Cancer Genetics Lecture 8 PDF

Cancer Genetics Lecture 8 Asst. Prof. Dr. Revathy Sankaran Learning Outcome Describe multistep evolution of cancer cells based on gene derangement. Describe classification of oncogenes and tumour suppressor genes Describe how activation of oncogenes lead to oncogenesis Is cancer a ge...

Cancer Genetics Lecture 8 Asst. Prof. Dr. Revathy Sankaran Learning Outcome Describe multistep evolution of cancer cells based on gene derangement. Describe classification of oncogenes and tumour suppressor genes Describe how activation of oncogenes lead to oncogenesis Is cancer a genetic disease? Is Cancer is a genetic disease It is caused by changes in genes that control the way cells grow and multiply. Each cell has a copy of your genes, which act like an instruction manual. Genes are sections of DNA that carry instructions to make a protein or several proteins. DNA and genetic changes (also called variants, mutations, or alterations) help cancer form, grow, and spread.  Genetic changes can occur because: Random mistakes in our DNA happen as our cells multiply DNA is altered by carcinogens in our environment, such as chemicals in tobacco smoke, UV rays from the sun, and the human papillomavirus (HPV) Inherited from one of our parents  The Genetic Basis of Cancer Complex disease that is caused by a series of genetic changes in a cell. These changes can occur over time, and they can be caused by a variety of factors, including carcinogens (cancer-causing substances), inherited mutations, and errors that occur during cell division. The genetic model of carcinogenesis is based on the idea that mutations at the DNA level create a functional imbalance between the oncogenes and the tumor- suppressor genes, resulting in uncontrolled clonal proliferation The Genetic Basis of Cancer The primary genetic changes that contribute to cancer include mutations in two main classes of genes: oncogenes and tumor suppressor genes. Oncogenes- must be activated to cause cancer. Tumor suppressor genes- which normally holds mitosis in check, must be inactivated or removed to eliminate control of the cell cycle and initiate cancer.  What is required for a cell to transform into “cancer”? Independent growth (growth autonomy) Insensitive to growth inhibitors Resistant to apoptosis No aging (continuous dividing) Sustained angiogenesis Ability to invade and metastasize  Oncogenes Oncogenes - encode proteins that promote cell growth and division. Proto-oncogenes are normal genes that plays a role in regulating normal cell division. It can be mutated into oncogenes. When a proto-oncogene is mutated, it can produce a protein that is more active or less regulated than the normal protein. Gene never stops sending signals telling cells to grow and divide lead to uncontrolled cell growth and division. Activation of Oncogene Point Mutations: Single nucleotide changes in the gene sequence can lead to the activation of oncogenes. For example, the Ras oncogene is commonly activated by point mutations in various cancers. Gene Amplification: In some cases, the entire oncogene or a segment of it is duplicated, leading to overexpression. This amplification can result in uncontrolled cell growth. Chromosomal Translocations: Some oncogenes are moved to new genomic locations due to translocations, bringing them under the control of strong promoters. The BCR-ABL fusion gene in chronic myeloid leukemia is an example of this.  Oncogenes Function: Oncogene products are often involved in promoting cell proliferation and survival. They may stimulate cell cycle progression, inhibit apoptosis (programmed cell death), or drive angiogenesis (formation of blood vessels). Examples: Common oncogenes include Ras: Mutations in the Ras family of oncogenes are HER2 (ERBB2): MYC: MYC is involved in frequently found in Amplification of the HER2 regulating cell growth and various cancers, including gene is observed in is associated with several pancreatic cancer and breast cancer. cancer types. colorectal cancer.  Different kind of oncogenes Medical researchers have linked about 100 different oncogenes to various kinds of cancer. For example, about 25% of all cancers involve various forms of Ras genes. Ras genes make proteins that manage how cells receive signals, grow and die. HER2 gene in breast cancer. BCR/ABL1 gene in chronic myeloid leukemia and some types of B-cell acute lymphocytic leukemia. CMYC gene in Burkitt lymphoma. NMYC gene in small cell lung cancer and neuroblastoma. EGFR and EML4AK genes in adenocarcinoma of the lung. KRAS gene in pancreatic cancer and lung cancer.  Tumor Suppressor Genes ❑ Tumor suppressor genes are genes that play a protective role in preventing the development of cancer. ❑ They act as "brakes" on cell growth and division. ❑ When mutations occur in these genes, they lose their inhibitory function, loss of its ability to inhibit cell growth and division that allows cancer to develop. Inactivation: Tumor Supressor Genes Tumor suppressor genes are typically inactivated through various mechanisms: Loss of Point Mutations Epigenetic Heterozygosity Silencing (LOH) Point mutations can also Tumor LOH occurs when the inactivate tumor functional copy of the suppressor gene is lost or suppressor genes can be mutated, leaving only genes, although silenced by DNA the mutated allele in a both alleles must cell. This results in methylation, often be mutated the complete loss of for a significant preventing their tumor suppressor loss of function. expression. function.  Tumor Suppressor Genes Function: Tumor suppressor genes help maintain genomic stability and prevent the proliferation of damaged or abnormal cells. They regulate cell cycle progression, initiate apoptosis in damaged cells, and repair DNA. Examples: Well-known tumor suppressor genes include: TP53 (p53) RB1 BRCA1 and (Retinoblastoma BRCA2 gene) Often referred to as the "guardian of the genome," p53 Mutations in monitors DNA Mutations in RB1 are these genes are damage and associated with linked to promotes cell cycle retinoblastoma and hereditary breast arrest or apoptosis are found in several and ovarian when necessary. other cancers. cancers. Multistep evolution of cancer cells based on gene derangement The multistep evolution of cancer cells, based on gene derangements, is a complex process that involves a sequence of genetic alterations and changes in normal cellular regulation. Typically consists of several distinct stages: 1. Initiation: Gene Derangement: The process begins with a genetic alteration in a single cell that confers a growth advantage. This alteration can be a mutation, chromosomal rearrangement, or other genomic changes. Consequence: The initiated cell acquires the ability to divide and survive better than its neighboring normal cells. However, it is not yet a full-blown cancer cell. 2. Promotion: Gene Derangement: Subsequent genetic alterations and changes accumulate in the initiated cell. These changes may include additional mutations in oncogenes or the inactivation of tumor suppressor genes. Consequence: The promoted cell undergoes uncontrolled proliferation, losing some of the normal regulatory mechanisms. It forms a pre-malignant or early- stage tumor but is not invasive. 3. Progression: Gene Derangement: Further genetic alterations occur in the promoted cell. These may include more mutations in key oncogenes and tumor suppressor genes, as well as chromosomal instability. Consequence: The progressing cell becomes increasingly malignant, gaining the ability to invade nearby tissues and blood vessels. At this stage, it may acquire the capability to metastasize, forming secondary tumors in distant sites. 4. Metastasis: Gene Derangement: Metastasis involves additional genetic changes that enable cancer cells to enter the bloodstream, survive the hostile conditions of circulation, and establish secondary tumors in distant organs or tissues. Consequence: Metastatic cancer cells can spread throughout the body, creating new tumor sites that are often more difficult to treat than the primary tumor. 5. Angiogenesis: Gene Derangement: To sustain tumor growth, cancer cells may induce angiogenesis, which involves genetic mechanisms that promote the formation of new blood vessels to supply nutrients and oxygen to the growing tumor. Consequence: The development of a blood supply network allows the tumor to continue growing and provides routes for metastatic spread.  Classification of oncogenes Proto-oncogenes are normal cellular genes that, when mutated or abnormally activated, can become oncogenes. They play crucial roles in regulating cell growth, division, and differentiation. Oncogenes can be classified into several categories: a) Growth Factor Genes: These genes encode growth factors, which promote cell proliferation. Mutations or overexpression of growth factor genes can lead to uncontrolled cell growth. Examples include epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR).  Classification of oncogenes Oncogenes can be classified into several categories: b) Growth Factor Receptor Genes: These genes encode receptors for growth factors. Mutations can lead to constitutive activation of these receptors, even in the absence of growth factors. Examples include HER2 (ERBB2) and EGFR. c) Signal Transduction Genes: These genes encode components of intracellular signaling pathways. Mutations can lead to continuous activation of these pathways, promoting cell growth. Examples include RAS and BRAF.  Classification of oncogenes Oncogenes can be classified into several categories: d) Transcription Factors: Some oncogenes encode transcription factors that regulate the expression of other genes. Mutations can lead to the abnormal activation of genes involved in cell proliferation. Examples include MYC and JUN.  Classification of Tumor Suppressor Genes 1. Loss-of-Function Tumor Suppressor Genes: Tumor suppressor genes are classified based on their mechanisms of inactivation. These genes are typically recessive, requiring both alleles to be inactivated to promote oncogenesis. They can be further categorized into: a) Gatekeeper Genes: These genes directly regulate cell cycle progression and prevent the uncontrolled proliferation of damaged or abnormal cells. Examples include TP53 (p53) and RB1 (retinoblastoma gene). b) Caretaker Genes: Caretaker genes are involved in maintaining genomic stability and repairing DNA. Mutations in caretaker genes can lead to an increased mutation rate, promoting oncogenesis. Examples include BRCA1 and BRCA2. Classification of Tumor Suppressor Genes 2. Haploinsufficient Genes: Some tumor suppressor genes follow a haploinsufficient pattern, meaning that a single functional copy of the gene is not sufficient to prevent oncogenesis. Mutations in the remaining allele can lead to cancer. 3. Epigenetic Tumor Suppressor Genes: Some tumor suppressor genes are silenced through epigenetic mechanisms, such as DNA methylation. Reversing these epigenetic changes may restore their normal function. Why is it important to understand the classifications? Understanding the classification of oncogenes and tumor suppressor genes is crucial for the development of targeted cancer therapies and for characterizing the molecular drivers of specific cancer types. It allows researchers and clinicians to identify potential targets for intervention and treatment.  Genetic Mechanisms of Oncogenesis Oncogenesis is the process through which healthy cells become transformed into cancer cells Cancer cell transformation Genetic mechanisms of oncogenesis, the process by which normal cells transform into cancer cells, involve a series of genetic alterations that disrupt the normal regulation of cell growth and division. 1. Somatic Mutations: Point Mutations: Changes in individual DNA base pairs can result in the activation of oncogenes or the inactivation of tumor suppressor genes. Insertions and Deletions: The insertion or deletion of nucleotides in a gene can disrupt its normal function. This can lead to the production of faulty proteins that contribute to oncogenesis. Cancer cell transformation 2. Chromosomal Abnormalities: Translocations: Translocations involve the exchange of genetic material between different chromosomes. This can lead to the formation of fusion genes, where portions of two different genes are combined. An example is the BCR-ABL fusion gene in chronic myeloid leukemia (CML). Gene Amplification: In some cases, entire genes or gene segments are duplicated, resulting in overexpression of the gene product. Amplification of the HER2 gene in breast cancer is an example. Deletions: The loss of specific chromosomal regions can result in the loss of critical tumor suppressor genes. For instance, the loss of the 17p chromosomal region leads to the inactivation of the TP53 gene. Cancer cell transformation 3. Epigenetic Changes: (modifications to DNA that regulate whether genes are turned on or off) DNA Methylation: Aberrant DNA methylation can silence tumor suppressor genes by adding methyl groups to their promoter regions, preventing their transcription. Histone Modification: Changes in histone proteins can influence chromatin structure, affecting gene expression. Altered histone modifications can lead to the activation of oncogenes.  Cancer cell transformation 4. MicroRNA Dysregulation: MicroRNAs are small RNA molecules that regulate gene expression post-transcriptionally. Dysregulation of microRNAs can lead to the overexpression of oncogenes or the downregulation of tumor suppressor genes. 5. Telomere Shortening: Telomeres are protective caps at the ends of chromosomes that shorten with each cell division. When telomeres become critically short, it can result in genomic instability and promote oncogenesis. Oncogenesis is often a multistep process that requires the accumulation of several of these genetic changes. The exact combination of alterations can vary between different types of cancer. Summary of : How oncogenes lead to oncogenesis Proto-oncogenes become oncogenes through various mechanisms, such as point mutations, gene amplifications, or chromosomal translocations. Result in the abnormal activation of the proto-oncogenes. Genetic changes that convert proto-oncogenes into oncogenes typically result in a gain of function. This means that the proteins encoded by the oncogenes acquire new, often hyperactive, properties.  Promotion of Uncontrolled Cell Growth: The oncogene products may promote uncontrolled cell growth in several ways: a. Stimulation of Cell Proliferation: They can activate signaling pathways that drive cell division and proliferation. This leads to an increased rate of cell replication. b. Inhibition of Apoptosis: Oncogenes can suppress apoptosis, which is the programmed cell death mechanism that eliminates abnormal or damaged cells. This inhibition allows cancer cells to survive and accumulate. c. Induction of Angiogenesis: Some oncogenes can promote the formation of new blood vessels (angiogenesis) around the tumor. This ensures a blood supply that provides nutrients and oxygen to support the growing tumor. Tumor Formation: The continuous activation of oncogenes causes affected cells to divide rapidly and uncontrollably, forming a mass of cells known as a tumor. This tumor is the hallmark of oncogenesis. Tumor Progression: As oncogenesis continues, the tumor may progress to more advanced stages. Additional genetic changes can occur, which allow cancer cells to acquire invasive properties, enabling them to penetrate nearby tissues and potentially metastasize to distant sites in the body. Points need to remember: Able to explain the classification of oncogenes and tumor suppressor genes Multistep evolution of cancer cells Genetic mechanism of oncogenesis Thank You Question to think! Is cancer hereditary?