Transcript Lecture 3: Tumor Marker

Tumor Markers
Epidemiology 243: Molecular
Epidemiology
SEVERAL MUTATED OR ALTERED GENES IN CANCER
Cancer cells contain several (6-8) mutated genes.
Several categories of genes
1. Oncogenes
-An oncogene is a gene that when mutated or altered contributes to
converting a normal cell into a cancer cell.
- The term oncogene is derived from the Greek word "oncos," meaning
tumor.
- The cellular oncogenes in their normal form are called proto-oncogenes
and do not cause cancer. They code for a variety of normal enzymes,
growth factors and receptors that relay signals to a cell's nucleus,
stimulating growth.
- The activation to oncogene may result in overproduction of growth
factors; flooding of the cell with replication signals; and/or unrestrained
cell growth.
- The activation of a proto-oncogene to oncogene can occur in several
ways:
-mistakes during DNA replication, ie. point mutation, chromosomal
rearrangement, gene amplification
-from damage to DNA cause by exposure to chemicals or radiation
-from viral infection and insertion into the DNA resulting in more
active production of oncogene
- from other causes not yet known
To other points about oncogenes:
- Oncogenes act as dominants; if the cell has one normal gene at a locus
and one mutated gene, the abnormal product takes control.
- No single oncogene can, by itself, cause cancer. It can increase the rate
of mitosis of the cell. Dividing cells are at increased risk of acquiring
mutations.
- Oncogenes may be transmitted from generation to generation when a
proto-oncogene mutates in the germ line. This results in a dominantly
inherited tumor predisposition. For example, multiple endocrine
neoplasia type 11 (MEN 2) is the outcome of a germline transmission of
an activated RET oncogene.
NORMAL CELL DIVISION
Regulated by tumor suppressor genes
Proto-oncogenes
Cell growth and proliferation
stimulate
CANCER DUE TO ACTIVATION OF ONCOGENES
Proto-oncogenes
oncogenes
activation
Increased rate of
misregulation
cell growth and
proliferation
Malignant transformation
CANCER DUE TO MUTATED TUMOR SUPPRESSOR GENES
Loss or mutation of tumor suppressor gene
Proto-oncogenes
Cell growth
Malignant
and proliferation
transformation
2. Tumor Suppressor genes
- Suppress tumor formation.
- Their protein products act to inhibit cell growth and the division cycle.
- Mutations in tumor suppressor genes cause the cell to ignore one or
more of the components of the network of inhibitory signals, resulting in
a higher rate of uncontrolled cell proliferation.
-One tumor suppressor locus is usually involved in controlling the
development of several different kinds of tumors.
- Tumor suppressor genes are often associated with the loss of one
chromosome or a part of a chromosome, resulting in a reduction to
homozygosity (or loss of heterozygosity-LOH) through elimination of
one allele of a tumor suppressor gene as well as surrounding markers; the
remaining tumor suppressor allele is inactivated by either an inherited or
a somatic mutation.
- Tumor suppressors behave as recessives. Both normal alleles must
mutate before cancerous growth begins.
Examples of Tumor Suppressor genes
1.
p53
-53 kD protein that prevents a cell from completing the cell cycle if its
DNA is not properly replicated in S phase. It responds to cell damage.
- It binds to transcription factor (E2F) and prevents E21F from binding to
the promoters of the proto-oncogenes c-myc and c-fos, needed for
mitosis
- The p53 protein may triggers programmed cell death (apoptosis) if the
damage to the cell is too great to be repaired.
- Defects in the p53 gene are found in most cancers.
Smoking and TP53 mutations in
Bladder Cancer
Case 607 Exon 8
1
2
Case 644 Exon 7
1
3
Wild Type
Mutant
G A T C G A T C
A
C/G
Arg
Thr
A
C/G
A
Codon 280
3
Wild Type Mutant
G A T C G A T C
A
G
A
A
2
C
G
A/G
C
G
G
Gly
Ser
A/G
G
C
Codon 244
Figure 8-1. IHC Analysis of p53, p21, and mdm2
Age and TP53 Mutations
Age
<50
P53+
No. (%)
6 (8.7)
P53No. (%)
11 (10.0)
Total
No. (%)
17 (9.5)
50-59
16 (23.2)
18 (16.4)
34 (19.0)
60+
47 (68.1)
81 (73.6)
128 (71.5)
Gender and TP53 Mutations
Gender
TP53+
No (%)
TP53No (%)
Total
No (%)
Male
47 (71.2)
89 (81.7)
136 (77.7)
Female
19 (28.8)
20 (18.4)
39 (22.3)
Race and TP53 Mutations
Race
TP53+
No (%)
TP53No (%)
Total
No. (%)
White
60 (87.0)
100 (90.9)
160 (89.4)
10 (9.1)
19 (10.6)
Non-White 9 (13.0)
Education and TP53 Mutations
Education
(years)
<12
TP53+
No. (%)
2 (2.9)
TP53No. (%)
4 (3.6)
Total
No. (%)
6 (3.4)
12-16
58 (84.1)
76 (69.1)
134 (74.9)
>16
9 (13.0)
30 (27.3)
39 (21.8)
TP53 Mutations in Bladder Cancer
BP changes
Transitions
GC AT
(at CpG)
ATGC
Transversions
GCTA
GCCG
ATTA
ATCG
Deletion/Insert.
Reported, n=200 Current study
41.0%
14.0%
10.0%
37.5%
12.5%
15.0%
13.0%
19.0%
3.0%
2.0%
12.0%
12.5%
10.0%
0.0%
2.5%
10.0%
Smoking and TP53 Mutations in
Bladder Cancer
Smoking TP53+
TP53-
OR
No
8
24
1.00
Yes
58
83
6.27
Adjusted for age, gender, and education
95%CI
1.29-30.2
Cigarettes/day and TP53
Mutations in Bladder Cancer
Cig/day
TP53+
TP53-
OR
No
8
24
1.00
1-20
8
21
2.07
0.22-19.9
21-40
36
47
5.50
1.08-28.2
>40
17
18
10.4
1.90-56.8
Trend
P=0.003
Adjusted for age, gender, and education
95%CI
Years of Smoking and TP53
Mutations in Bladder Cancer
Years of TP53+
smoking
No
8
TP53-
OR
24
1.00
1-20
5
10
5.64
0.82-38.7
21-40
42
58
6.45
1.24-33.4
>40
14
18
6.20
1.17-32.8
Trend
P=0.041
Adjusted for age, gender and education
95%CI