Cancer Genetics
Medical Genetics
Cancer is a class of diseases caused
by loss of cell cycle control.
Cancer
In animals,cell numbers are under
exquisite control
Loss of this control leads to proliferation
of unwanted cells
Cancer arises when the above situation
reaches a certain degree
Cancer & Tumor
Cancer cells are malignant tumor (vs.
benign tumor) cells
All cancer cells are eventually capable
of metastasis
Cancer Family
Unusually large numbers of blood
relatives develop certain kinds of
cancers.
Lynch Cancer Family Syndrome Ⅱ
“Family G”,Italian family
Warthin AS,Heredity with reference to
carcinoma,Arch,Intern,Med,1913,12,546-555
Hauser IJ,Weller C,VA further report on the
cancer family of Warthin,Am,J,Cancer,1936.
27,434-449
Lynch HT,Krush AJ,Cancer family 'G'
revisited,1895-1970,Cancer,1971,27,1505-1511
Lynch Cancer Family Syndrome Ⅱ
“Family G”,Italian family
MIM 114400
Lynch Cancer Family Syndrome Ⅱ
HNPCC,18q11-q12
Adenocarcinomas of the colon
“Family G”,Italian family
Carcinoma of endometrium
Gastric cancer,ovary cancer,breast cancer
Li-Fraumeni Syndrome
Studies by Li and Fraumeni led to
first evidence of inherited predisposition
to cancer,(MIM 151623)
Breast tumors
Sarcoma,leukemia,lung cancer,and
adrenal cortical carcinoma
Cancer Family
Earlier age of onset
Multiple close relatives affected
Multiple primary tumours/bilateral
disease
Multiple tumours in specific cancer
syndrome
Inherited Cancer
Retinoblastoma,RB (MIM 180200)
Retinoblastoma occurs sporadically in
most cases,but in some families it displays
autosomal dominant inheritance.
Retinoblastoma
A rare malignant tumor of the developing
retina that occurs in children,usually before
the age of four years.
An abnormal appearance of the pupil which
reflects light like a cat's eye.
Retinoblastoma
A rare malignant tumor of the developing
retina that occurs in children,usually before
the age of four years.
An abnormal appearance of the pupil which
reflects light like a cat's eye.
Some forms represent a deletion in the
region 13q14.1-q14.2
Two Mutation Theory
Knudson (1971)
Two Mutation Theory
Two mutations are required,one in each
copy of the RB gene
The first mutation is present in the
germline and thus in all cells of the body
For familial cases
The second somatic mutation is necessary
for initiating tumor formation
Inherited cancer
Initiation
Promotion
Clone Origin Theory
Sporadic cancer
Clone Origin Theory
Initiation
Loss of Heterozygosity
malignant
transformation
RB
Loss of Heterozygosity
RB rb
gene
conversion
Wilms’ Tumor
Nephroblastoma (MIM 194070)
Embryonic kidney tumor
Accounts for 3/4 occurring before age four,
90% before twenty.
Inherited cases of nephroblastoma display
autosomal dominant inheritance.
A noninvasive lesion with a predictable
likelihood of becoming malignant,Most
display autosomal dominant inheritance.
Precancerous Lesion
Familial Polyposis Coli
FPC (MIM 175100)
Average onset is 25 years old
Adenomatous polyps,mostly colorectal
Minimum 100 polyps,average 1,000 polyps
APC gene (Adenomatous Polyposis Coli)
localized to chromosome 5q21
100% will develop cancer within 10 to 15
years
Neurofibromatosis
NF1 (MIM 162200)
Generally includes multiple café-au-lait
spots,cutaneous neurofibromas
NF1 gene (nerve growth factor) localized
to chromosome 17q11.2
The presence of one or more genetic
factors,not necessarily abnormal,that is
associated with an increased risk for the
cancer.
Genetic Susceptibility
Fragile site
Chromosome unstable
Immune deficiency
Metabolism of carcinogen
Fragile Site
A genetic defect makes the chromosome
fragile and susceptible to breakage at a
specific point.
Inheritable Fragile Site
Such fragile sites show high expression
and inherited in a Mendelian fashion.
Susceptible to folic acid supplements
Susceptible to 5-BrdU supplements
Susceptible to telomycin supplements
Non-inheritable Fragile Site
Such fragile sites show low expression.
4q31
Fragile Site & Cancer
The locations of fragile sites have been
shown to correlate with sites of translocation
breakpoints and deletions commonly found
in cancer.
—— Yunis JJ,1975
Chromosome Unstable
Chromosome unstable caused by DNA
repair-deficiency susceptible to breakage
or rearrangement.
Bloom Syndrome,BS
A rare AR disorder (MIM 210900)
Possible phenotypes
Narrow face
Prominent nose or ears
Immunodeficiency
More cancer prone
,Butterfly rash” with skin sensitivity to sun
Hypo/hyperpigmented skin lesions
Bloom Syndrome,BS
A rare AR disorder (MIM 210900)
Bloom Syndrome,BS
A rare AR disorder (MIM 210900)
Cellular level
Genetic instability
Sister chromosome exchange (SCE)
Excessive numbers of somatic mutations
Chromosomal aberrations
Possible phenotypes
Bloom Syndrome,BS
A rare AR disorder (MIM 210900)
Bloom Syndrome,BS
A rare AR disorder (MIM 210900)
Bloom Syndrome,BS
A rare AR disorder (MIM 210900)
DNA helicase protein of Rec Q family
Cellular level
Possible phenotypes
Xeroderma Pigmentosum,XP
AR disorder (MIM 278700)
Inherited nucleotide excision repair
(NER) deficiency
Xtreme skin sensitivity to UV light
Abnormal skin pigmentation
High frequency of skin cancers
Xeroderma Pigmentosum,XP
AR disorder (MIM 278700)
Xeroderma Pigmentosum,XP
AR disorder (MIM 278700)
Immune Deficiency
Agammaglobulinemia,Swiss Type
SCID,Severe combined
immunodeficiency disorder
(“bubble boy” syndrome)
SCID gene,Xq13,XR
(MIM 300400)
Immune Deficiency
ADA deficiency (MIM 102700)
Severe combined immunodeficiency
(SCID) caused by mutation in
adenosine deaminase gene in T cells,
ADA gene,20q13.11,AD
Immune Deficiency
AIDS
Acquired immune deficiency syndrome
HIV (human immunodeficiency virus)
Metabolism of Carcinogen
AHH (MIM 108330)
Aryl hydrocarbon hydroxylase
AHH inducibility (MIM 108340)
CYP1A1 gene,15q22-q24
Chromosome Theory
Boveri T (1902)
Abnormal fertilization of
sea urchin eggs by two
sperm cells causes
unequal distribution of
chromosomes in resulting
daughter cells.
Chromosome Theory
Boveri T (1902)
The unequal distributions
of chromosomes could be
the causal factors in tumor
formation.
Chromosome Theory
Boveri T & Sutton W (1903)
Chromosome Theory
Boveri T & Sutton W (1903)
Tumor cells come from normal cells.
Tumor cells are defective cells with
chromosomal abnormality.
The chromosomal aberrations are the
causal factors in tumor formation.
Chromosomal Abnormality
Clone evolution
Stem line & Side line
Stem line & Modal number
Chromosomal Abnormality
Numerical abnormality
Chromosomal Abnormality
Structural aberration
Structural Aberration
Ph chromosome
Nowell & Hungerford,1960
Chronic Myeloid Leukemia (CML)
Rowley,1973
Recognition of t(9;22)
t(9;22)(22pter→22q11::9q34→9qter)
Structural Aberration
Ph chromosome
Structural Aberration
Ph chromosome
Structural Aberration
Burkitt lymphoma (BL)
t(8;14)(q24;q32)
Oncogene
A gene that causes normal cells to change
into cancerous tumor cells.
1910,Rous,Rous sarcoma virus (RSV)
1963,Dulbecco,virus can change normal cell into
tumor cell
The Nobel Prize in Physiology or Medicine 1975
Renato Dulbecco
"for their discoveries concerning the
interaction between tumour viruses and
the genetic material of the cell"
Oncogene
A gene that causes normal cells to change
into cancerous tumor cells.
1910,Rous,Rous sarcoma virus (RSV)
1963,Dulbecco,virus can change normal cell into
tumor cell
1970,malignant conversion caused by retrovirus
1970,Martin,v-src (viral oncogene,v-onc)
1971,Dresberg,v-src in RSV
Oncogene
LTR ψ GAG POL ENV V-src LTR
v-src
Oncogene
A gene that causes normal cells to change
into cancerous tumor cells.
1910,Rous,Rous sarcoma virus (RSV)
1963,Dulbecco,virus can change normal cell into
tumor cell
1970,malignant conversion caused by retrovirus
1970,Martin,v-src (viral oncogene,v-onc)
1971,Dresberg,v-src in RSV
1976,Bishop,C-SRC (cellular oncogene,C-ONC)
Oncogene
LTR ψ GAG POL ENV V-src LTR
v-src
C-SRC
Oncogene
A gene that causes normal cells to change
into cancerous tumor cells.
Proto-oncogene,A gene that normally
directs cell growth.
Categories of Oncogene
Growth factor
Some cells normally produce mitogens
ISI,Platelet-derived growth factor (PDGF)
Genetic changes may enhance this
production or make it continuous
Categories of Oncogene
Growth factor receptors
Receptor Genes may be mutated so that
They are over-expressed
Be changed to a continuously active state
Categories of Oncogene
Protein kinase
Membranous effects
Tyr kinase
Cytoplasmic effects
Ser/Thr Kinase
Categories of Oncogene
Signal-transduction protein
Ras family
GTP-binding proteins (G proteins)
Bound to GDP,Ras proteins are neutral
in regard to mitotis
Bound to GTP,Ras proteins send signals
to the nucleus
Categories of Oncogene
Transcription factor
Nuclear transcription Factor
activating
SRC,ABL,ROS,YES
HRAS
KRAS
NRAS
MAPKK
MAPK
CYTOPLASM
NUCLEUS
SIS,INT2,HST
ERBB1,FMS,ERBA,KIT
Cytoskeleton
SRC,ABL,ROS,YES
Cascade reaction
MYC JUN,FOS
DNA
replication
Transcription
regulation
EXTRACELLULAR
Schematic of
Oncogene
Mechanisms of Oncogene Activation
Mutation
Point mutations/deletions/insertions
Most characterized in transcription-
regulating sequence (TRS),frequent
in Ras
Mechanisms of Oncogene Activation
Mutation
Virus (promoter) insertion
LTR of retrovirus
Mechanisms of Oncogene Activation
Mutation
Virus (promoter) insertion
Results from several rounds of unscheduled
DNA synthesis occurring during a single cell
cycle
Gene amplification
Homogeneously staining region (HSR)
Double minutes (DMs)
Double Minutes
Mechanisms of Oncogene Activation
Mutation
Virus (promoter) insertion
Gene amplification
Chromosomal rearrangement
Translocations; inversions
Gene Activation
Transcriptional activation
Burkitt lymphoma
75 ％,t(8;14)(q24;q32)
16 ％,t(8;22)(q24;q11)
9 ％,t(2;8)(q12;q24)
14q32,IGH
8q24.1,C-MYC
22q11,IGL
2q12,IGK
Gene Fusion
Codes for mosaic protein
Ph chromosome (CML)
t(9;22)(q34;q11)
9q34.1,C-ABL
22q11,breakpoint cluster region,BCR1
BCR1-ABL,8.5 kb mRNA,210 kD pr.
Tumor Suppressor Gene
Anti-oncogene
Recessive oncogene
A class of genes that are involved
in the negative regulation of normal
growth.
PDGFR EGFR
Cyclin D
CDK4,6
Cyclin E
CDK2
E2F
G
S
G2
M
G0
p16,p15
p53
p21
p27
Schematic of
Cell Cycle
pRB
PDGFR EGFR
Cyclin D
CDK4,6
Cyclin E
CDK2
E2F
G
S
G2
M
G0
p16,p15
p53
p21
p27
Schematic of
Cell Cycle
pRB
Normal cellular genes that inhibits
tumor invasion and progression.
Tumor Metastasis Suppressor Gene
nm23H1
Mechanisms of Oncogenesis
Monoclonal origin theory
Two mutation theory
Multistep oncogenesis theory
Multistep Oncogenesis Theory
Normal
epithelium
Hyper-
proliferative
epithelium
DNA
hypomethylation
Activation
of K-RAS
APC
LOH
Early
adenoma
Intermediate
adenoma
Late
adenoma
DCC
LOH
Carcinoma
p53
LOH
Metastasis
nm23H1
LOH
Medical Genetics
Cancer is a class of diseases caused
by loss of cell cycle control.
Cancer
In animals,cell numbers are under
exquisite control
Loss of this control leads to proliferation
of unwanted cells
Cancer arises when the above situation
reaches a certain degree
Cancer & Tumor
Cancer cells are malignant tumor (vs.
benign tumor) cells
All cancer cells are eventually capable
of metastasis
Cancer Family
Unusually large numbers of blood
relatives develop certain kinds of
cancers.
Lynch Cancer Family Syndrome Ⅱ
“Family G”,Italian family
Warthin AS,Heredity with reference to
carcinoma,Arch,Intern,Med,1913,12,546-555
Hauser IJ,Weller C,VA further report on the
cancer family of Warthin,Am,J,Cancer,1936.
27,434-449
Lynch HT,Krush AJ,Cancer family 'G'
revisited,1895-1970,Cancer,1971,27,1505-1511
Lynch Cancer Family Syndrome Ⅱ
“Family G”,Italian family
MIM 114400
Lynch Cancer Family Syndrome Ⅱ
HNPCC,18q11-q12
Adenocarcinomas of the colon
“Family G”,Italian family
Carcinoma of endometrium
Gastric cancer,ovary cancer,breast cancer
Li-Fraumeni Syndrome
Studies by Li and Fraumeni led to
first evidence of inherited predisposition
to cancer,(MIM 151623)
Breast tumors
Sarcoma,leukemia,lung cancer,and
adrenal cortical carcinoma
Cancer Family
Earlier age of onset
Multiple close relatives affected
Multiple primary tumours/bilateral
disease
Multiple tumours in specific cancer
syndrome
Inherited Cancer
Retinoblastoma,RB (MIM 180200)
Retinoblastoma occurs sporadically in
most cases,but in some families it displays
autosomal dominant inheritance.
Retinoblastoma
A rare malignant tumor of the developing
retina that occurs in children,usually before
the age of four years.
An abnormal appearance of the pupil which
reflects light like a cat's eye.
Retinoblastoma
A rare malignant tumor of the developing
retina that occurs in children,usually before
the age of four years.
An abnormal appearance of the pupil which
reflects light like a cat's eye.
Some forms represent a deletion in the
region 13q14.1-q14.2
Two Mutation Theory
Knudson (1971)
Two Mutation Theory
Two mutations are required,one in each
copy of the RB gene
The first mutation is present in the
germline and thus in all cells of the body
For familial cases
The second somatic mutation is necessary
for initiating tumor formation
Inherited cancer
Initiation
Promotion
Clone Origin Theory
Sporadic cancer
Clone Origin Theory
Initiation
Loss of Heterozygosity
malignant
transformation
RB
Loss of Heterozygosity
RB rb
gene
conversion
Wilms’ Tumor
Nephroblastoma (MIM 194070)
Embryonic kidney tumor
Accounts for 3/4 occurring before age four,
90% before twenty.
Inherited cases of nephroblastoma display
autosomal dominant inheritance.
A noninvasive lesion with a predictable
likelihood of becoming malignant,Most
display autosomal dominant inheritance.
Precancerous Lesion
Familial Polyposis Coli
FPC (MIM 175100)
Average onset is 25 years old
Adenomatous polyps,mostly colorectal
Minimum 100 polyps,average 1,000 polyps
APC gene (Adenomatous Polyposis Coli)
localized to chromosome 5q21
100% will develop cancer within 10 to 15
years
Neurofibromatosis
NF1 (MIM 162200)
Generally includes multiple café-au-lait
spots,cutaneous neurofibromas
NF1 gene (nerve growth factor) localized
to chromosome 17q11.2
The presence of one or more genetic
factors,not necessarily abnormal,that is
associated with an increased risk for the
cancer.
Genetic Susceptibility
Fragile site
Chromosome unstable
Immune deficiency
Metabolism of carcinogen
Fragile Site
A genetic defect makes the chromosome
fragile and susceptible to breakage at a
specific point.
Inheritable Fragile Site
Such fragile sites show high expression
and inherited in a Mendelian fashion.
Susceptible to folic acid supplements
Susceptible to 5-BrdU supplements
Susceptible to telomycin supplements
Non-inheritable Fragile Site
Such fragile sites show low expression.
4q31
Fragile Site & Cancer
The locations of fragile sites have been
shown to correlate with sites of translocation
breakpoints and deletions commonly found
in cancer.
—— Yunis JJ,1975
Chromosome Unstable
Chromosome unstable caused by DNA
repair-deficiency susceptible to breakage
or rearrangement.
Bloom Syndrome,BS
A rare AR disorder (MIM 210900)
Possible phenotypes
Narrow face
Prominent nose or ears
Immunodeficiency
More cancer prone
,Butterfly rash” with skin sensitivity to sun
Hypo/hyperpigmented skin lesions
Bloom Syndrome,BS
A rare AR disorder (MIM 210900)
Bloom Syndrome,BS
A rare AR disorder (MIM 210900)
Cellular level
Genetic instability
Sister chromosome exchange (SCE)
Excessive numbers of somatic mutations
Chromosomal aberrations
Possible phenotypes
Bloom Syndrome,BS
A rare AR disorder (MIM 210900)
Bloom Syndrome,BS
A rare AR disorder (MIM 210900)
Bloom Syndrome,BS
A rare AR disorder (MIM 210900)
DNA helicase protein of Rec Q family
Cellular level
Possible phenotypes
Xeroderma Pigmentosum,XP
AR disorder (MIM 278700)
Inherited nucleotide excision repair
(NER) deficiency
Xtreme skin sensitivity to UV light
Abnormal skin pigmentation
High frequency of skin cancers
Xeroderma Pigmentosum,XP
AR disorder (MIM 278700)
Xeroderma Pigmentosum,XP
AR disorder (MIM 278700)
Immune Deficiency
Agammaglobulinemia,Swiss Type
SCID,Severe combined
immunodeficiency disorder
(“bubble boy” syndrome)
SCID gene,Xq13,XR
(MIM 300400)
Immune Deficiency
ADA deficiency (MIM 102700)
Severe combined immunodeficiency
(SCID) caused by mutation in
adenosine deaminase gene in T cells,
ADA gene,20q13.11,AD
Immune Deficiency
AIDS
Acquired immune deficiency syndrome
HIV (human immunodeficiency virus)
Metabolism of Carcinogen
AHH (MIM 108330)
Aryl hydrocarbon hydroxylase
AHH inducibility (MIM 108340)
CYP1A1 gene,15q22-q24
Chromosome Theory
Boveri T (1902)
Abnormal fertilization of
sea urchin eggs by two
sperm cells causes
unequal distribution of
chromosomes in resulting
daughter cells.
Chromosome Theory
Boveri T (1902)
The unequal distributions
of chromosomes could be
the causal factors in tumor
formation.
Chromosome Theory
Boveri T & Sutton W (1903)
Chromosome Theory
Boveri T & Sutton W (1903)
Tumor cells come from normal cells.
Tumor cells are defective cells with
chromosomal abnormality.
The chromosomal aberrations are the
causal factors in tumor formation.
Chromosomal Abnormality
Clone evolution
Stem line & Side line
Stem line & Modal number
Chromosomal Abnormality
Numerical abnormality
Chromosomal Abnormality
Structural aberration
Structural Aberration
Ph chromosome
Nowell & Hungerford,1960
Chronic Myeloid Leukemia (CML)
Rowley,1973
Recognition of t(9;22)
t(9;22)(22pter→22q11::9q34→9qter)
Structural Aberration
Ph chromosome
Structural Aberration
Ph chromosome
Structural Aberration
Burkitt lymphoma (BL)
t(8;14)(q24;q32)
Oncogene
A gene that causes normal cells to change
into cancerous tumor cells.
1910,Rous,Rous sarcoma virus (RSV)
1963,Dulbecco,virus can change normal cell into
tumor cell
The Nobel Prize in Physiology or Medicine 1975
Renato Dulbecco
"for their discoveries concerning the
interaction between tumour viruses and
the genetic material of the cell"
Oncogene
A gene that causes normal cells to change
into cancerous tumor cells.
1910,Rous,Rous sarcoma virus (RSV)
1963,Dulbecco,virus can change normal cell into
tumor cell
1970,malignant conversion caused by retrovirus
1970,Martin,v-src (viral oncogene,v-onc)
1971,Dresberg,v-src in RSV
Oncogene
LTR ψ GAG POL ENV V-src LTR
v-src
Oncogene
A gene that causes normal cells to change
into cancerous tumor cells.
1910,Rous,Rous sarcoma virus (RSV)
1963,Dulbecco,virus can change normal cell into
tumor cell
1970,malignant conversion caused by retrovirus
1970,Martin,v-src (viral oncogene,v-onc)
1971,Dresberg,v-src in RSV
1976,Bishop,C-SRC (cellular oncogene,C-ONC)
Oncogene
LTR ψ GAG POL ENV V-src LTR
v-src
C-SRC
Oncogene
A gene that causes normal cells to change
into cancerous tumor cells.
Proto-oncogene,A gene that normally
directs cell growth.
Categories of Oncogene
Growth factor
Some cells normally produce mitogens
ISI,Platelet-derived growth factor (PDGF)
Genetic changes may enhance this
production or make it continuous
Categories of Oncogene
Growth factor receptors
Receptor Genes may be mutated so that
They are over-expressed
Be changed to a continuously active state
Categories of Oncogene
Protein kinase
Membranous effects
Tyr kinase
Cytoplasmic effects
Ser/Thr Kinase
Categories of Oncogene
Signal-transduction protein
Ras family
GTP-binding proteins (G proteins)
Bound to GDP,Ras proteins are neutral
in regard to mitotis
Bound to GTP,Ras proteins send signals
to the nucleus
Categories of Oncogene
Transcription factor
Nuclear transcription Factor
activating
SRC,ABL,ROS,YES
HRAS
KRAS
NRAS
MAPKK
MAPK
CYTOPLASM
NUCLEUS
SIS,INT2,HST
ERBB1,FMS,ERBA,KIT
Cytoskeleton
SRC,ABL,ROS,YES
Cascade reaction
MYC JUN,FOS
DNA
replication
Transcription
regulation
EXTRACELLULAR
Schematic of
Oncogene
Mechanisms of Oncogene Activation
Mutation
Point mutations/deletions/insertions
Most characterized in transcription-
regulating sequence (TRS),frequent
in Ras
Mechanisms of Oncogene Activation
Mutation
Virus (promoter) insertion
LTR of retrovirus
Mechanisms of Oncogene Activation
Mutation
Virus (promoter) insertion
Results from several rounds of unscheduled
DNA synthesis occurring during a single cell
cycle
Gene amplification
Homogeneously staining region (HSR)
Double minutes (DMs)
Double Minutes
Mechanisms of Oncogene Activation
Mutation
Virus (promoter) insertion
Gene amplification
Chromosomal rearrangement
Translocations; inversions
Gene Activation
Transcriptional activation
Burkitt lymphoma
75 ％,t(8;14)(q24;q32)
16 ％,t(8;22)(q24;q11)
9 ％,t(2;8)(q12;q24)
14q32,IGH
8q24.1,C-MYC
22q11,IGL
2q12,IGK
Gene Fusion
Codes for mosaic protein
Ph chromosome (CML)
t(9;22)(q34;q11)
9q34.1,C-ABL
22q11,breakpoint cluster region,BCR1
BCR1-ABL,8.5 kb mRNA,210 kD pr.
Tumor Suppressor Gene
Anti-oncogene
Recessive oncogene
A class of genes that are involved
in the negative regulation of normal
growth.
PDGFR EGFR
Cyclin D
CDK4,6
Cyclin E
CDK2
E2F
G
S
G2
M
G0
p16,p15
p53
p21
p27
Schematic of
Cell Cycle
pRB
PDGFR EGFR
Cyclin D
CDK4,6
Cyclin E
CDK2
E2F
G
S
G2
M
G0
p16,p15
p53
p21
p27
Schematic of
Cell Cycle
pRB
Normal cellular genes that inhibits
tumor invasion and progression.
Tumor Metastasis Suppressor Gene
nm23H1
Mechanisms of Oncogenesis
Monoclonal origin theory
Two mutation theory
Multistep oncogenesis theory
Multistep Oncogenesis Theory
Normal
epithelium
Hyper-
proliferative
epithelium
DNA
hypomethylation
Activation
of K-RAS
APC
LOH
Early
adenoma
Intermediate
adenoma
Late
adenoma
DCC
LOH
Carcinoma
p53
LOH
Metastasis
nm23H1
LOH
