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An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or reduction in its function. In combination with other genetic mutations, this could allow the cell to grow abnormally. The loss of function for these genes may be even more significant in the development of human cancers, compared to the activation of oncogenes.
Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common primary malignant intraocular cancer in children, especially those under 3 years old.
In genetics, loss of heterozygosity (LOH) is a type of genetic abnormality in diploid organisms in which one copy of an entire gene and its surrounding chromosomal region are lost. Since diploid cells have two copies of their genes, one from each parent, a single copy of the lost gene still remains when this happens, but any heterozygosity is no longer present.
Alfred George Knudson, Jr. was an American physician and geneticist specializing in cancer genetics. Among his many contributions to the field was the formulation of the Knudson hypothesis in 1971, which explains the effects of mutation on carcinogenesis.
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnormal cell division. Cell division is a physiological process that occurs in almost all tissues and under a variety of circumstances. Normally, the balance between proliferation and programmed cell death, in the form of apoptosis, is maintained to ensure the integrity of tissues and organs. According to the prevailing accepted theory of carcinogenesis, the somatic mutation theory, mutations in DNA and epimutations that lead to cancer disrupt these orderly processes by interfering with the programming regulating the processes, upsetting the normal balance between proliferation and cell death. This results in uncontrolled cell division and the evolution of those cells by natural selection in the body. Only certain mutations lead to cancer whereas the majority of mutations do not.
Multiple endocrine neoplasia type 1 (MEN-1) is one of a group of disorders, the multiple endocrine neoplasias, that affect the endocrine system through development of neoplastic lesions in pituitary, parathyroid gland and pancreas. Individuals suffering from this disorder are prone to developing multiple endocrine and nonendocrine tumors. It was first described by Paul Wermer in 1954.
A blastoma is a type of cancer, more common in children, that is caused by malignancies in precursor cells, often called blasts. Examples are nephroblastoma, medulloblastoma, and retinoblastoma. The suffix -blastoma is used to imply a tumor of primitive, incompletely differentiated cells, e.g., chondroblastoma is composed of cells resembling the precursor of chondrocytes.
Adenomatous polyposis coli (APC) also known as deleted in polyposis 2.5 (DP2.5) is a protein that in humans is encoded by the APC gene. The APC protein is a negative regulator that controls beta-catenin concentrations and interacts with E-cadherin, which are involved in cell adhesion. Mutations in the APC gene may result in colorectal cancer and desmoid tumors.
Menin is a protein that in humans is encoded by the MEN1 gene. Menin is a putative tumor suppressor associated with multiple endocrine neoplasia type 1 and has autosomal dominant inheritance. Variations in the MEN1 gene can cause pituitary adenomas, hyperparathyroidism, pancreatic neuroendocrine tumors, gastrinoma, and adrenocortical cancers.
Caretaker genes encode products that stabilize the genome. Fundamentally, mutations in caretaker genes lead to genomic instability. Tumor cells arise from two distinct classes of genomic instability: mutational instability arising from changes in the nucleotide sequence of DNA and chromosomal instability arising from improper rearrangement of chromosomes.
CDKN2A, also known as cyclin-dependent kinase inhibitor 2A, is a gene which in humans is located at chromosome 9, band p21.3. It is ubiquitously expressed in many tissues and cell types. The gene codes for two proteins, including the INK4 family member p16 and p14arf. Both act as tumor suppressors by regulating the cell cycle. p16 inhibits cyclin dependent kinases 4 and 6 and thereby activates the retinoblastoma (Rb) family of proteins, which block traversal from G1 to S-phase. p14ARF activates the p53 tumor suppressor. Somatic mutations of CDKN2A are common in the majority of human cancers, with estimates that CDKN2A is the second most commonly inactivated gene in cancer after p53. Germline mutations of CDKN2A are associated with familial melanoma, glioblastoma and pancreatic cancer. The CDKN2A gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
Somatic evolution is the accumulation of mutations and epimutations in somatic cells during a lifetime, and the effects of those mutations and epimutations on the fitness of those cells. This evolutionary process has first been shown by the studies of Bert Vogelstein in colon cancer. Somatic evolution is important in the process of aging as well as the development of some diseases, including cancer.
Thaddeus P. Dryja is an American ophthalmologist and geneticist known for his role in the 1986 discovery of the retinoblastoma (Rb) tumor suppressor gene. and the 1990 discovery of mutations in the rhodopsin gene as the cause of autosomal dominant retinitis pigmentosa . He was the David G. Cogan Professor of Ophthalmology at Harvard University and was the Global Head of Ophthalmology Research at Novartis. He was elected a member of the National Academy of Sciences in 1996.
The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. When the cell is ready to divide, pRb is phosphorylated, inactivating it, and the cell cycle is allowed to progress. It is also a recruiter of several chromatin remodeling enzymes such as methylases and acetylases.
Genome instability refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy.
A hereditary cancer syndrome is a genetic disorder in which inherited genetic mutations in one or more genes predispose the affected individuals to the development of cancer and may also cause early onset of these cancers. Hereditary cancer syndromes often show not only a high lifetime risk of developing cancer, but also the development of multiple independent primary tumors.
Suresh H. Moolgavkar is an Indian mathematician and epidemiologist who was at the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle. He is a Senior Fellow and Research Scientist at Exponent, a consulting firm. Among his many scientific contributions is the development of the two-stage clonal expansion (TSCE) model of carcinogenesis, also known as the Moolgavkar-Venzon-Knudson (MVK) model, a stochastic cell-level description of carcinogenesis based on Alfred G. Knudson’s two-hit hypothesis. In its original development the TSCE model represents tumor initiation as the first hit, followed by cell proliferation and malignant transformation as the second hit. It has been interpreted as describing the initiation-promotion-progression sequence observed in chemical carcinogenesis and has been applied widely for the analysis of both experimental and epidemiological data for purposes of quantitative risk assessment.
GTP-binding protein Di-Ras3 (DIRAS3) also known as aplysia ras homology member I (ARHI) is a protein that in humans is encoded by the DIRAS3 gene.
CpG island hypermethylation is a phenomenon that is important for the regulation of gene expression in cancer cells, as an epigenetic control aberration responsible for gene inactivation. Hypermethylation of CpG islands has been described in almost every type of tumor.
References
- ↑ Abeloff's Clinical Oncology. Niederhuber, John E.,, Armitage, James O., Doroshow, James H.,, Kastan, M. B. (Michael B.), Tepper, Joel E.,, Preceded by: Abeloff, Martin D. (6th ed.). Philadelphia, PA. 2019. p. 218. ISBN 978-0-323-56815-9. OCLC 1089396489.
{{cite book}}: CS1 maint: location missing publisher (link) CS1 maint: others (link) - ↑ Knudson A (1971). "Mutation and cancer: statistical study of retinoblastoma". Proc Natl Acad Sci USA . 68 (4): 820–823. Bibcode:1971PNAS...68..820K. doi: 10.1073/pnas.68.4.820 . PMC 389051 . PMID 5279523.
- ↑ Fang, Yanan; Tsao, Cheng-Chung; Goodman, Barbara K.; Furumai, Ryohei; Tirado, Carlos A.; Abraham, Robert T.; Wang, Xiao-Fan (4 August 2004). "ATR functions as a gene dosage-dependent tumor suppressor on a mismatch repair-deficient background". The EMBO Journal. 23 (15): 3164–3174. doi:10.1038/sj.emboj.7600315. ISSN 0261-4189. PMC 514932 . PMID 15282542.
- ↑ Stephens PJ, Greenman CD, Fu B, et al. (January 2011). "Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development". Cell. 144 (1): 27–40. doi:10.1016/j.cell.2010.11.055. PMC 3065307 . PMID 21215367.
- ↑ Kumar, Vinay; Abbas, Abul K.; Aster, Jon C. (5 September 2014). Robbins & Cotran Pathologic Basis of Disease. Elsevier Health Sciences. ISBN 9780323296359.