Post on 22-Dec-2015
transcript
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 Increased rate of
activation 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 3 1 2 3
Case 644 Exon 7
G A T C G A T C G A T C G A T C
AC/G
A
AG
A
ThrArg Gly Ser
C
GA/GG
G
C
MutantWild Type MutantWild Type
A C/G A A/G G C
Codon 280 Codon 244
Figure 8-1. IHC Analysis of p53, p21, and mdm2
Age and TP53 Mutations
Age P53+
No. (%)
P53-
No. (%)
Total
No. (%)
<50 6 (8.7) 11 (10.0) 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 (%)
TP53-
No (%)
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 (%)
TP53-
No (%)
Total
No. (%)
White 60 (87.0) 100 (90.9) 160 (89.4)
Non-White 9 (13.0) 10 (9.1) 19 (10.6)
Education and TP53 Mutations
Education
(years)
TP53+
No. (%)
TP53-
No. (%)
Total
No. (%)
<12 2 (2.9) 4 (3.6) 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 Reported, n=200 Current study
Transitions
GC AT 41.0% 37.5%
(at CpG) 14.0% 12.5%
ATGC 10.0% 15.0%
Transversions
GCTA 13.0% 12.5%
GCCG 19.0% 10.0%
ATTA 3.0% 0.0%
ATCG 2.0% 2.5%
Deletion/Insert. 12.0% 10.0%
Smoking and TP53 Mutations in Bladder Cancer
Smoking TP53+ TP53- OR 95%CI
No 8 24 1.00
Yes 58 83 6.27 1.29-30.2
Adjusted for age, gender, and education
Cigarettes/day and TP53 Mutations in Bladder Cancer
Cig/day TP53+ TP53- OR 95%CI
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
Years of Smoking and TP53 Mutations in Bladder Cancer
Years of smoking
TP53+ TP53- OR 95%CI
No 8 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