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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 are 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.

Growth Factors

The c-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 c-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 [fims] 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 c-Kit gene encodes the mast cell growth factor receptor.

Membrane Associated Non-Receptor Tyrosine Kinases

The v-src gene was the first identified oncogene. The c-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 c-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 c-Myc gene has been found to be involved in numerous hematopoietic neoplasias. Disruption of c-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

SyndromeCloned GeneFunctionChromosomal LocationTumor Types
Li-Fraumeni Syndrome

OMIM data

P53
tumor suppressor
cell cycle regulation, apoptosis17p13brain tumors, sarcomas, leukemia, breast cancer
Familial Retinoblastoma

OMIM data

RB1
tumor suppressor
cell cycle regulation13q14retinoblastoma, osteogenic sarcoma
Wilms Tumor

OMIM data

WT1
tumor suppressor
transcriptional regulation11p13pediatric kidney cancer
Neurofibromatosis Type 1

OMIM data

NF1
protein=neurofibromin 1
tumor suppressor
catalysis of RAS inactivation17q11.2neurofibromas, sarcomas, gliomas
Neurofibromatosis Type 2

OMIM data

NF2
protein = merlin or
neurofibromin 2
tumor suppressor
linkage of cell membrane to cytoskeleton22q12.2Schwann cell tumors, astrocytomas, meningiomas, ependynomas
Familial Adenomatous Polyposis

OMIM data

APC
tumor suppressor
signaling through adhesion molecules to nucleus5q21colon cancer
Tuberous sclerosis 1

OMIM data

TSC1
protein = hamartin
tumor suppressor
 9q34facial angiofibromas
Tuberous sclerosis 2

OMIM data

TSC2
protein = tuberin
tumor suppressor
GTPase activation16benign growths (hamartomas) in many tissues, astrocytomas, rhabdomyosarcomas
Deleted in Pancreatic Carcinoma 4

OMIM data

DPC4
also known as Smad4
tumor suppressor
regulation of TGF-b/BMP signal transduction18q21.1pancreatic carcinoma, colon cancer
Deleted in Colorectal Carcinoma

OMIM data

DCC
tumor suppressor
transmembrane receptor involved in axonal guidance via netrins18q21.3colorectal cancer
Familial Breast Cancer

OMIM data

BRCA1
tumor suppressor
repair of double strand breaks by association with Rad51 protein17q21breast and ovarian cancer
Familial Breast Cancer

OMIM data

BRCA2
tumor suppressor
similar to BRCA1?13q12.3breast and ovarian cancer
Peutz-Jeghers Syndrome

OMIM data

STK11
tumor suppressor
protein = serine-threonine kinase 11
potential regulation of vascular endothelial growth factor (VEGF) pathway19p13.3hyperpigmentation, multiple hamartomatous polyps, colorectal, breast and ovarian cancers
Hereditary Nonpolyposis Colorectal Cancer type 1
HNPCC1

OMIM data

MSH2
tumor suppressor
DNA mismatch repair2p22-p21colorectal cancer
Hereditary Nonpolyposis Colorectal Cancer type 2
HNPCC2

OMIM data

MLH1
tumor suppressor
DNA mismatch repair3p21.3colorectal cancer
von Hippel-Lindau Syndrome

OMIM data

VHL
tumor suppressor
regulation of transcription elongation3p26-p25renal cancers, hemangioblastomas, pheochromocytoma
Familial Melanoma

OMIM data

CDKN2A
protein = cyclin-dependent kinase inhibitor 2A
tumor suppressor
inhibits cell-cycle kinases CDK4 and CDK69p21melanoma, pancreatic cancer, others
Gorlin Syndrome:
Nevoid basal cell carcinoma syndrome (NBCCS)

OMIM data

PTCH
protein = patched
tumor suppressor
transmembrane receptor for hedgehog signaling protein9q22.3basal cell skin cancer
Multiple Endocrine Neoplasia Type 1

OMIM data

MEN1
tumor suppressor
unknown11q13parathyroid and pituitary adenomas, islet cell tumors, carcinoid
Multiple Endocrine Neoplasia Type 2

OMIM data

RET, MEN2transmembrane receptor tyrosine kinase for glial-derived neurotrophic factor (GDNF)10q11.2medullary thyroid cancer, type 2A pheochromocytoma, mucosal hartoma
Beckwith-Wiedmann Syndrome

OMIM data

p57, KIP2cell cycle regulator11p15.5Wilms tumor, adrenocortical cancer, hepatoblastoma
Hereditary papillary renal cancer (HPRC)

OMIM data

METtransmembrane receptor for hepatocyte growth factor (HGF)7q31renal papillary cancer
Cowden syndrome

OMIM data

PTEN
tumor suppressor
phosphoinositide 3-phosphatase
protein tyrosine phosphatase
10q23.3breast cancer, thyroid cancer, head & 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 degradation1q24-q25prostate cancer
Ataxia telangiectasia (AT)

OMIM data

ATMDNA repair11q22.3lymphoma, cerebellar ataxia, immunodeficiency
Bloom syndrome

OMIM data

BLMDNA helicase?15q26.1solid tumors, immunodeficiency
Xeroderma pigmentosum (XP)
7 complentation groups

OMIM data for
XPA XPC XPD

XPA - XPGDNA repair helicases, nucleotide excision repairXPA = 9q22.3
XPC = 3p25
XPD=19q13.2-q13.3
XPE=11p12-p11
XPF=16p13.3-p13.13
skin cancer
Fanconi's anemia
8 complementation groups

OMIM data for FACA
FACC

FANCA - FANCHcomponents of DNA repair machineryFANCA=16q24.3
FANCC = 9q22.3
FANCD=3p25.3
FANCE=11p15
acute myeloid leukemia (AML), pancytopenia, chromosomal instability

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This article has been modified by Dr. M. Javed Abbas.
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23:09 19/12/2002