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

http://www.the-scientist.library.upenn.edu/yr1997/august/aug_art/affymetrix.jpg

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