7. Genetics of biological processes
7.4. Oncogenetics
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origin, with the exception of rare monogenic tumors such as retinoblastoma, or Li-Fraumeni syndrome. There are a number of underlying genetic susceptibility factors (mutations) and environmental effects.
The cancer can be described as a group of diseases characterized by unlimited proliferation and spread of mutant cells in the body.
The following steps are the hallmarks of carcinogenesis:
a. growth signal autonomy b. unlimited replicative potential c. evasion of growth inhibitory signals d. evasion of apoptosis
e. angiogenesis
f. invasion and metastasis
Mutations can be spontaneous as well as induced by some environmental factor as it is discussed in the chapter of Mutations and polymorphisms. Most mutagens are also carcinogens. The mutations of three large gene families play key roles in carcinogenesis. These are the oncogenes, tumor suppressor genes, and the so-called mutator genes. The mutator genes involved in DNA repair (see there), so through their malfunctions mutations are fixed in the genome leading to tumorigenesis.
7.4.1. Oncogenes
Oncogenes are actually genes (proto-oncogenes) of changed normal function, which are essentially involved in cell cycle regulation. Such genes include genes encoding growth factors (such as EGF) and their receptors (such as EGFR), the components involved in their signal transduction (such as Ras, Raf,) and transcription factors. Mutations of these lead to the growth factor independent unlimited cell proliferation – e.g. this can be the result of the constitutive activation of mutant receptor tyrosine kinases. Oncogenes are activated not only by point mutations in the above players, but by gene amplification or chromosome translocations (e.g. the t(9;22) translocation leading to Ph1 chromosome described in chronic myeloid leukemia which results in a fusion protein with increased tyrosine kinase activity) as well.
In addition to classic genetic alterations, epigenetic changes - epimutations - also can cause oncogene activation. It is known that increased genome hypomethylation during aging often affects oncogenes. This not only explains the higher activity of oncogenes, but the known phenomenon that certain cancers’ incidence increases with age. A specific example for the relationship between oncogenes and epigenetics is given by the imprinted IGF2 (insulin-like growth factor 2). Normal colonic epithelial cells express only the maternal allele, but in colon tumors the imprinting is lost (LOI = Loss Of Imprinting), the paternal allele is expressed, and the tumor develops.
7.4.2. Tumor suppressor genes
The evasion of growth inhibitory signals is due to mutations of the tumor suppressor genes. The normal tumor suppressors together with protooncogenes regulate cell cycle and control the integrity of the genome. If damage is detected in the genome the cell cycle is stopped and the cell starts error correction. On the bases of these two
sub-functions there are gate keepers and care takers mentioned. The former includes the classic tumor suppressors e.g. RB and TP53 genes, the latter the DNA repair genes - also known as mutator genes - (e.g. MLH1 and MSH2 mismatch repair genes).
While a single mutant allele of protooncogenes is sufficient for oncogenesis, so there must be dominant mutation, in the case of tumor suppressors both alleles should be mutated for the loss of the growth inhibiting function. Here, then, the mutant is recessive. In the care taker or mutator genes the haploinsufficiency phenomenon may play a role in oncogenesis, as in the case of mutation of one allele, the remaining normal allele has only reduced ability to function, and in many cases even this is sufficient to tumor induction due to the large number of uncorrected mutations.
Knudson set up the so-called two-hit hypothesis after investigating the tumor suppressors (RB). Thus, the development of certain cancers requires two successive mutational events affecting tumor suppressor genes. It is usually already inherently present (familial retinoblastoma), while the other is formed only in one or certain organs and as the previously heterozygous state is lost the homozygous mutant tumor suppressor gene leads to tumor formation. In sporadic cases, both mutations take place in the same person. The phenomenon is called loss of heterozygosity = LOH, and after being identified by the modern molecular biological experimental methods, it may be suitable for the detection of pre-cancerous condition.
Similarly to oncogenes in tumor suppressor genes epigenetics and epimutations may play a role as well. While CpG dinucleotides in the promoters of normal tumor suppressors are not methylated, thereby ensuring gene expression, in tumors they are often hypermethylated so the transcription of the gene is inhibited, and the protection against excessive cell proliferation is lost. Another epigenetic relationship is the formation of tumor suppressor protein and HDAC (histone deacetylase) complex. The normal suppressor proteins interact with HDAC, thereby triggering the chromatin remodelling, the heterochromatinization which limits the functioning of genes in the affected area, thereby inhibiting cell proliferation. The mutant suppressors are unable to do so, therefore the euchromatic structure remains and proliferation continues.
7.4.3. Anti-apoptotic genes
The TP53 tumor suppressor gene as a guardian of the genome plays a role not only in cell cycle arrest and DNA repair stimulation just after the DNA damage, but also in the induction of apoptosis when for large scale irreparable damages are present. That is because of the mutation not only the cell cycle may proceed invariably, but also severely damaged mutant cells will survive, so TP53 mutations bilaterally contribute to tumorigenesis. This can explain why Li-Fraumeni syndrome associated mutations of this gene cause a wide variety of tumors affecting many different organs simultaneously.
Malfunctions of the intrinsic apoptotic pathway, due to the involvement of p53 and /or mitochondrial Bcl-2 may cause not only the lack of apoptosis, but the resistance of tumor cells to chemotherapy.
7.4.4. Telomerase
It is known that eukaryotic DNA is shortened in somatic cells from division to division because of the characteristics of replication. This occurs in the subtelomeric and telomeric repetitive sequences of chromosomes, and following approx. 50-70 divisions it
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leads to cell senescence, arrest of cell division and aging. In germ line cells the telomerase enzyme, which comprises a reverse transcriptase, and a telomeric DNA complementary RNA can restore the length of the telomere. It's crucial in the transmission of the same sized genome from generation to generation. However, telomerase activity is also linked to cancer cells. They can restore the telomeres either by up-regulating telomerase enzyme or by recombination based alternative telomere lengthening.
If a cell - due to different mutations - avoids cell death caused by the extreme short telomeres its genome becomes unstable, leading to the oncogenic transformation of the cell through the aforementioned mutations (amplifications, translocations). This can be further strengthened by mutated genes induced telomerase (e.g. c-MYC via binding to the promoter of telomerase can activate it).