Cancer Genetics Chapter 11

Cancer Overview

• Cancer is a prevalent and deadly disease affecting millions worldwide, accounting for approximately one in four deaths.
• More than half of the population is expected to be diagnosed with invasive cancer in their lifetime.
• Cancer arises from a combination of environmental exposures and genetic mutations.

Tumorigenesis

• Tumorigenesis involves pivotal processes, such as:
  • Heightened growth signals
  • Resistance to growth-inhibiting cues
  • 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 (mesenchymal tissue, bone, muscle, or connective tissue, or nervous system tissue)
  • Carcinomas (epithelial tissue, such as the cells lining the intestine, bronchi, or mammary ducts)
  • Hematopoietic and lymphoid malignant neoplasms (leukemia and lymphoma, arising 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 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.

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.
• Identification of individuals at elevated risk allows for more intensive screening of high-risk groups, leading to better prognoses, reduced morbidity, and mortality rates.

Environmental Considerations

• 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.
• Different populations exhibit varying cancer frequencies, suggesting environmental and genetic influences.

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:
  • Growth factors that transmit signals from one cell to another
  • Specific receptors for the growth factors
  • Signal transduction molecules that activate a cascade of phosphorylating reactions within the cell
  • Nuclear transcription factors
• Mutations can occur in any of the steps involved in regulation of cell growth and differentiation.

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.

Major Classes of Cancer Genes

• 1. Inhibit Cellular Proliferation: 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.
• 2. Activate Proliferation: Oncogenes
  • 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).
• 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.