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GENETICS OF CANCER

Salwa Hassan Teama M.D. Molecular Biology Department/ Medical Research Center Ain Shams University/ Cairo/ Egypt

ContentsCancerThe Genetic Nature of CancerCauses: Genetic MutationGenes That play a Role in CancerOncogenes Tumor Suppressor GeneViruses and CancerCancerCancer 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.

CancerUncontrolled 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.

Cancer

Characteristic's of Cancer CellsDedifferentiated;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/ CancerEnvironmental & Genetic FactorsEnvironmental factors are of primary importance e.g. Industrial cancer which result from prolonged exposure to carcinogenic chemicals as cancer of the skin in tar workers , cancer of the bladder in aniline dye workers,..

Genetic factors play an important role e.g. breast and bowel cancer,, but not exclusive role in the etiology.

The Genetic Nature of CancerAbnormalities in the genetic material of the transformed cell.

Genes which regulate cell growth and differentiation must be altered.

Source: National Cancer InstituteGenetic changes can occur at many levels:Gain or loss of entire chromosomes. Mutation affecting a single DNA nucleotide.

DNA methylation andMicroRNAs increasingly recognized.

Causes: Genetic MutationGermline mutationsFamilial cancer5% 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 a series of mutations that develop during a person's lifetime called acquired mutations.Cancer develops when several genes in a cell become mutated in a way that overrides the checks and balances of the cell. However, many cancers cannot be tied to a specific gene, and some genes may interact in unpredictable ways with other genes or factors in the environment 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 opposite effects in carcinogenesis:Oncogenes facilitate malignant transformation,

Tumor suppressor genes, block tumor development by regulating genes. involved in cell growth.

OncogeneOncogenes are known by three letter abbreviation which reflect their origin or the type of tumor with which they are associated.

Oncogene are genes that affect normal cell growth and development. If an oncogene is altered or overexpressed, the cell in which the change occur can undergo uncontrolled growth, become malignant.

Most oncogenes are mutated forms of normal genes, called proto-oncogenes.

Proto-oncogeneProto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression.

Proto-oncogenes code for proteins that help to regulate cell growth and differentiation.

Proto-oncogenes are often involved in signal transduction and execution of mitogenic signals, usually through its protein product.

Types of OncogeneOncogene can be classified according to their cellular location and function of their encoded oncoproteins in the signal transduction pathway:

Growth factorsGrowth factor receptorsGTP binding proteinsPost receptor tyrosine kinaseCytoplasmic oncogenesNuclear oncogenesApoptotic oncogenes

Some oncogene and their functionSource: http://www.copewithcytokines.de/cope.cgi?key=Oncogene

Activation of Proto-oncogene to Oncogene Point mutations in a somatic cell of the tumor, lead to synthesis of an abnormal gene product.

Geneamplification events leading to extra chromosomal copies of aproto-oncogene.

Chromosomaltranslocation Relocation of aproto-oncogeneto a new chromosomal site that leads to higher expression. Source: http://www.nature.com/scitable/topicpage/proto-oncogenes-to-oncogenes-to-cancer-883

Source: http://cancergenome.nih.gov

Source: http://www.cancer-biomarkers.com/2012/06/proto-oncogenes.htm

Oncogene/ Dominant MutationMost oncogenes are dominant mutations; a single Copy of this gene is sufficient for expression of the growth trait.

Most oncogenes are gain of function mutation because the cells with the mutant form of the protein have gained a new function not present in cells with the normal gene.

Tumor Suppressor Gene

Tumor suppressor gene or anti oncogene; normal genes implicated in the control of cell cycle, repair DNA mistakes, and tell cells when to die (apoptosis or programmed cell death).

Tumor suppressor gene or anti oncogene are genes when deleted or mutated, the loss of their function result in malignant transformation.

Tumor Suppressor Genes

Genes that control cell divisionGenes that repair DNACell suicide genes

Genes That Control Cell Division

Some tumor suppressor genes help control cell cycle regulation, cell growth and reproduction. The (RB1 (retinoblastoma gene Abnormalities of the RB1 gene can lead to a type of eye cancer (retinoblastoma) in infants, as well as to other cancers.

Cell "suicide" genes

P53 gene: About 50% of human cancers can be associated with a p53 mutation including cancers of the bladder, breast, cervix, colon, lung, liver, prostate, and skin.

DNA repair genes

The genes responsible for HNPCC (hereditary non-polyposis colon cancer). HNPCC accounts for up to 5% of all colon cancers and some endometrial cancers.

Familial CancerFeatures suggestive of an inherited cancer susceptibility syndrome in a family: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 endometrialTwo family members with the same rare cancerAn unusually early age of onsetBilateral tumors in paired organsSynchronous or successive tumorsTumors in two different organ systems in one individual

Inherited familial cancer-predisposing syndromesSyndromeMode of InheritanceGeneChromosomal siteCancerBreastADBRCA117qBreastHNPCCLynch 1Lynch 2ADADMSH2LCF218q2pColorectalColorectal, endometrial, ovarian,..Familial adenomatous polyposisADAPC5qColorectal, duodenal,thyroidLi-FraumeniADP5317pSarcoma, breast,leukemia,.. MEN type a2ADMENa210qThyroid (medullary)phenohromocytomaAD autosomal dominant

ConclusionCancer is a genetic disorder in which the normal control of cell growth is lost.

Cancer is multi-factorial diseases. The basic mechanism in all cancer is mutation, either in the germ line or much more frequently, in somatic cells.

Much remains to be learned about the genetic processes of carcinogenesis and about he environmental factors that alter DNA and thus lead to malignancy.

References and Further ReadingRobert F. Mueller, Ian D. Young. Emery's 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; 1999American cancer society: http://www.cancer.org/American. Cancer. http://www.nlm.nih.gov/medlineplus/cancer.htmlChial,H.(2008)Proto-oncogenes to oncogenes to cancer.Nature Education1. Comprehensive Cancer Information: National institute of cancer.www.cancer.gov

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