Javed's notes of Biochemistry

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Introduction to Cancer
Viruses and Cancer
Classifications of Proto-Oncogenes
(representative examples only)

Table of Hereditary Cancers
(non-inclusive list)

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

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 protein=neurofibromin 1 tumor suppressor	catalysis of RAS inactivation	17q11.2	neurofibromas, sarcomas, gliomas
Neurofibromatosis Type 2 OMIM data	NF2 protein = merlin or neurofibromin 2 tumor suppressor	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 protein = hamartin tumor suppressor		9q34	facial angiofibromas
Tuberous sclerosis 2 OMIM data	TSC2 protein = tuberin tumor suppressor	GTPase activation	16	benign 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 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 protein = cyclin-dependent kinase inhibitor 2A tumor suppressor	inhibits cell-cycle kinases CDK4 and CDK6	9p21	melanoma, pancreatic cancer, others
Gorlin Syndrome: Nevoid basal cell carcinoma syndrome (NBCCS) OMIM data	PTCH protein = patched tumor suppressor	transmembrane receptor for hedgehog signaling protein	9q22.3	basal cell skin cancer
Multiple Endocrine Neoplasia Type 1 OMIM data	MEN1 tumor suppressor	unknown	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-Wiedmann Syndrome OMIM data	p57, KIP2	cell cycle regulator	11p15.5	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 & 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	DNA repair	11q22.3	lymphoma, cerebellar ataxia, immunodeficiency
Bloom syndrome OMIM data	BLM	DNA helicase?	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 8 complementation groups OMIM data for FACA FACC	FANCA - FANCH	components of DNA repair machinery	FANCA=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