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Introduction
to Cancer Viruses and Cancer Classifications of Proto-Oncogenes (representative examples only) Table of Hereditary Cancers (non-inclusive list) |
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Introduction
Most, if not all, cancer cells contain genetic damage that appears to be the responsible event leading to tumorigenesis. The genetic damage present in a parental tumorigenic cell is maintained (i.e. not correctable) such that it is a heritable trait of all cells of subsequent generations. Genetic damage found in cancer cells is of two types:
1. Dominant and the genes have been termed proto-oncogenes. The distinction between the terms proto-oncogene and oncogene relates to the activity of the protein product of the gene. A proto-oncogene is a gene whose protein product has the capacity to induce cellular transformation given it sustains some genetic insult. An oncogene is a gene that has sustained some genetic damage and, therefore, produces a protein capable of cellular transformation.
The process of activation of proto-oncogenes to oncogenes can include retroviral transduction or retroviral integration (see below), point mutations, insertion mutations, gene amplification, chromosomal translocation and/or protein-protein interactions.
Proto-oncogenes can be classified into many different groups based upon their normal function within cells or based upon sequence homology to other known proteins. As predicted, proto-oncogenes have been identified at all levels of the various signal transduction cascades that control cell growth, proliferation and differentiation. The list of proto-oncogenes identified to date is too lengthy to include here, therefore, only those genes that have been highly characterized are described. Proto-oncogenes that were originally identified as resident in transforming retroviruses were initially designated as c- indicative of the cellular origin as opposed to v- to signify original identification in retroviruses.
2. Recessive and the genes variously termed tumor suppressors, growth suppressors, recessive oncogenes or anti-oncogenes.
Given the complexity of inducing and regulating
cellular growth, proliferation and differentiation, it was suspected for many
years that genetic damage to genes encoding growth factors, growth factor
receptors and/or the proteins of the various signal transduction cascades would
lead to cellular transformation. This suspicion has proven true with the
identification of numerous genes, whose products function in cellular
signaling, that are involved in some way in the genesis of the tumorigenic
state. The majority of these proto-oncogenes were identified by either of two
means: as the transforming genes (oncogenes) of transforming retroviruses or
through transfection of DNA from tumor cell lines into non-transformed cell lines
and screening for resultant tumorigenesis.
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Viruses and Cancer
Tumor cells also can arise by non-genetic means through the actions of specific tumor viruses. Tumor viruses are of two distinct types. There are viruses with DNA genomes (e.g. papilloma and adenoviruses) and those with RNA genomes (termed retroviruses).
RNA tumor viruses are common in chickens, mice and cats but rare in humans. The only currently known human retroviruses are the human T-cell leukemia viruses (HTLVs) and the related retrovirus, human immunodeficiency virus (HIV).
Retroviruses can induce the transformed state within the cells they infect by two mechanisms. Both of these mechanisms are related to the life cycle of these viruses. When a retrovirus infects a cell its RNA genome is converted into DNA by the viral encoded RNA-dependent DNA polymerase (reverse transcriptase). The DNA then integrates into the genome of the host cell where it can remain being copied as the host genome is duplicated during the process of cellular division. Contained within the sequences at the ends of the retroviral genome are powerful transcriptional promoter sequences termed long terminal repeats (LTRs). The LTRs promote the transcription of the viral DNA leading to the production of new virus particles.
At some frequency the integration process leads to rearrangement of the viral genome and the consequent incorporation of a portion of the host genome into the viral genome. This process is termed transduction. Occasionally this transduction process leads to the virus acquiring a gene from the host that is normally involved in cellular growth control. Because of the alteration of the host gene during the transduction process as well as the gene being transcribed at a higher rate due to its association with the retroviral LTRs the transduced gene confers a growth advantage to the infected cell. The end result of this process is unrestricted cellular proliferation leading to tumorigenesis. The transduced genes are termed oncogenes. The normal cellular gene in its unmodified, non-transduced form is termed a proto-oncogene since it has the capacity to transform cells if altered in some way or expressed in an uncontrolled manner. Numerous oncogenes have been discovered in the genomes of transforming retroviruses.
The second mechanism by which retroviruses can transform cells relates to the powerful transcription promoting effect of the LTRs. When a retrovirus genome integrates into a host genome it does so randomly. At some frequency this integration process leads to the placement of the LTRs close to a gene that encodes a growth regulating protein. If the protein is expressed at an abnormally elevated level it can result in cellular transformation. This is termed retroviral integration induced transformation. It has recently been shown that HIV induces certain forms of cancers in infected individuals by this integration induced transformation process.
Cellular transformation by DNA tumor viruses, in most
cases, has been shown to be the result of protein-protein interaction. Proteins
encoded by the DNA tumor viruses, termed tumor antigens or T antigens, can interact with cellular proteins.
This interaction effectively sequesters the cellular proteins away from their
normal functional locations within the cell. The predominant types of proteins
that are sequestered by viral T antigens have been shown to be of the tumor
suppressor type. It is the loss of their normal suppressor functions that
results in cellular transformation.
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Classifications of Proto-Oncogenes
Although there are numerous examples of each classification of proto-oncogene, the lists here are by no means exhaustive. New genes with tumor causing capabilitites are being isolated continuously. Additional details on genes and their functions for the various categories listed below can be found in the Signal Transduction page.
Growth Factors
The SIS gene (the v-sis gene is the oncogene in simian sarcoma virus) encodes the PDGF B chain. The v-sis gene was the first oncogene to be identified as having homology to a known cellular gene. The int-2 gene (named for the fact that it is a common site of integration of mouse mammary tumor virus) encodes an FGF-related growth factor. The KGF (also called HST) gene also encodes an FGF-related growth factor and was identified in gastric carcinoma and Kaposi's sarcoma cells.
Receptor Tyrosine Kinases
The FMS (“fims”) gene encodes the colony stimulating factor-1 (CSF-1) receptor and was first identified as a retroviral oncogene. The FLG (“flag”) gene (named because it has homology to the FMS gene, hence fms-like gene) encodes a form of the FGF receptor. The NEU (“new”) gene was identified as an EGF receptor-related gene in an ethylnitrosourea-induced neuroblastoma. The conversion of proto-oncogenic to oncogenic Neu requires only a single amino acid change in the transmembrane domain. The TRK (“track”) genes encodes the NGF receptor-like proteins. The first TRK gene was found in a pancreatic cancer. Subsequently, two additional TRK-related genes were identified. These three are now identified as TRKA, TRKB and TRKC. The MET gene encodes the hepatocyte growth factor(HGF)/scatter factor (SF) receptor. The KIT gene encodes the mast cell growth factor receptor.
Membrane Associated Non-Receptor Tyrosine Kinases
The SRC gene was the first identified oncogene. The SRC gene is the archetypal protein tyrosine kinase. The LCK gene was isolated from a T cell tumor line (LYSTRA cell kinase) and has been shown to be associated with the CD4 and CD8 antigens of T cells.
G-Protein Coupled Receptors
The MAS gene was identified in a mammary carcinoma and has been shown to be the angiotensin receptor.
Membrane Associated G-Proteins
There are three different homologs of the RAS gene, each of which was identified in a different type of tumor cell. The RAS gene is one of the most frequently disrupted genes in colorectal carcinomas.
Serine/Threonine Kinases
The RAF gene is involved in the signaling pathway of most RTKs. It is likely responsible for threonine phosphorylation of MAP kinase following receptor activation.
Nuclear DNA-Binding/Transcription Factors
The MYC gene was originally identified in the avian myelocytomatosis virus. A disrupted human MYC gene has
been found to be involved in numerous hematopoietic neoplasias. Disruption of
MYC has been shown to be the result of retroviral integration and
transduction as well as chromosomal rearrangements. The FOS gene was identified
in the feline osteosarcoma
virus. The protein interacts with a second proto-oncogenic protein, JUN to form
a transcriptional regulatory complex. The p53 gene was originally identified as
a major nuclear antigen in transformed cells. The p53 gene is the single most
identified mutant protein in human tumors. Mutant forms of the p53 protein interfere
with cell growth suppressor effects of wild-type p53 indicating that the p53
gene product is actually a tumor
suppressor.
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Hereditary Cancer Syndromes
Syndrome |
Cloned Gene |
Function |
Chromosomal Location |
Tumor Types |
|
Li-Fraumeni
Syndrome OMIM data |
P53 = tumor suppressor | cell cycle regulation, apoptosis | 17p13 | brain tumors, sarcomas, leukemia, breast cancer |
|
Familial
Retinoblastoma OMIM data |
RB1 = tumor suppressor | cell cycle regulation | 13q14 | retinoblastoma, osteogenic sarcoma |
|
Wilms Tumor OMIM data |
WT1 = tumor suppressor | transcriptional regulation | 11p13 | pediatric kidney cancer |
|
Neurofibromatosis
Type 1 OMIM data |
NF1 = tumor suppressor protein = neurofibromin 1 |
catalysis of RAS inactivation | 17q11.2 | neurofibromas, sarcomas, gliomas |
|
Neurofibromatosis Type 2 OMIM data |
NF2 = tumor suppressor
protein = merlin, also called neurofibromin 2 |
linkage of cell membrane to cytoskeleton | 22q12.2 | Schwann cell tumors, astrocytomas, meningiomas, ependynomas |
|
Familial
Adenomatous Polyposis OMIM data |
APC = tumor suppressor | signaling through adhesion molecules to nucleus | 5q21 | colon cancer |
|
Tuberous sclerosis 1 OMIM data |
TSC1= tumor suppressor
protein = hamartin |
forms complex with TSC2 protein, inhibits signaling to downstream effectors of mTOR | 9q34 | seizures, mental retardation, facial angiofibromas |
|
Tuberous sclerosis 2 OMIM data |
TSC2 = tumor suppressor
protein = tuberin |
see TSC1 above | 16p13.3 | benign growths (hamartomas) in many tissues, astrocytomas, rhabdomyosarcomas |
|
Deleted in Pancreatic Carcinoma 4 OMIM data |
DPC4 = tumor suppressor
also known as SMAD4 |
regulation of TGF-β/BMP signal transduction | 18q21.1 | pancreatic carcinoma, colon cancer |
|
Deleted in
Colorectal Carcinoma OMIM data |
DCC = tumor suppressor | transmembrane receptor involved in axonal guidance via netrins | 18q21.3 | colorectal cancer |
|
Familial Breast Cancer OMIM data |
BRCA1 = tumor suppressor | repair of double strand breaks by association with Rad51 protein | 17q21 | breast and ovarian cancer |
|
Familial Breast Cancer OMIM data |
BRCA2 = tumor suppressor | similar to BRCA1 | 13q12.3 | breast and ovarian cancer |
|
Peutz-Jeghers Syndrome OMIM data |
STK11 = tumor suppressor protein = serine-threonine kinase 11 |
potential regulation of vascular endothelial growth factor (VEGF) pathway | 19p13.3 | hyperpigmentation, multiple hamartomatous polyps, colorectal, breast and ovarian cancers |
|
Hereditary Nonpolyposis Colorectal Cancer type 1: HNPCC1 OMIM data |
MSH2 = tumor suppressor | DNA mismatch repair | 2p22-p21 | colorectal cancer |
|
Hereditary Nonpolyposis Colorectal Cancer type 2: HNPCC2 OMIM data |
MLH1 = tumor suppressor | DNA mismatch repair | 3p21.3 | colorectal cancer |
|
von Hippel-Lindau Syndrome OMIM data |
VHL = tumor suppressor | regulation of transcription elongation | 3p26-p25 | renal cancers, hemangioblastomas, pheochromocytoma |
|
Familial Melanoma OMIM data |
CDKN2A = tumor suppressor
protein = cyclin-dependent kinase inhibitor 2A |
inhibits cell-cycle kinases CDK4 and CDK6 | 9p21 | melanoma, pancreatic cancer, others |
|
Gorlin Syndrome: Nevoid basal cell carcinoma syndrome (NBCCS) OMIM data |
PTCH = tumor suppressor
protein = patched |
transmembrane receptor for hedgehog signaling protein | 9q22.3 | basal cell skin cancer |
|
Multiple Endocrine Neoplasia Type 1 OMIM data |
MEN1 = tumor suppressor | intrastrand DNA crosslink repair | 11q13 | parathyroid and pituitary adenomas, islet cell tumors, carcinoid |
|
Multiple Endocrine Neoplasia Type 2 OMIM data |
RET, MEN2 | transmembrane receptor tyrosine kinase for glial-derived neurotrophic factor (GDNF) | 10q11.2 | medullary thyroid cancer, type 2A pheochromocytoma, mucosal hartoma |
|
Beckwith-Wiedemann Syndrome OMIM data |
P57(KIP2), CDKN1c | cyclin-dependent kinase inhibitor, cell cycle regulator | 11p15.5 | genomic imprinting disorder resulting in Wilms tumor, adrenocortical cancer, hepatoblastoma |
|
Hereditary papillary renal cancer (HPRC) OMIM data |
MET | transmembrane receptor for hepatocyte growth factor (HGF) | 7q31 | renal papillary cancer |
|
Cowden syndrome OMIM data |
PTEN = tumor suppressor |
phosphoinositide 3-phosphatase, protein tyrosine phosphatase |
10q23.3 | breast cancer, thyroid cancer, head and neck squamous carcinomas |
|
Hereditary prostate cancer, numerous loci:
HPC1(PRCA1), HPCX, MXI1, KAI1, PCAP OMIM data |
HPC1 and PRCA1 are same designation, ribonuclease L (RNaseL) maps to this locus | RNaseL involved in mRNA degradation | 1q24-q25 | prostate cancer |
|
Ataxia telangiectasia (AT) OMIM data |
ATM: 4 complementation groups: ATA, ATC, ATD, ATE, are associated with mutations in the ATM gene | gene product likely halts cell cycle after DNA damage | 11q22.3 | lymphoma, cerebellar ataxia, immunodeficiency |
|
Bloom syndrome OMIM data |
BLM | DNA helicase RecQ protein-like-3 | 15q26.1 | solid tumors, immunodeficiency |
|
Xeroderma pigmentosum (XP), 7 complentation groups OMIM data for XPA XPC XPD |
XPA - XPG | DNA repair helicases, nucleotide excision repair |
XPA = 9q22.3 XPC = 3p25 XPD=19q13.2-q13.3 XPE=11p12-p11 XPF=16p13.3-p13.13 |
skin cancer |
|
Fanconi's anemia, 11 complementation groups OMIM data for FANCA FANCC |
FANCA, B, C, D1, D2, E, F, G, I, J, L FANCD1 = BRCA2 | components of DNA repair machinery |
FANCA=16q24.3 FANCC = 9q22.3 FANCD2=3p25.3 FANCE=11p15 |
acute myeloid leukemia (AML), pancytopenia, chromosomal instability |
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Michael W. King, Ph.D / IU School of Medicine / miking at iupui.edu