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Genetics of Cancer Cancer is a genetic disease Cancers result from mutations in the genes that regulate cell growth. DNA damage increases the risk of developing cancer. Familial cancer syndromes are due to mutations in genes affecting DNA repair or genes that regulate cell growth. 1. What is an oncogene? 2. How do oncogenes arise and cause cancer? 3. What is a tumor suppressor gene, how does it work? Causes of Cancer Oncogenes-an altered forms of normal genes-proto-oncogenes that have key roles in cell growth and differentiation. o Want these methylated Tumor Suppressor Genes-normal cells contain genes with tumor suppressor activity, if lost of inactive, can lead to malignancy much like a recessive trait. o Don’t want these methylated Epigenetics and Cancer-refers to heritable changes to gene expression that are not due to differences in the genetic code Cancers are associated with mutations that “activate” proteins that stimulate cell growth DNA is responsible for transforming normal cells into cancer cells The demonstration that certain transduced cellular genes (“oncogenes”) cause cancer earned Varmus and Bishop the Nobel Prize in Medicine. This provided direct evidence that DNA was the element of cancerous “transformation.” Similarly, Weinberg demonstrated that DNA extracted from human bladder cancer could transform cultured cells, independently confirmed the that DNA was the element responsible for cancerous transformation. 4. Clinical example of CML and Philadelphia chromosome Chronic myelogenous (or myeloid) leukemia (CML) Chronic myelogenous (or myeloid) leukemia (CML), also known as chronic granulocytic leukemia (CGL), is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which proliferation of mature granulocytes (neutrophils, eosinophils, and basophils) and their precursors is the main finding. It is a type of myeloproliferative disease associated with a characteristic chromosomal translocation called the Philadelphia chromosome. The Philadelphia Ph1 chromosome In 1960, Nowell demonstrated that the leukemic cells from CML patients had a characteristic chromosomal abnormality, t(9:22). o This 9 to 22 chromosomal rearrangement is seen is over 90% of those patients with CML. o The translocation has been found to transfer the cellular ABL (Abelson) resulting in a abberant transcript c-ABL. This was not present in the patient’s normal cells. Thus, the Ph1 chromosome is an acquired genetic abnormality. This was the first example of a genetic abnormality consistently associated with cancer. Evidence that Ph1 provides a growth advantage Ph1 translocation creates a novel protein that fuses Bcr and Abl proteins While the function of Bcr is unknown, Abl is a known retroviral oncogene and a tyrosine kinase 1 The Ph chromosome Chronic myelogenous leukemia (CML) is a malignant disorder of blood cells that ultimately evolves into acute leukemia, which is rapidly fatal. The Ph1 chromosome In CML the abnormal clone of cells (which possess Ph 1) overgrow the normal blood cells. This implies that Ph1 provides a growth advantage to the blood cells that acquire it. BCR-ABL transcript is continuously active and does not require activation by other cellular messaging proteins. In turn, BCR-ABL activates a cascade of proteins that control the cell cycle, speeding up cell division. Moreover, the BCR-ABL protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic abnormalities. The action of the BCR-ABL protein is the pathophysiologic cause of chronic myelogenous leukemia. 5. Clinical example of Retinoblastoma Tumour Suppressor Genes- are genes that act to inhibit cell proliferation and tumour development. Mutation or inactivation of the tumour suppressor gene will cause cancer or cell transformation. RB gene is a tumor suppresser protein The retinoblastoma protein (abbreviated pRb, RB or RB1) is a tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. Example; deletion of Rb gene will cause retinoblastoma. The development of retinoblastoma can be either: Hereditary: a defective copy of Rb gene is inherited from the affected parents. Nonhereditary: in which 2 normal Rb genes are inherited and develop mutation during life. Retinoblastoma is developed if 2 somatic mutations inactivate both copies of Rb in the same cell. A (pediatric) cancer with a strong genetic component. Retinoblastoma and Knudson’s “two hit” theory hypothesis Genetic mapping identified RB as the mutant gene in individuals with inherited susceptibility to retinoblastoma. Retinoblastoma occurs when the second RB allele becomes inactivated. Somatic mutations in RB occur in a large number of cancers. Inactivation of Tumour suppressor gene will cause cancer. - If the Rb gene interact with DNA tumour virus (SV40) it will induce cell transformation. 6. What is the role of telomeres and cancer? Telomere Length and Cancer- If they become short 2 chromosomes Can stick together and some of these cells would die due to this. In cancer you normally see long telomeres because cancer cells resemble stem cells, because they have high telomerase activity to create long telomeres. In the lab, it must be confirmed that stems cells have long telomeres before stem cells are given to a patient. If the stem cells do not have long telomeres they will not be efficient. Cell Senescence- telomeres are shorter in disease state and aging Epigenetics and Different Aspects of Life Means “on/over” the genetic information encoded in DNA The study of reversible heritable changes in gene function that occur without a change in the sequence of nuclear DNA Gene-regulatory information that is not expressed in DNA sequences is transmitted from one generation (of cells or organisms) to the next Molecular Mechanisms that Mediate Epigenetic Phenomena DNA methylation (CpG dinucleotides)- turn “off” genes o First DNA methylation It is the covalent addition of methyl group to 5th Position of cystosine with in CPG dinucleotides which are frequently located in the promoter region of genes. It is a complex process catalyzed by DNA methyl transferases, DNMTS. o Deoxycytosine 5-methylcytosine via the enzyme DNA-methyltransferase o Most embryonic genes are unmethylated o Terminal cells are heavily methylated o CpG island: a cluster of CpG residues often found near gene promoters (at least 200 bp and with a GC percentage that is greater than 50% and with an observed/expected CpG ratio that is greater than 0.6). ~29,000 CpG islands in human genome (~60% of all genes are associated with CpG islands) Most CpG islands are unmethylated in normal cells. Histone modifications- acetylation turns genes “on” Epigenetics and Cancer Chromosomal infrastructure is essential for gene control, determining both active and repressed states It is important not only to turn the right genes on but also to turn the right genes off Histones and chromatin components have key roles in this decision making process If as few as three inappropriate genes are turned off, a normal cell can be converted into a cancer cell This epigenetic silencing of genes underlies a new approach to cancer therapy Mistargeting of these enzymes leads to tumorigenesis, but inhibition of their activity presents a novel approach to therapy Neoplastic Transformation means “new” transformation It is a complex multi-event and multi-stage process. The process can be divided into two requisite sequences o Neoplastic conversion – DNA alteration o Neoplastic development Alternative Sequencing Methods: Bisulfite sequencing is used to detect methylation in DNA. o Bisulfite deaminates cytosine, making uracil. o Methylated cytosine is not changed by bisulfite treatment. o The bisulfite-treated template is then sequenced. o The sequence of treated and untreated templates is compared. “We want a cure for cancer, not to just cut it out.” – Dr. Brenner Recent Cancer methylation studies predict that hundred (100) of CPG islands could be methylated in a tumor cell. However, it is clear that both the genome-wide methylation studies and candidate gene approaches that each tumor type may have its own set of cancer cell type specific genes that are more susceptible to methylation. Thus each cancer type may have the potential to be typed or classified according to methylation profile. In colorectal cancer: Progressive methylation of DNA and subsequent silencing of a subset of genes occurs in normal tissues along side age and time dependent events which predispose these normal cells to neoplastic transformation. Cytosine methylation of CPG loci underlies many of the genetic events in colorectal carcinogenesis which can be discovered in very early stage. The inactivation of adenomatous polyposis coli (Apc): o The gene is believed to initiate colorectal carcinogenesis in 80% of the cases therefore, it has potential as sensitive marker of on early stage of the disease. In lung cancer It has been shown that a panel of markers, for aberrant methylation that detects lung cancer at the early stages of development has been observed. This panel includes the following genes: -P 16 -APC -G-ST -E-cadhrin In breast cancer BRCA gene is a breast cancer susceptibility gene, that is tumor suppressor gene responsible for both normal development and carcinogenesis in breast. BRCA1, reveals multi functional protein involved in DNA repair. Cell cycle regulation, transcription and apoptosis. BRCA1 mutations may play a significant role in the tumor-genesis of familial breast cancer. Aberrant methylation of BRCA1 CPG island Promoter is associated with decreased BRCA1 mRNA in sporadic breast cancer cells. There is a strong relationship between BRCA1 promoter hyper-methylation and the existence of LOH (loss of hetero-zygosity) at the BRCA locus. This finding suggested that one allele has been lost by deletion and the other is inactivated by aberrant methylation. Both events simultaneously leading to the bi-allelic inactivation and complete lack of function of the BRCA1 gene. Epigenome in relation to cancer drug resistance Intrinsic and acquired drug resistance remain the most unpredictable factor affecting chemotherapy. DNA hypermethylation has been found to be associated with drug resistance acquired during cancer chemotherapy and therefore, re-expression of methylation-silenced genes resulted in increased sensitivity to existing chemotherapy. CONCLUSION Hyper methylation of CPG islands associated With tumor suppressor genes has been proposed to contribute to carcinogenesis. Epigenetic markers open new avenues for an early detection, diagnosis , prognosis as well as therapeutic targets in cancers. DNA demethylating agents and histone deacetylase inhibitors are underway to awake those silent tumor suppressor genes for a better treatment of patients suffering from cancers . Focus of Epigenetic Cancer Lecture Understand cytosine methylation and CpG island and gene expression. Understand alternative DNA sequencing methods to determine if a gene is methylated in a specific cancer Understand how epigenetics can cause lung and breast cancers. Understand how epigentic inhibitors may be used to develop new cancer therapeutics