Published on March 15, 2009
GENETICS OF CANCERSalwa Hassan Teama M.D.Molecular Biology Department/ Medical Research CenterAin Shams University/ Cairo/ Egypt
Contents Cancer The Genetic Nature of Cancer Causes: Genetic Mutation Genes That play a Role in Cancer Oncogenes Tumor Suppressor Gene Viruses and Cancer
Cancer Cancer is one of the most common and severe problems of clinical medicine. The normal balance between cell proliferation and cell death in normal tissues is lost. Cancer has both genetic and environmental causes.
Cancer Uncontrolled growth, Cell proliferation results in a mass that invades neighboring tissues, May metastasize to more distant sites, Some cancers, however, such as blood cancers, do not form tumors.
Characteristics of Cancer Cells Dedifferentiated; Less adherent; Loss of cell cycle control; Tissue invasion and metastasis; Evading apoptosis; Insensitivity to antigrowth factor; Increased mutation rate; Induce local blood vessel formation angiogenesis.
Cell Cycle/ Cancer
Environmental & Genetic FactorsEnvironmental factors are of primary importance e.g.Industrial cancer which result from prolongedexposure to carcinogenic chemicals as cancer of theskin in tar workers , cancer of the bladder in anilinedye workers,…..Genetic factors play an important role e.g. breast andbowel cancer,, but not exclusive role in the etiology.
The Genetic Nature of Cancer Abnormalities in the genetic material of the transformed cell. Genes which regulate cell growth and differentiation must be altered.
Source: National Cancer Institute
Genetic changes can occur at many levels: Gain or loss of entire chromosomes. Mutation affecting a single DNA nucleotide. DNA methylation and MicroRNAs increasingly recognized.
Causes: Genetic MutationGermline mutations Familial cancer 5% to 10% of cancer cases.Sporadic cancer or somatic mutation Acquired mutation caused by tobacco, over-exposure to UV radiation, and other toxins and chemicals,… Not present in every cell of the body and Not passed from parent to child
Most cancers are caused by aseries of mutations that developduring a persons lifetime calledacquired mutations.Cancer develops when severalgenes in a cell become mutatedin a way that overrides thechecks and balances of the cell.However, many cancers cannotbe tied to a specific gene, andsome genes may interact inunpredictable ways with othergenes or factors in theenvironment to cause cancer.
Genes That play a Role in CancerOncogeneTumor suppressor gene
Distribution of Oncogenes, Cancer Genes and Tumor Suppressor Genes in the Human Genomen the Human GenomeThe two types have oppositeeffects in carcinogenesis:Oncogenes facilitate malignanttransformation,Tumor suppressor genes, blocktumor development byregulating genes. involved incell growth.
OncogeneOncogenes are known by three letter abbreviation whichreflect their origin or the type of tumor with which they areassociated.Oncogene are genes that affect normal cell growth anddevelopment. If an oncogene is altered or overexpressed,the cell in which the change occur can undergo uncontrolledgrowth, become malignant.Most oncogenes are mutated forms of normal genes, calledproto-oncogenes.
Proto-oncogeneProto-oncogene is a normal gene that can become anoncogene due to mutations or increased expression.Proto-oncogenes code for proteins that help to regulatecell growth and differentiation.Proto-oncogenes are often involved in signaltransduction and execution of mitogenic signals,usually through its protein product.
Types of OncogeneOncogene can be classified according to their cellular location andfunction of their encoded oncoproteins in the signal transductionpathway: Growth factors Growth factor receptors GTP binding proteins Post receptor tyrosine kinase Cytoplasmic oncogenes Nuclear oncogenes Apoptotic oncogenes
Some oncogene and their function Source: http://www.copewithcytokines.de/cope.cgi?key=Oncogene
Activation of Proto-oncogene to OncogenePoint mutations in a somatic cell of the tumor, lead to synthesis of anabnormal gene product.Gene amplification events leading to extra chromosomal copies ofa proto-oncogene.Chromosomal translocationRelocation of a proto-oncogene to a new chromosomal site that leadsto higher expression. Source: http://www.nature.com/scitable/topicpage/proto-oncogenes-to-oncogenes-to-cancer-883
Oncogene/ Dominant MutationMost oncogenes are dominant mutations; a single Copy of thisgene is sufficient for expression of the growth trait.Most oncogenes are gain of function mutation because the cellswith the mutant form of the protein have gained a new functionnot present in cells with the normal gene.
Tumor Suppressor GeneTumor suppressor gene or anti oncogene; normal genesimplicated in the control of cell cycle, repair DNA mistakes, andtell cells when to die (apoptosis or programmed cell death).Tumor suppressor gene or anti oncogene are genes whendeleted or mutated, the loss of their function result in malignanttransformation.
Tumor Suppressor Genes Genes that control cell division Genes that repair DNA Cell suicide genes
GENES THAT CONTROL CELL DIVISIONSome tumor suppressor genes help control cell cycle regulation,cell growth and reproduction.The (RB1 retinoblastoma gene Abnormalities of the RB1 genecan lead to a type of eye cancer (retinoblastoma) in infants, aswell as to other cancers.
CELL "SUICIDE" GENESP53 gene: About 50% of human cancers can be associated witha p53 mutation including cancers of the bladder, breast, cervix,colon, lung, liver, prostate, and skin.
DNA REPAIR GENESThe genes responsible for HNPCC (hereditary non-polyposiscolon cancer). HNPCC accounts for up to 5% of all coloncancers and some endometrial cancers.
Familial CancerFeatures suggestive of an inherited cancer susceptibility syndrome in afamily: Several close (first or second degree) relatives with a common cancer. Several close relatives with related cancers. e.g. breast and ovary or bowel ad endometrial Two family members with the same rare cancer An unusually early age of onset Bilateral tumors in paired organs Synchronous or successive tumors Tumors in two different organ systems in one individual
Inherited familial cancer-predisposing syndromes Syndrome Mode of Gene Chromosomal Cancer Inheritance site Breast AD BRCA1 17q Breast HNPCC Lynch 1 AD MSH2 18q Colorectal Lynch 2 AD LCF2 2p Colorectal, endometrial, ovarian,.. Familial AD APC 5q Colorectal, duodenal, adenomatous thyroid polyposis Li-Fraumeni AD P53 17p Sarcoma, breast, leukemia,.. MEN type a2 AD MENa2 10q Thyroid (medullary) phenohromocytomaAD autosomal dominant
ConclusionCancer is a genetic disorder in which the normal controlof cell growth is lost.Cancer is multi-factorial diseases. The basic mechanism inall cancer is mutation, either in the germ line or much morefrequently, in somatic cells.Much remains to be learned about the genetic processes ofcarcinogenesis and about he environmental factors that alterDNA and thus lead to malignancy.
References and Further Reading Robert F. Mueller, Ian D. Young. Emerys Elements of Medical Genetics: Publisher: Churchill Livingstone. 1995. ISBN. 044307125X. Available in paper copy from the publisher. Strachan T, Read AP. Human Molecular Genetics. 2nd edition. New York: Wiley-Liss; 1999 American cancer society: http://www.cancer.org/American. Cancer. http://www.nlm.nih.gov/medlineplus/cancer.html Chial, H. (2008) Proto-oncogenes to oncogenes to cancer. Nature Education 1. Comprehensive Cancer Information: National institute of cancer.www.cancer.gov
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