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Md. Mohsin Uddin Howlader 12/22/2012
Assignment On Gene Mutation And Cancer
Submitted To: Dr. Kabirul Bashar Lecturer Department Of Zoology Jahangirnagar University, Dhaka
Md. Mohsin Uddin Howlader Roll no: 468 Session: 2010-11 Department Of Zoology Jahangirnagar University, Dhaka
5th January, 2013
The types of mutation include: • Missense mutation This type of mutation is a change in one DNA base pair that results in the substitution of one amino acid for another in the protein made by a gene. Types of gene mutation The DNA sequence of a gene can be altered a number of ways. Instead of substituting one amino acid for another. Whether they alter the function of essential proteins.Gene Mutation A gene mutation is a personal change in the DNA sequence that makes up a gene. Mutation range in size from a single DNA building block (DNA base) to a large segment of a chromosome. • Nonsense mutation A nonsense mutation is also a change in one DNA base pair. however the altered DNA sequence prematurely signals the cell to stop building a protein. .
• Insertion An incertion changes the number of DNA bases in a gene by adding a piece of DNA. • Deletion A deletion changes the number of DNA Bases By Removing a piece of DNA. As a result the protein made by the gene may not function properly. • Duplication A duplication consists of a piece of DNA that is abnormally copied one or more times .
Transitions: A purine(or a pyrimidine) replaced by another. This are two types: 1.• Point mutation The replacement base pair by another. 2.Transversion Replacement of a by a pyrimidine .
both physicians and patients associated this field with uncommon diseases. eg-Trinucleotide repeat is made 3 base pair sequences.• Frameshift mutations This occur when one or more base pair are inserted in or detected from DNA. Detecting mutations in human genes In the first decades of medical genetics. This is no longer so: our understanding of the genetics underlying susceptibility to common disorders. • Reapeat expansion Nucleotide repeats are short DNA sequence that repeated a number of times in a row. . such as diabetes mellitus. relevant only to specialists and those affected. changing the genes leading frame.
Moreover. the use of DNA microarrays or “chips. phrases and sentences of the “genetic instruction manual. Genetic information is encoded by the sequence of the bases along a single strand of DNA. as well as in determining prognosis and monitoring response to therapy. Genetic information is transmitted by the geometry of pairing of the bases in this double helix.” How does DNA encode information? The gene is the fundamental unit of genetic information. Only certain associations among the 4 different types of bases are permitted. either strand alone contains the information required to rebuild the other.” When 2 DNA strands combine to form a double helix. is bringing genetics into not only the medical mainstream. Each gene is a DNA sequence — tens to millions of nucleotide bases in length and bounded by recognized control regions — which produces one or several related proteins. As a consequence. . the nucleotide bases of one strand associate one-to-one with those on the other. but also the public mainstream. the bases are therefore often regarded as the alphabet forming the words. such that there are 2 sets of pairs allowed. This paper describes current methods of studying the changes that underlie inherited and acquired disease and concludes with discussion of a technique that is generating excitement while still in development.cardiovascular disease and various cancers. molecular methods are becoming important in the diagnosis and classification of malignant disease.
such as the RAD . most notably a predisposition to cancer. In addition. cells have evolved a number of mechanisms to detect and repair the various types of damage that can occur to DNA. In fact. Because DNA is a molecule that plays an active and critical role in cell division. Defects in DNA repair underlie a number of human genetic diseases that affect a wide variety of body systems but share a constellation of common traits. and many of the proteins involved have been highly conserved throughout evolution. a condition characterized by sensitivity to sunlight and linked to a defect in an important ultraviolet (UV) damage repair pathway. no matter whether this damage is caused by the environment or by errors in replication. a degenerative motor condition caused by failure to repair oxidative damage in the cerebellum. These disorders include ataxia-telangiectasia (AT). (Recall that cells transit through a cycle involving the G1. and M phases. with DNA replication occurring in the S phase and mitosis in the M phase.) During the cell cycle. which in turn leads to mutations. and xeroderma pigmentosum (XP). Failures in these checkpoints can lead to an accumulation of damage. checkpoint mechanisms ensure that a cell's DNA is intact before permitting DNA replication and cell division to occur. control of DNA repair is closely tied to regulation of the cell cycle.DNA Repair Mechanisms and Human Disease DNA repair processes exist in both prokaryotic and eukaryotic organisms. G2. a number of genes that have been implicated in cancer. S.
Although cancer cells can be quite common in a person they are only malignant when the other cells (particularly natural killer cells) fail to recognize and/or destroy them. quickened pace. have also been determined to encode proteins critical for DNA damage repair. more recent research has shown that the failure to recognize cancer cells is caused by the lack of particular co-stimulated molecules that aid in the way antigens react with lymphocytes. However.group. Tumor cells have high levels of a protein (survivin) that inhibits apoptosis. . Characteristics of cancer cells Exhibit Uncontrolled Growth (Immortality) Abnormal DNA (Mutations) Apoptosis Cells with damaged DNA that cannot be repaired normally undergo apoptosis. Cancer cells Cancer cells are cells that grow and divide at an unregulated. In the past a common belief was that cancer cells failed to be recognized and destroyed because of a weakness in the immune system. a process in which the cell kills itself.
Cancer cells continue to divide and produce a mass of cells called a tumor. Cancer cells continue to divide and produce a mass of cells called a tumor.Lack Differentiation Normally. cells become differentiated and become capable of specific functions Lack Contact Inhibition Normal cells stop dividing when they become crowded because mitosis is inhibited when cells contact nearby cells. Normally. Lack Anchorage Dependence Normal cells cling to neighboring cells. cells cannot penetrate this barrier and therefore cannot invade neighboring tissues and organs. Have a Reduced Need for Growth Factors Normal cells stop dividing when they become crowded because mitosis is inhibited when cells contact nearby cells. internal cavities. cancer cells do not. Ability to Penetrate the Lamina The lamina is a noncellular barrier that is attached to cells that line the surfaces. and organs (epithelial tissue). .
etc. A gene capable. Oncogenes are generally mutated forms of normal cellular genes (proto-oncogenes). . Oncogenes A gene that contributes to the production of a cancer.) because they have proteins and other structures that are different from the body’s "self" markers. of transforming a cell. Cancer cells release growth factors that cause nearby blood vessels to produce branches that grow into the cancerous tissue. viruses. Oncogenes are found in the oncogenically activated state in retroviruses and transformed cells and in their normal non-oncogenically activated state in nontransformed cells in which they are called proto-oncogenes.Immune System The immune system can recognize foreign cells and invaders (bacteria. Angiogenesis Tumors need a blood supply for food and oxygen. when activated.
They are sometimes grouped both spatially (moving from outside the cell inwards) and chronologically (parallelling the "normal" process of signal transduction). . receptor (EGFR).Classification There are several systems for classifying oncogenes. osteosarcomas. or mitogens Examples c-Sis Cancers glioblastomas. non-small-cell lung cancer and pancreatic cancer transduce signals for cell growth and differentiation. and Receptor tyrosine kinases melanomas epidermal growth factor Breast cancer. and vascular endothelial growth gastrointestinal stromal tumours. but there is not yet a widely accepted standard. breast carcinomas. Gene functions induces cell proliferation. platelet-derived growth factor receptor (PDGFR). fibrosarcomas. There are several categories that are commonly used: Category Growth factors.
pancreatice cancer. and cyclindependent kinases (through overexpression). apoptosis involved in signalling a major pathway leading to cell proliferation.factor receptor Cytoplasmic tyrosine kinases (VEGFR). and survival Involved in organism development.Philadelphia chromosome colorectal and breast cancers. and the activation receptors of cell proliferation. cancers malignant melanoma. melanomas. differentiation. Syk-ZAP70 family. migration. gastric cancers. -They regulate transcription of genes that induce . lung cancer. and Regulatory GTPases Ras protein adenocarcinomas of the pancreas and colon. colorectal cancer. thyroid tumors. HER2/neu Src-family. cell proliferation. the Abl gene in CML . brain cancers. and ovarian cancer mediate the responses to. head and neck cancers. differentiation. cell cycle regulation. cells survival. and Transcription factors myc gene myeloid leukemia malignant T-cell lymphomas and acute myleoid leukemias. ovarian cancers. and BTK family of tyrosine kinases. papillary thyroid cancer. and blood Cytoplasmic Serine/threonine kinases and their regulatory subunits Raf kinase.
but requiring biallelic mutation. the second can still produce the correct protein. He recognized that this was consistent with a recessive mutation involving a single gene. in contrast. such as certain mutations in the p53 gene product. tumor suppressor genes generally follow the "two-hit hypothesis". nlike oncogenes. or anti-oncogene. Knudson observed that the age of onset of retinoblastoma followed 2nd order kinetics.G. Tumer suppressor genes A tumor suppressor gene. implying that two independent genetic events were necessary. When this gene is mutated to cause a loss or reduction in its function. is a gene that protects a cell from one step on the path to cancer. There are exceptions to the "two-hit" rule for tumor suppressors. Oncogene mutations. pancreatic cancer. usually in combination with other genetic changes.breast cancer. and small cell proliferation. the cell can progress to cancer. The twohit hypothesis was first proposed by A. Knudson for cases of retinoblastoma. which implies that both alleles that code for a particular protein must be affected before an effect is manifested. mutant tumor suppressors alleles are usually recessive whereas mutant oncogene alleles are typically dominant. generally involve a single allele because they are gain-of-function mutations. This is because if only one allele for the gene is damaged. In other words. p53 . retinoblastoma.
The functions of tumor-suppressor proteins fall into several categories including the following: 1. Coupling the cell cycle to DNA damage. 3. . 2. it should not divide. An example of this is the p27Kip1 cell-cycle inhibitor. effectively inhibiting cell division. the cell cycle does not continue. Repression of genes that are essential for the continuing of the cell cycle. Functions Tumor-suppressor genes. and sometimes do both. in which mutation of a single allele causes increased carcinogen susceptibility.mutations can function as a "dominant negative". If these genes are not expressed. the cell should initiate apoptosis (programmed cell death) to remove the threat it poses for the greater good of the organism. If the damage cannot be repaired. Other tumor-suppressor genes that are exceptions to the "two-hit" rule are those that exhibit haploinsufficiency for example PTCH in medulloblastoma. If the damage can be repaired. the proteins for which they code. either have a dampening or repressive effect on the regulation of the cell cycle or promote apoptosis. As long as there is damaged DNA in the cell. the cell cycle can continue. or more precisely. meaning that a mutated p53 protein can prevent the function of normal protein from the un-mutated allele.
and neurogenic tumors. Abnormalities of the p53 gene can be inherited in LiFraumeni syndrome (LFS).4. MEN1 and BRCA. lymphomas. Homozygous loss of p53 is found in 70% of colon cancers. Examples The first tumor-suppressor protein discovered was the Retinoblastoma protein (pRb) in human retinoblastoma. sarcomas. however. Furthermore. 30–50% of breast cancers. recent evidence has also implicated pRb as a tumor-survival factor. . DNA repair proteins are usually classified as tumor suppressors as well. and inhibit metastasis. Mutated p53 is also involved in the pathophysiology of leukemias. These proteins are known as metastasis suppressors. increased mutation rate from decreased DNA repair leads to increased inactivation of other tumor suppressors and activation of oncogenes. Another important tumor suppressor is the p53 tumor-suppressor protein encoded by the TP53 gene. as mutations in such their genes increase the risk of cancer. Some proteins involved in cell adhesion prevent tumor cells from dispersing. block loss of contact inhibition. for example mutations in HNPCC. and 50% of lung cancers. 5. which increases the risk of developing various types of cancers.
can cause a change in the protein structure. caused by o o an increase of protein expression (through misregulation) an increase of protein (mRNA) stability. prolonging its existence and thus its activity in the cell . pro-tumorogenic Akt activation. ST7. which is essential for antiapoptotic. and ST14. causing o o an increase in protein (enzyme) activity a loss of regulation 2.PTEN acts by opposing the action of PI3K. Other examples of tumor suppressors include VHL. A mutation within a proto-oncogene. There are three basic methods of activation: 1. CD95. YPEL3. ST5. or within a regulatory region (for example the promoter region). Molecular mechanism of oncogene activation From proto-oncogene to oncogene The proto-oncogene can become an oncogene by a relatively small modification of its original function. APC. An increase in the amount of a certain protein (protein concentration).
This fused gene encodes for a protein that displays high protein tyrosine kinase activity (this activity is due to the "ABL1" half .o gene duplication (one type of chromosome abnormality). This chromosome was discovered in 1960 by Peter Nowell and David Hungerford. which fuses with a fragment of chromosome 9 that contains the "ABL1" gene. resulting in an increased amount of protein in the cell 3. When these two chromosome fragments fuse the genes also fuse creating a new gene: "BRC-ABL". This type of mutation in a dividing stem cell in the bone marrow leads to adult leukemia Philadelphia Chromosome is an example of this type of translocation event. and it is a fusion of parts of DNA from chromosome 22 and chromosome 9. The broken end of chromosome 22 contains the "BCR" gene. A chromosomal translocation (another type of chromosome abnormality) o There are 2 different types of chromosomal translocations that can occur: translocation events which relocate a proto-oncogene to a new chromosomal site that leads to higher expression 2. 1. translocation events that lead to a fusion between a protooncogene and a 2nd gene (this creates a fusion protein with increased cancerous/oncogenic activity) the expression of a constitutively active hybrid protein.
As a result.of the protein). Mutations in such microRNAs (known as oncomirs) can lead to activation of oncogenes. small RNAs 21-25 nucleotides in length that control gene expression by downregulating them. . The expression of oncogenes can be regulated by microRNAs (miRNAs). Antisense messenger RNAs could theoretically be used to block the effects of oncogenes. The unregulated expression of this protein activates other proteins that are involved in cell cycle and cell division which can cause a cell to grow and divide uncontrollably (the cell becomes cancerous). the Philadelphia Chromosome is associated with Chronic Myelogenous Leukemia (as mentioned before) as well as other forms of Leukemia.