Cancer Genetics PDF

Cancer Genetics Chapter 11  Cancer is a prevalent and deadly disease affecting millions worldwide. Approximately one in four deaths is now due to cancer, with more than half of the population expected to be diagnosed with invasive cancer in their lifetime. Cancer arises from a combinat...

Cancer Genetics Chapter 11  Cancer is a prevalent and deadly disease affecting millions worldwide. Approximately one in four deaths is now due to cancer, with more than half of the population expected to be diagnosed with invasive cancer in their lifetime. Cancer arises from a combination of environmental exposures and genetic mutations. Some families have a genetic predisposition to certain types of cancer.  Cancer is characterized by uncontrolled cell proliferation, culminating in tumor formation (neoplasm). Tumorigenesis involves pivotal processes, such as heightened growth signals, resistance to growth-inhibiting cues, and evasion of apoptosis. Tumors necessitate a fresh blood supply acquired through angiogenesis. Malignant tumors infiltrate nearby tissues and disseminate to distant body sites (metastasize). Types of Tumors Tumors are categorized based on their tissue of origin, including  Sarcomas, in which the tumor has arisen in mesenchymal tissue, such as bone, muscle, or connective tissue, or in nervous system tissue  Carcinomas, which originate in epithelial tissue, such as the cells lining the intestine, bronchi, or mammary ducts  Hematopoietic and lymphoid malignant neoplasms, such as leukemia and lymphoma, which arise in cells of hematopoietic lineage, including bone marrow and the lymphatic system Single-Origin Cells: Tumor cells typically originate from a singular ancestral cell, forming a monoclonal population. Causes of Cancer Genetic Alterations in Carcinogenesis Genetic alterations of cell regulatory systems are the primary basis of carcinogenesis. Cancer can be induced in animal models by damaging specific genes. Introduction of normal copies of damaged genes can reverse a cancer phenotype in cell culture systems. Most genetic events causing cancer occur in somatic cells. Frequency of these events can be altered by exposure to mutagens, linking them to environmental carcinogens. Causes of Cancer Genetic Alterations in Carcinogenesis Cancer-predisposing mutations can occur in germline cells, leading to transmission of cancer-causing alleles from one generation to the next. Families with high incidence of specific cancers demonstrate the inheritance of damaged genes causing cancer. Inherited mutant allele can lead to tumor development, as each cell carries the altered gene. Identification of individuals at elevated risk allows for more intensive screening of high-risk groups. Early detection and intervention lead to better prognoses, reduced morbidity, and mortality rates. Causes of Cancer Genetic Alterations in Carcinogenesis  Causes of Cancer Environmental Consideration Genetic alterations in cell regulatory systems are the primary basis of carcinogenesis. Frequency and consequences of mutations can be altered by environmental factors. Interaction of genes with the environment plays a key role in determining carcinogenesis. Many chemicals causing mutations in experimental animals also cause cancer in humans. Examples include carcinogens found in cigarette smoke, leading to lung and other types of cancer. Other environmental agents can enhance the growth of genetically altered cells without causing new mutations.  Causes of Cancer Environmental Consideration Different populations exhibit varying cancer frequencies, suggesting environmental and genetic influences. Breast cancer is prevalent among northern Europeans and European Americans but rare in developing countries. Examination of genetically similar populations under differing lifestyles reveals insights into cancer risk.  Causes of Cancer Both genetics and environment contribute to cancer risk, with interactions between the two. Differences in cancer incidence within the same environment may result from genetic predisposition and environmental factors. Genetic factors remain important, as evidenced by increased risk with a family history of cancer.  Cancer Genes Genetic Control of Cell Growth and Differentiation Cancers arise from clones of cells losing normal growth and differentiation controls. The regulation of cell growth is accomplished by substances that include: (1) Growth factors that transmit signals from one cell to another (2) Specific receptors for the growth factors (3) Signal transduction molecules that activate a cascade of phosphorylating reactions within the cell (4) Nuclear transcription factors The cell integrates and interprets the host of signals it receives from its environment. Decisions to grow and divide, or to stop growing and differentiate, result from processing of these Cancer Genes Genetic Control of Cell Growth and Differentiation Mutations can occur in any of the steps involved in regulation of cell growth and differentiation. Accumulation of such mutations within a cell lineage can result in a progressive deregulation of growth, eventually producing a tumor cell. The Inherited Cancer Gene Versus the Somatically Altered Gene The two-hit theory of carcinogenesis states that a cell can initiate a tumor only when it contains two damaged alleles. A person who inherits one copy of a mutant gene must experience a second, somatic mutation in one or more of that gene in order to develop cancer. Two somatic mutations can also occur in a single gene of a non-predisposed fetus, producing sporadic cancer. Understanding mutated genes that are inherited in families can increase our understanding of the somatic pathway to common cancers. Major Classes of Cancer Genes 1. Inhibit Cellular Proliferation: Tumor Suppressor Genes 2.Activate Proliferation: Oncogenes 3.DNA Repair Genes, Chromosome Integrity, and Tumorigenesis  1- Tumor Suppressor Genes Class of genes that play a crucial role in regulating cell growth and preventing the development of cancer. These genes act as "brakes" on cell division and proliferation, helping to maintain the normal function and integrity of cells. When tumor suppressor genes are mutated or inactive, they lose their ability to control cell growth effectively, leading to uncontrolled cell division and the formation of tumors. One of the primary functions of tumor suppressor genes is to repair DNA damage or induce apoptosis 2- Oncogenes (Cancer Genes) Most oncogenes originate from proto-oncogenes Oncogene develops from mutations in any of the four basic regulators of normal cell growth (growth factors, growth factor receptors, signal transduction molecules, and nuclear transcription factors). A single copy of a mutated oncogene is required to contribute to the multistep process of tumor progression (Dominant). 2- Oncogenes (Cancer Genes) 2- Oncogenes (Cancer Genes) Retroviruses are capable of inserting oncogenes into the DNA of a host cell, thus transforming the host into a tumor-producing cell. The study of such retroviral transmission has identified a number of specific oncogenes. The transfection of oncogenes from tumor cells to normal cells can cause transformation of the normal cells.  3- DNA Repair Genes, Chromosome Integrity, and Tumorigenesis Tumor cells typically are characterized by widespread mutations, chromosome breaks, and aneuploidy (genomic instability). Genomic instability can occur because of defects in the proteins required for accurate cell division or in proteins responsible for DNA repair. There are a number of ways various types of genomic instability can give rise to cancer: - Defective repair of double-stranded breaks that occur in DNA (e.g. breast cancer). - Faulty DNA mismatch repair (e.g. colon cancer). - Impaired nucleotide excision repair (e.g. Xeroderma Genetic Alterations and Cancer Cell Immortality Normally progressive shortening of telomeres limits the number of divisions of a cell to about 50 to 70 (senescent cell apoptosis). Tumor cells overcome this limitation by activating telomerase, which replaces the telomere segments that are lost during each cell division. This uninhibited division allows the tumor to become large, continuously replicating the DNA, which accumulates additional mutations that can