Molecular Basis of Cancer: Genetic Alterations PDF

27 Molecular Basis of Cancer: Genetic Alterations ILOs By the end of this lecture, students will be able to 1. Discuss general basic concept of cancer development. 2. Outline the Hallmarks of cancer. 3. Explore mechanisms of oncogene activation and...

27 Molecular Basis of Cancer: Genetic Alterations ILOs By the end of this lecture, students will be able to 1. Discuss general basic concept of cancer development. 2. Outline the Hallmarks of cancer. 3. Explore mechanisms of oncogene activation and tumor suppressor gene inactivation. 4. Apply the two-hit theory in the process of carcinogenesis. Molecular basis of cancer The mechanism as to how a normal cell is transformed to a cancer cell is complex. At different times, attempts have been made to unravel this mystery by various mechanisms. General basic concept of cancer; Monoclonality of tumors; Tumors are monoclonal in origin, they originate from a single progenitor cell line, opposite to the polyclonal population of non-neoplastic tissues. Multi-step process of cancer growth , Molecular studies have revealed that Carcinogenesis is a multistep process resulting from the accumulation of multiple genetic alterations that collectively give rise to the transformed phenotype and all of its associated hallmarks. The various causes may act on the cell one after another (multi-hit process). Tumor heterogeneity, as a result of continuing mutation, tumor cells are genetically heterogeneous by the time of their clinical presentation, and behavior. Tumor progression continuous mutations is also involved in further progression of the genetically and phenotypically transformed malignant cells acquiring greater malignant potential and more aggressive behaviour with excessive growth, survival, invasiveness, distant metastasis and immune evasion. Genetic theory of cancer , In cancer, there are either genetic abnormalities in the cell, or there are normal genes with abnormal expression. The genetic abnormalities may be from inherited or induced mutations (induced by etiologic carcinogenic agents namely: chemicals, viruses, radiation). Eventually, the mutated cells transmit their characters to the next progeny of cells and result in cancer. Genetic regulators of cell cycle, and Cancer genes Cell cycle and division is controlled by regulatory genes that control mitosis, cell ageing, and termination in cell death by apoptosis. In normal cell growth, there are 4 regulatory genes that whenever damaged or abnormal, they can contribute directly to the malignant behaviour of cells. i) Proto-oncogenes; Growth-promoting genes that encode for cell proliferation pathway, make cell growth possible, inhibiting cell differentiation. These processes are all essential for cells to maintain healthy tissues and organs in the body. These could be a growth factor bound to cell surface receptors, signal-transduction proteins, or transcription factors. Oncogenes: Oncogenes are mutated or overexpressed versions of normal cellular proto-oncogenes. Activation of growth-promoting oncogenes promotes increased cell growth and proliferation. They Page 1 of 4  are considered dominant genes because a mutation involving a single allele is sufficient to produce a pro-oncogenic effect. Examples of oncogenes; The Ras gene; that encode an intracellular signal-transduction protein (one of the on-and-off switches in cell growth pathway. When Ras mutates, it encodes for a protein that causes an uncontrolled growth-promoting signal. Ras gene mutations is associated with cancer of urinary bladder, pancreas, lung, colon and thyroid. The HER2 gene makes protein receptors that are involved in the growth and division of cells in the breast cancer. The Myc gene is associated with lymphoma. ii) Growth suppressor genes \ antioncogenes [Gate keeper of the genome]: Tumor suppressor genes are responsible for; control the progression of a specific stage of the cell cycle, inhibit the replication of the cell, stop the cell cycle in response to DNA damage, signal for the self-destruction of the cell and repair mistakes in DNA. Tumor suppressor genes; Inactivation, mutation or loss of growth-suppressor genes allow the transformed phenotype to proliferate. They are considered recessive genes; often both normal alleles must be damaged for transformation to occur. Examples; P53 gene, Guardian of the genome, normally prevents genome mutations. it is the most commonly mutated gene in cancer cells, found in more than half of cancers. Mutated in Bladder cancer, breast cancer, brain cancers. Retinoblastoma (RB) genes, mutated in the majority of cancers, particularly retinoblastoma of the eye in children and osteosarcoma. iii) Apoptosis regulatory genes control the programmed cell death. Mutation in apoptosis genes inhibit apoptosis and allow survival of abnormal cells with DNA defects and tumor progression [rather than stimulating proliferation]. Examples; BCL2 is an anti-apoptotic gene overexpressed, in follicular lymphoma. iv) DNA repair genes are those normal genes which regulate the repair of DNA damage that has occurred during mitosis and also control the damage to proto-oncogenes and antioncogenes. Failure of DNA repair genes (Caretakers): maintain the integrity of the DNA during replication and correct DNA damage that occurs as a result of exposure to environmental factors. The loss of function in a recessive way results in accumulation of mutations in Tumor Suppressor Genes and oncogenes. Hallmarks of Cancer It appears that all cancers display eight fundamental changes in cell physiology, which are considered the hallmarks of cancer: 1. Self-sufficiency in growth signals; Tumors have the capacity to proliferate without external stimuli, usually as a consequence of oncogene activation. 2. Insensitivity to growth-inhibitory signals, Tumors may not respond to molecules that inhibit the proliferation of normal cells, usually because of inactivation of tumor suppressor genes that encode components of growth inhibitory pathways. Page 2 of 4  3. Evasion of apoptosis, Tumors are resistant to programmed cell death. 4. Limitless replicative potential (immortality), Tumors have unrestricted proliferative capacity, a stem cell–like property that permits tumor cells to avoid cellular senescence and mitotic catastrophe. 5. Sustained angiogenesis, Tumor cells, like normal cells, are not able to grow without a vascular supply to bring nutrients and oxygen and remove waste products. Hence, tumors must induce angiogenesis. 6. Ability to invade and metastasize. Tumor metastases are the cause of the vast majority of cancer deaths and arise from the interplay of processes that are intrinsic to tumor cells and signals that are initiated by the tissue environment. 7. Ability to evade the host immune response. Cancer cells exhibit a number of alterations that allow them to evade the host immune response. 8. Altered cellular metabolism. Tumor cells undergo a metabolic switch to aerobic glycolysis, which enables the synthesis of the macromolecules and organelles that are needed for rapid cell growth. Genetic aberrations causing oncogene activation and tumor suppressor gene inactivation: Mutation of normal genes may occur by four main mechanisms: 1. Point mutations: An alteration of a single base in the DNA chain. Can either activate or inactivate the protein products of the affected genes depending on their precise position and consequence. Point mutations that convert proto-oncogenes into oncogenes generally produce a gain-of-function, as in RAS gene mutation. By contrast, point mutations in tumor suppressor genes reduce or disable the function of the encoded protein, P53 gene mutation. 2. Gene rearrangements: Gene rearrangements may be produced by chromosomal translocations or inversions. A. Philadelphia (Ph) chromosome, in chronic myeloid leukemia A piece of chromosome 9 with ABL gene and a piece of chromosome 22 with BCR gene break off and trade places [ balanced reciprocal translocation], encoding a novel tyrosine kinase with potent transforming activity. BCR-ABL fusion gene. B. MYC In Burkitt lymphoma; the cells have a translocation between chromosomes 8 and 14 that leads to overexpression of the proto-oncogenes MYC gene on chromosome 8 by removing it from their normal regulatory elements and juxtaposition with inappropriate regulatory gene on chromosome 14 placing it under control of an, highly active promoter or enhancer. 3. Deletions: Deletion of specific regions of chromosomes may result in the loss of particular tumor suppressor genes. Example: deletion of 17p is associated with loss of TP53, arguably the most important tumor suppressor gene. 4. Gene amplifications: Proto-oncogenes may be converted to oncogenes by gene amplification, with consequent overexpression and hyperactivity of otherwise normal proteins. Example: HER2 gene in breast cancers. Page 3 of 4 Clinical Value of determining cancer genes; Targeted gene therapies target oncogenes and not tumor suppressor genes. They use drugs to target cancer cells while leaving healthy cells mostly undamaged. Targeted gene therapy modifies specific genes in cancer cells. Genetic testing is a tool that can be used to learn about inherited cancer risks. Some examples of cancers where specific genes appear to play a role in cancer risk include: breast, colon, prostate and ovary. Page 4 of 4