Introduction to Cancer Genetics
Cancer is a general term, describing a group of different diseases. Because these diseases are different, it is unlikely that a general cure for cancer will evolve. Each type of cancer needs its own treatment program.
There are two common properties for all types of cancer:
1. Abnormal proliferation (so called neoplasia, that results in a neoplasm structure)
2. Invasive ability. Property that separates benign tumors from cancer.
Cancer cells invade other regions by traveling through the circulatory system or lymphatic system. This process is called metastasis, in which disease is spread from one organ to another non-adjacent organ.
Cancers can be classified according to cell type.
1.Leukemia and Lymphoma
5.Retinoblastoma, Neuroblastoma, Glioblastoma
(1: blood-borne cancers, 2-5: solid tumors)
Cancer is a genetic disease and can also be seen as a disturbance in the cell cycle regulation system. You can inherit a predisposition for cancer, but for the disease to break out additional somatic mutations are required. These mutations arise from:
1. Environmental mutagens (physical or chemical agents that change DNA)
2. Imperfections during DNA copying and repair (so called spontaneous mutations).
There are two ways to categorize mutated genes based on function:
1.Function in a cancer cell
– Genes that have been activated or over expressed = oncogenes (one mutated allele is enough)
– Genes that have been inactivated:
1.Tumor suppressor genes.
Both alleles need to be mutated. Eg RB1 and p53
2. DNA-mismatch repair genes
Both alleles need to be mutated.
2.Function in normal cell:
– Genes that directly control proliferation (controlling cell birth rate or death rate) = Gatekeepers
– Genes that control the rate of mutation = Caretakers
Mutation in some genes always leads to the same type of cancer, independent of what kind of mutation or where it has arisen (egWT1). Mutations in other genes result in many different forms of cancer (eg p53).
Neoplasms have genetic instability. It is not clear if the instability is the reason for tumor formation or just a consequence. This instability can be divided into two major groups:
1.Instability at the chromosomal level (CIN)
Mutation in one allele enough. Hypomethylation increases instability.
2.Instability at the nucleotide level: Faulty DNA repair pathways
-Nucleotide Excision Repair Instability (NIN)
-Microsatellite instability (MIN)
Mutation in both alleles necessary.
DNA alterations found in tumors (both malignant and benign):
Small deletions, small insertions and base-pair substitutions.
2.Chromosome number change (aneuploidy):
Gain and loss of chromosomes (Which may result in that both chromosomes are from the same parent. A loss of one chromosome often leads to the duplication of the remaining chromosome).
A typical phenomena is loss of heterozygosity (LOH), which can lead to the inactivation of genes (these genes may be suppressor genes, that protect the cell from cancer)
- Chromosome translocation:
Can be either:
1.Balanced (even exchange of material)
2.Unbalanced (unequal exchange of material). Results in extra or missing genes.
Translocation leads to Malignity:
– Transcription factor genes are moved (to the vicinity of highly active promotor / enhancer elements) and thus become over expressed.
– Tyrosine kinase genes are fused with normal genes and translation results in a chimeric protein with oncogenic properties = fusion protein (growth factor receptor or intracellular signal transducers).
Chromosome translocation in Leukemia and Lymphoma:
Translocations are specific (not random).
Transcription factor translocation:
A. Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma (eg MYC)
B. Acute Myeloid Leukemia (eg AML1-CBF² complex)
C. Acute Mixed-Lineage Leukemia
Tyrosine kinase translocation
A. Chronic Myeloid Leukemia (ABL fusion gene)
B. Acute Lymphoblastic Leukemia (ABL fusion gene)
The Philadelphia chromosome is used as a marker in prognosis and in follow- up of treatment.
Defined as over 6 copies of a DNA region (called the amplicon).
These regions most frequently code for:
1.Transcriptional factors (MYC-family, eg MYCN amplification seen in neuroblastoma)
2.Signal transduction molecules (Ras-family)
3.Growth factors (EGF, FGF), Growth factor receptors (EGFR, FGFR)
4.Regulators of the cell cycle.
Over expression of these genes gives cancer a growth advantage.
The amplification can be outside the chromosome (double minute chromatin bodies) or within the chromosome.
Amplifications can be used in prognosis and targeted gene therapy.
Eg tumor viruses which activate either human genes or viral genes that lead to the accumulation of mutations.