Genetics of Cancer

GENETICS OF CANCERSalwa Hassan TeamaAin Shams University

Contents Cancer The Genetic Nature of Cancer Causes: Genetic Mutation Genes That play a Role in Cancer Oncogenes Tumor Suppressor Gene DNA Repair Gene Viruses and Cancer

CancerCancer is one of the most common and severeproblems of clinical medicine.Cancer is uncontrolled growth and Cell proliferationresults in a mass that invades neighboring tissues andmay metastasize to more distant sites. Some cancers,however, such as blood cancers, do not form tumors.The normal balance between cell proliferation andcell death in normal tissues is lost.

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.

Environmental & Genetic Factors There are cancers in which environmental factors are of primary importance and hereditary seems to play no part in causation. 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,….. In certain cancers, such as breast and bowel cancer, genetic factors play an important , but not exclusive role in the etiology.

The Genetic Nature of Cancer Abnormalities in the genetic material of thetransformed cell. Genetic changes can occur at many levels, from gainor loss of entire chromosomes to a mutation affecting asingle DNA nucleotide. New aspects of the genetics ofcancer pathogenesis, such as DNA methylation andmicroRNAs are increasingly recognized.Genes which regulate cell growth and differentiationmust be altered.

Source: National Cancer Institute

Causes: Genetic Mutation Germline mutations Acquired mutations (Sporadic cancer or somatic mutation).

Germline Mutations Germline mutations are responsible for 5% to 10% of cancer cases. This is also called familial cancer (occurring in families). Inherited and thus present in all cells from birth.

Acquired Mutations Acquired mutations (Sporadic cancer or somatic mutation). Most cancers are caused by a series of mutations that develop during a persons lifetime. Acquired mutations are not in every cell of the body and are not passed from parent to child. Acquired mutations are caused by; Tobacco, Over- exposure to UV radiation, and Toxins and chemicals,…………….

Many Mutation Lead to Cancer  Source: Wikipedia

Genes That play a Role in Cancer p53 Source: Wikipedia Source: National Cancer Institute

Genes and Cancer Cancer Gene Disease Function Oncogene Myc Burkitts lymphoma Protein-protein interaction Ras Pancreatic, colorectal, bladder,kidney, GTP binding/signal lung, leukemia, Melanoma transduction pathwayTumor suppressor P53 Li-Fraumeni Apoptotic/ Colorectal neoplasms transcription factor BRCA1 Breast, ovarian, prostatic,clonic Cell cycle control neoplasms DNA Repair BLM Bloom syndrome DNA Repair XP Xeroderma pigmentosa DNA Repair

Oncogenes Oncogenes are known by three letter abbreviation which reflect their origin or the type of tumor with which they are associated. Oncogenes are genes able to produce cancer when overexpressed, amplified, or mutated. Cancer-promoting oncogenes: Most oncogenes are mutated forms of normal genes, called proto- oncogenes.

Source: http://cancergenome.nih.gov

Types of Oncogene Oncogene can be classified according to their cellular location and function of their encoded oncoproteins in the signal transduction pathway: Growth factors Growth factor receptors GTP binding proteins Post receptor tyrosine kinase Cytoplasmic oncogenes Nuclear oncogenes Apoptotic oncogenes

The functional classification of oncogenes Post Growth Growth GTP binding receptor Cytoplasmic Nuclear factor factors proteins tyrosine oncogenes oncogenes receptors kinase fos sis erb-B N-ras Src mos junInt (FGF- erb-B2 Ha-ras Abl A-raf related) mybhst(FGF- fms Ki-ras yes B-raf related) myc

Proto-oncogene Proto-oncogenes code for proteins that help toregulate cell growth and differentiation. Proto-oncogenes are often involved in signaltransduction and execution of mitogenic signals,usually through its protein product. Proto-oncogene is a normal gene that can become anoncogene due to mutations or increased expression.

Activation of Protooncogene to OncogenePoint mutationsDeletions, or insertions that lead to a hyperactive gene product.Deletions, or insertions in the promoter region of a proto-oncogene that lead to increased transcription.Gene amplification events leading to extra chromosomal . copies of a proto-oncogene. Chromosomal translocation Relocation of a proto-oncogene to a new chromosomal site that leads to higher expressionFusion between a proto-oncogene and a second gene, whichproduces a fusion protein with oncogenic activity. Source: http://www.nature.com/scitable/topicpage/proto-oncogenes-to-oncogenes-to-cancer-883

Illustration by Argosy Publishing.

Change in Cellular Oncogene in Human Cancer Oncogene Type of cancer Gene modification Ab1 Chronic myeloid Translocation leukemia Myc Burkitts lymphoma Translocation Small cell lung cancer Amplification L-Myc Small cell lung cancer Amplification N-Myc Neuroblastoma Amplification Ras Bladder cancer Mutation K-ras Colon cancer Mutation N-ras Acute myeloid leukemia Mutation

Oncogene/Dominant Mutation Most 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 Division Some tumor suppressor genes help control cell growth and reproduction. Example: 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.

Tumor Suppressor Genes Genes that repair DNA DNA repair genes Examples The genes responsible for HNPCC (hereditary nonpolyposis colon cancer). When these genes do not repair the errors in DNA, HNPCC can result. HNPCC accounts for up to 5% of all colon cancers and some endometrial cancers.

Tumor Suppressor Genes Cell "suicide" genes Destroying the cell (cell suicide). ; if there is too much damage to a cell’s DNA to be fixed by the DNA repair genes. Example; 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.

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 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

Viruses and CancerViruses promoting human cancer. These include both DNA viruses and retroviruses, a type of RNA virus. Tumor Viruses  Human papillomavirus (genital carcinomas), Hepatitis B; Hepatitis C (liver carcinoma), Epstein-Barr virus (Burkitts lymphoma and nasopharyngeal carcinoma), Human T-cell leukemia virus (T-cell lymphoma); and Herpes virus called KSHV (Kaposis sarcoma and some B cell lymphomas).

DNA Tumor Viruses Viruses can contribute to cancer by inserting their DNA into a chromosome in a host cell. Insertion of the virus DNA directly into a proto- oncogene may mutate the gene into an oncogene, resulting in a tumor cell.

RNA Tumor VirusesThe ability of retroviruses to promote cancer isassociated with the presence of oncogenes in theseviruses.An example of this is the normal cellular c-SIS proto-oncogene, which makes a cell growth factor. The viralform of this gene is an oncogene called v-SIS. Cellsinfected with the virus that has v-SIS overproduce thegrowth factor, leading to high levels of cell growth andpossible tumor cells.

Conclusion Cancer is a genetic disorder in which the normal control of cell growth is lost. The basic mechanism in all cancer is mutation, either in the germ line or much more frequently, in somatic cells. Cancer is multi-factorial diseases, 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 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

Image Citation Jpbrody. Cancer requires multiple mutations from NIH.31-8-2004. http://en.wikipedia.org/wiki/File:Cancer_requires_multiple_mutations_from_ NIHen.png ThomasSplettstoesser.P53.05.10.2006http://en.wikipedia.org/wiki/File:P53. png Normal cell changed to cancer cell when oncogene activated. http://cancergenome.nih.gov/newsevents/multimedialibrary/images/CancerB iology

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Genetics of Cancer

by Salwa Hassan Teama on Mar 15, 2009

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