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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) ATGC Transversions GCTA GCCG ATTA ATCG 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