Gene Mutation And Cancer

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

Submitted by:

Md. Mohsin Uddin Howlader Roll no: 468 Session: 2010-11 Department Of Zoology Jahangirnagar University, Dhaka

Submssion date:

5th January, 2013

however the altered DNA sequence prematurely signals the cell to stop building a protein. 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. 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. Instead of substituting one amino acid for another. . • Nonsense mutation A nonsense mutation is also a change in one DNA base pair. Types of gene mutation The DNA sequence of a gene can be altered a number of ways.

As a result the protein made by the gene may not function properly.• Insertion An incertion changes the number of DNA bases in a gene by adding a piece of DNA. • Duplication A duplication consists of a piece of DNA that is abnormally copied one or more times . • Deletion A deletion changes the number of DNA Bases By Removing a piece of DNA.

2.Transversion Replacement of a by a pyrimidine . This are two types: 1.• Point mutation The replacement base pair by another.Transitions: A purine(or a pyrimidine) replaced by another.

both physicians and patients associated this field with uncommon diseases. relevant only to specialists and those affected. such as diabetes mellitus. • Reapeat expansion Nucleotide repeats are short DNA sequence that repeated a number of times in a row. Detecting mutations in human genes In the first decades of medical genetics.• Frameshift mutations This occur when one or more base pair are inserted in or detected from DNA. . This is no longer so: our understanding of the genetics underlying susceptibility to common disorders. changing the genes leading frame. eg-Trinucleotide repeat is made 3 base pair sequences.

either strand alone contains the information required to rebuild the other. as well as in determining prognosis and monitoring response to therapy. 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. such that there are 2 sets of pairs allowed. Genetic information is encoded by the sequence of the bases along a single strand of DNA. the use of DNA microarrays or “chips. molecular methods are becoming important in the diagnosis and classification of malignant disease. but also the public mainstream. is bringing genetics into not only the medical mainstream. the nucleotide bases of one strand associate one-to-one with those on the other.” How does DNA encode information? The gene is the fundamental unit of genetic information.” When 2 DNA strands combine to form a double helix. the bases are therefore often regarded as the alphabet forming the words. Genetic information is transmitted by the geometry of pairing of the bases in this double helix. phrases and sentences of the “genetic instruction manual. Only certain associations among the 4 different types of bases are permitted. 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. Moreover.cardiovascular disease and various cancers. . As a consequence.

) During the cell cycle. and many of the proteins involved have been highly conserved throughout evolution. cells have evolved a number of mechanisms to detect and repair the various types of damage that can occur to DNA. control of DNA repair is closely tied to regulation of the cell cycle. a number of genes that have been implicated in cancer. Failures in these checkpoints can lead to an accumulation of damage. a degenerative motor condition caused by failure to repair oxidative damage in the cerebellum. which in turn leads to mutations. and xeroderma pigmentosum (XP). checkpoint mechanisms ensure that a cell's DNA is intact before permitting DNA replication and cell division to occur.DNA Repair Mechanisms and Human Disease DNA repair processes exist in both prokaryotic and eukaryotic organisms. 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. a condition characterized by sensitivity to sunlight and linked to a defect in an important ultraviolet (UV) damage repair pathway. and M phases. Because DNA is a molecule that plays an active and critical role in cell division. (Recall that cells transit through a cycle involving the G1. S. such as the RAD . with DNA replication occurring in the S phase and mitosis in the M phase. G2. These disorders include ataxia-telangiectasia (AT). In fact. no matter whether this damage is caused by the environment or by errors in replication. most notably a predisposition to cancer. In addition.

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. In the past a common belief was that cancer cells failed to be recognized and destroyed because of a weakness in the immune system. Tumor cells have high levels of a protein (survivin) that inhibits apoptosis. quickened pace. 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.group. However. a process in which the cell kills itself. 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.

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. Ability to Penetrate the Lamina The lamina is a noncellular barrier that is attached to cells that line the surfaces.Lack Differentiation Normally. Cancer cells continue to divide and produce a mass of cells called a tumor. cancer cells do not. internal cavities. Have a Reduced Need for Growth Factors Normal cells stop dividing when they become crowded because mitosis is inhibited when cells contact nearby cells. and organs (epithelial tissue). cells cannot penetrate this barrier and therefore cannot invade neighboring tissues and organs. Cancer cells continue to divide and produce a mass of cells called a tumor. Lack Anchorage Dependence Normal cells cling to neighboring cells. . Normally.

when activated. viruses.Immune System The immune system can recognize foreign cells and invaders (bacteria. etc. A gene capable. Oncogenes A gene that contributes to the production of a cancer. Oncogenes are generally mutated forms of normal cellular genes (proto-oncogenes). .) because they have proteins and other structures that are different from the body’s "self" markers. 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. of transforming a cell. Cancer cells release growth factors that cause nearby blood vessels to produce branches that grow into the cancerous tissue. Angiogenesis Tumors need a blood supply for food and oxygen.

non-small-cell lung cancer and pancreatic cancer transduce signals for cell growth and differentiation. platelet-derived growth factor receptor (PDGFR). osteosarcomas. breast carcinomas. and Receptor tyrosine kinases melanomas epidermal growth factor Breast cancer. fibrosarcomas. Gene functions induces cell proliferation. .Classification There are several systems for classifying oncogenes. or mitogens Examples c-Sis Cancers glioblastomas. and vascular endothelial growth gastrointestinal stromal tumours. They are sometimes grouped both spatially (moving from outside the cell inwards) and chronologically (parallelling the "normal" process of signal transduction). but there is not yet a widely accepted standard. receptor (EGFR). There are several categories that are commonly used: Category Growth factors.

and BTK family of tyrosine kinases. gastric cancers. lung cancer. and Transcription factors myc gene myeloid leukemia malignant T-cell lymphomas and acute myleoid leukemias. and cyclindependent kinases (through overexpression). cancers malignant melanoma. and survival Involved in organism development. the Abl gene in CML . and blood Cytoplasmic Serine/threonine kinases and their regulatory subunits Raf kinase. and Regulatory GTPases Ras protein adenocarcinomas of the pancreas and colon. ovarian cancers.Philadelphia chromosome colorectal and breast cancers. and the activation receptors of cell proliferation. head and neck cancers. migration. colorectal cancer. cell proliferation. HER2/neu Src-family. cell cycle regulation. apoptosis involved in signalling a major pathway leading to cell proliferation. and ovarian cancer mediate the responses to. papillary thyroid cancer. cells survival. differentiation. brain cancers. -They regulate transcription of genes that induce . melanomas. Syk-ZAP70 family.factor receptor Cytoplasmic tyrosine kinases (VEGFR). pancreatice cancer. thyroid tumors. differentiation.

When this gene is mutated to cause a loss or reduction in its function. and small cell proliferation. or anti-oncogene. In other words. This is because if only one allele for the gene is damaged. in contrast. but requiring biallelic mutation. Tumer suppressor genes A tumor suppressor gene. the cell can progress to cancer. the second can still produce the correct protein. tumor suppressor genes generally follow the "two-hit hypothesis".breast cancer. such as certain mutations in the p53 gene product.G. is a gene that protects a cell from one step on the path to cancer. pancreatic cancer. Oncogene mutations. generally involve a single allele because they are gain-of-function mutations. mutant tumor suppressors alleles are usually recessive whereas mutant oncogene alleles are typically dominant. The twohit hypothesis was first proposed by A. p53 . which implies that both alleles that code for a particular protein must be affected before an effect is manifested. He recognized that this was consistent with a recessive mutation involving a single gene. Knudson observed that the age of onset of retinoblastoma followed 2nd order kinetics. implying that two independent genetic events were necessary. There are exceptions to the "two-hit" rule for tumor suppressors. usually in combination with other genetic changes. nlike oncogenes. retinoblastoma. Knudson for cases of retinoblastoma.

Repression of genes that are essential for the continuing of the cell cycle. As long as there is damaged DNA in the cell. If these genes are not expressed. The functions of tumor-suppressor proteins fall into several categories including the following: 1. or more precisely. the cell cycle does not continue. 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. An example of this is the p27Kip1 cell-cycle inhibitor. 3. in which mutation of a single allele causes increased carcinogen susceptibility. and sometimes do both. either have a dampening or repressive effect on the regulation of the cell cycle or promote apoptosis. . If the damage can be repaired. the proteins for which they code. Coupling the cell cycle to DNA damage.mutations can function as a "dominant negative". effectively inhibiting cell division. meaning that a mutated p53 protein can prevent the function of normal protein from the un-mutated allele. it should not divide. Functions Tumor-suppressor genes. the cell cycle can continue. 2.

as mutations in such their genes increase the risk of cancer. and 50% of lung cancers. increased mutation rate from decreased DNA repair leads to increased inactivation of other tumor suppressors and activation of oncogenes. 5. sarcomas. recent evidence has also implicated pRb as a tumor-survival factor. block loss of contact inhibition. and neurogenic tumors. MEN1 and BRCA. which increases the risk of developing various types of cancers. Examples The first tumor-suppressor protein discovered was the Retinoblastoma protein (pRb) in human retinoblastoma. Another important tumor suppressor is the p53 tumor-suppressor protein encoded by the TP53 gene. Mutated p53 is also involved in the pathophysiology of leukemias. Homozygous loss of p53 is found in 70% of colon cancers. Furthermore. These proteins are known as metastasis suppressors. Abnormalities of the p53 gene can be inherited in LiFraumeni syndrome (LFS).4. however. and inhibit metastasis. 30–50% of breast cancers. . for example mutations in HNPCC. DNA repair proteins are usually classified as tumor suppressors as well. lymphomas. Some proteins involved in cell adhesion prevent tumor cells from dispersing.

or within a regulatory region (for example the promoter region). caused by o o an increase of protein expression (through misregulation) an increase of protein (mRNA) stability. 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. prolonging its existence and thus its activity in the cell . APC. can cause a change in the protein structure. CD95. ST7. pro-tumorogenic Akt activation. Other examples of tumor suppressors include VHL. ST5.PTEN acts by opposing the action of PI3K. A mutation within a proto-oncogene. There are three basic methods of activation: 1. An increase in the amount of a certain protein (protein concentration). causing o o an increase in protein (enzyme) activity a loss of regulation 2. YPEL3. and ST14. which is essential for antiapoptotic.

1. 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. When these two chromosome fragments fuse the genes also fuse creating a new gene: "BRC-ABL". which fuses with a fragment of chromosome 9 that contains the "ABL1" gene. 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. The broken end of chromosome 22 contains the "BCR" gene.o gene duplication (one type of chromosome abnormality). resulting in an increased amount of protein in the cell 3. 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. This chromosome was discovered in 1960 by Peter Nowell and David Hungerford. and it is a fusion of parts of DNA from chromosome 22 and chromosome 9. This fused gene encodes for a protein that displays high protein tyrosine kinase activity (this activity is due to the "ABL1" half .

Antisense messenger RNAs could theoretically be used to block the effects of oncogenes. the Philadelphia Chromosome is associated with Chronic Myelogenous Leukemia (as mentioned before) as well as other forms of Leukemia. . 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). small RNAs 21-25 nucleotides in length that control gene expression by downregulating them. Mutations in such microRNAs (known as oncomirs) can lead to activation of oncogenes. As a result.of the protein). The expression of oncogenes can be regulated by microRNAs (miRNAs).

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