceptibility Genes: BRCA2
On chromosome 13
Autosomal dominant
transmission
Nonsense/Frameshift
Missense
Normal
Affected
Examples of
Dominantly Inherited Cancer Syndromes
Cancer Susceptibility:
Incomplete Penetrance and Phenocopies
Normal
Susceptible carrier
Carrier, affected with
cancer
Sporadic cancer
Example: BRCA1-Linked
Hereditary Breast and Ovarian Cancer
92
73
Breast,
dx 45, d. 89
68
Ovary,
dx 59,
d. 62
Noncarrier
BRCA1-mutation carrier
Affected with cancer
86
Breast,
dx 36
Breast,
dx 59
Noncarrier
Nonaffected carrier
Affected carrier
X-Linked Inheritance
Mutant genes are on the
X (sex) chromosome
Carrier female
Affected male
Normal male
Normal female
G1 (cell growth)
M (mitosis)
Oncogenes
G2
Tumor
suppressor
genes
DNA repair
genes
S (synthesis)
Normal genes
(regulate cell
growth)
1st mutation
(leads to accelerated
cell division)
Proto-oncogene to oncogene
Active oncogene
Active oncogene
No brakes!
2nd mutation or loss
(leads to cancer)
No brakes!
Active oncogene
Two-Hit Hypothesis
No cancer
Germline mutation
Somatic mutation
Cancer
Heterozygous Condition
Normal allele
Mutant allele
Chromosome loss
Deletion
Unbalanced
translocation
Loss and
reduplication
Mitotic
recombination
Point
mutation
Loss of Heterozygosity
Normal
allele
Mutant
allele
Germline mutation