| Cancer is a general term, describing a group of | | | | -Microsatellite instability (MIN) |
| different diseases. Because these diseases are | | | | Mutation in both alleles necessary. |
| different, it is unlikely that a general cure for | | | | DNA alterations found in tumors (both malignant |
| cancer will evolve. Each type of cancer needs its | | | | and benign): |
| own treatment program. | | | | 1.Subtle alterations: |
| There are two common properties for all types | | | | Small deletions, small insertions and base-pair |
| of cancer: | | | | substitutions. |
| 1. Abnormal proliferation (so called neoplasia, that | | | | 2.Chromosome number change (aneuploidy): |
| results in a neoplasm structure) | | | | Gain and loss of chromosomes (Which may result |
| 2. Invasive ability. Property that separates benign | | | | in that both chromosomes are from the same |
| tumors from cancer. | | | | parent. A loss of one chromosome often leads to |
| Cancer cells invade other regions by travelling | | | | the duplication of the remaining chromosome). |
| through the circulatory system or lymphatic | | | | A typical phenomena is loss of heterozygosity |
| system. This process is called metastasis, in which | | | | (LOH), which can lead to the inactivation of genes |
| disease is spread from one organ to another | | | | (these genes may be suppressor genes, that |
| non-adjacent organ. | | | | protect the cell from cancer) |
| Cancers can be classified according to cell type. | | | | 3. Chromosome translocation: |
| 1.Leukemia and Lymphoma | | | | Can be either: |
| 2.Carcinoma | | | | 1.Balanced (even exchange of material) |
| 3.Sarcoma | | | | 2.Unbalanced (unequal exchange of material). |
| 4.Melanoma | | | | Results in extra or missing genes. |
| 5.Retinoblastoma, Neuroblastoma, Glioblastoma | | | | Translocation leads to Malignity: |
| (1: blood-borne cancers, 2-5: solid tumors) | | | | - Transcription factor genes are moved (to the |
| Cancer is a genetic disease and can also be seen | | | | vicinity of highly active promotor/enhancer |
| as a disturbance in the cell cycle regulation | | | | elements) and thus become over expressed. |
| system. You can inherit a predisposition for | | | | - Tyrosine kinase genes are fused with normal |
| cancer, but for the disease to break out additional | | | | genes and translation results in a chimeric protein |
| somatic mutations are required. These mutations | | | | with oncogenic properties = fusion protein (growth |
| arise from: | | | | factor receptor or intracellular signal transducers). |
| 1. Environmental mutagens (physical or chemical | | | | Chromosome translocation in Leukemia and |
| agents that change DNA) | | | | Lymphoma: |
| 2. Imperfections during DNA copying and repair | | | | Translocations are specific (not random). |
| (so called spontaneous mutations). | | | | - Transcription factor translocation: |
| There are two ways to categorize mutated | | | | A. Acute Lymphoblastic Leukemia and |
| genes based on function: | | | | Non-Hodgkin Lymphoma (e.g. MYC) |
| 1.Function in a cancer cell | | | | B. Acute Myeloid Leukemia (e.g. AML1-CBF² |
| - Genes that have been activated or over | | | | complex) |
| expressed = oncogenes (one mutated allele is | | | | C. Acute Mixed-Lineage Leukemia |
| enough) | | | | - Tyrosine kinase translocation |
| - Genes that have been inactivated: | | | | A. Chronic Myeloid Leukemia (ABL fusion gene) |
| 1.Tumor suppressor genes. | | | | B. Acute Lymphoblastic Leukemia (ABL fusion |
| Both alleles need to be mutated. E.g. RB1 and p53 | | | | gene) |
| 2. DNA-mismatch repair genes | | | | The Philadelphia chromosome is used as a marker |
| Both alleles need to be mutated. | | | | in prognosis and in follow- up of treatment. |
| 2.Function in normal cell: | | | | 4. Amplification: |
| - Genes that directly control proliferation | | | | Defined as over 6 copies of a DNA region (called |
| (controlling cell birth rate or death rate) = | | | | the amplicon). |
| Gatekeepers | | | | These regions most frequently code for: |
| - Genes that control the rate of mutation = | | | | 1.Transcriptional factors (MYC-family, e.g. MYCN |
| Caretakers | | | | amplification seen in neuroblastoma) |
| Mutation in some genes always leads to the same | | | | 2.Signal transduction molecules (Ras-family) |
| type of cancer, independent of what kind of | | | | 3.Growth factors (EGF, FGF), Growth factor |
| mutation or where it has arisen (e.g.WT1). | | | | receptors (EGFR, FGFR) |
| Mutations in other genes result in many different | | | | 4.Regulators of the cell cycle. |
| forms of cancer (e.g. p53). | | | | Over expression of these genes gives cancer a |
| Neoplasms have genetic instability. It is not clear if | | | | growth advantage. |
| the instability is the reason for tumor formation or | | | | The amplification can be outside the chromosome |
| just a consequence. This instability can be divided | | | | (double minute chromatin bodies) or within the |
| into two major groups: | | | | chromosome. |
| 1.Instability at the chromosomal level (CIN) | | | | Amplifications can be used in prognosis and |
| Mutation in one allele enough. Hypomethylation | | | | targeted gene therapy. |
| increases instability. | | | | 5. Exogenous sequences: |
| 2.Instability at the nucleotide level: Faulty DNA | | | | E.g. tumor viruses which activate either human |
| repair pathways | | | | genes or viral genes that lead to the accumulation |
| -Nucleotide Excision Repair Instability (NIN) | | | | of mutations. |