Genetic Basis of Cancer

Genetic Basis of Cancer

• Cancer is a disease of uncontrolled cell division, a genetic disease at the cellular level.
• Human cancers are categorized by the cell type that becomes cancerous; more than 100 types have been identified.
• Most cancers arise from a single cell, a clonal growth.
• Cancer development is a multistep process, starting as a benign, non-invasive growth, then progressing with genetic changes to become cancerous.
• Cancer can be staged based on its invasiveness; malignant is invasive, and metastatic spreads to a different body site.

Characteristics of Cancer

• Most cancers originate from a single cell with clonal growth.
• Cancer cells divide repeatedly forming a growth.
• Cancer begins as a benign growth, not invasive.
• Cancer's multi-step process involves additional genetic changes leading to cancerous growth.
• Cancers are staged based on:
  • Malignant, meaning invasive, and spreading to surrounding tissues
  • Metastatic, meaning spread to different sites in the body.

Causes of Cancer

• Radiation and many chemical carcinogens cause damage to DNA, leading to mutations.
• Other chemical carcinogens stimulate cell proliferation, contributing to cancer development.
• Viruses can cause cancer in humans and other species.
• Members of several families of tumor viruses directly cause cancer in both experimental animals and humans.

Tumor Viruses

• Specific virus families cause specific types of human cancers:
• DNA viruses: Hepatitis B viruses, SV40 and polyomaviruses, Papillomaviruses, Adenoviruses, Herpesviruses
• RNA viruses: Hepatitis C virus, Retroviruses

Oncogenes

• Specific genes called oncogenes cause cell transformation, providing insights into cancer's molecular basis.
• Studies of viral oncogenes led to the discovery of cellular oncogenes, involved in non-virus-induced cancers.
• The key link between viral and cellular oncogenes was identified through retroviruses.
• The first oncogene identified was the src gene of Rouse sarcoma virus. -Further studies have identified more than two dozen distinct oncogenes in various retroviruses.
• Proto-oncogenes are normal genes that can mutate into oncogenes, causing cancer. -Mutations in proto-oncogenes are typically dominant, where a mutated gene product promotes cancer. -Oncogenes are mutated forms of proto-oncogenes, that are either overexpressed or are mutated in structure, resulting in the promotion of cancer.

Tumor Suppressor Genes

• Tumor suppressor genes are involved in controlling cell growth, acting to inhibit proliferation and tumor development.
• The Rb gene, a prototypical tumor suppressor gene is identified by studies of retinoblastoma inheritance patterns.
  • Loss or inactivation of Rb and other tumor suppressors, including p53, lead to numerous human cancers.
• Tumor suppressor proteins act as inhibitors of cell proliferation and cell survival. -Rb, INK4, p53 proteins negatively regulate cell cycle progression. -p53 is essential in apoptosis, induced by DNA damage or other stimuli. Inactivation enhances tumor cell survival.

Rb Protein

• Rb protein controls cell division, regulating the transcription factor E2F. -Phosphorylation of Rb by cyclin-dependent kinases causes detachment from E2F. This allows E2F and therefore activating cell cycle genes. -Binding of Rb to E2F inhibits its function, and prevents the cell from progressing through the cell cycle. -In the absence of a functional Rb protein, cells can progress through the cell cycle continually.

p53

• p53 is a tumor suppressor gene involved in determining cell damage.
• If DNA damage is detected, p53 promotes cellular pathways, activating DNA repair, halting cell division, and inducing apoptosis (programmed cell death).
• About 50% of human cancers are connected with p53 gene defects.

Apoptosis

• Apoptosis is a process of programmed cell death, involving cell shrinkage, chromatin condensation, and DNA degradation.
• Caspases are proteases in apoptosis that act like "executioners".
• In apoptosis, the cell breaks down into vesicles, and the immune system eventually removes them.

Epigenetics

• Epigenetics is the study of heritable changes in gene expression that occur without changes to the underlying DNA sequence.
• Epigenetic mechanisms such as DNA methylation and histone modifications alter gene expression without changing the DNA sequence.
• Epigenetic factors are also linked to cancer.

Epigenetic Changes in Cancer

• Several chromatin modifications, DNA methylation, histone modification, chromatin remodeling are abnormal in cancer cells.
• Mutations in genes encoding chromatin-modifying proteins can cause inhibition, or increased function, influencing gene expression patterns.
• Environmental agents can alter chromatin modifying protein functions.

Environmental Agents that Alter Chromatin Modifying Proteins

• Some environmental agents directly alter chromatin-modifying protein functions.
• Scientists are still investigating whether epigenetic changes from environmental agents cause cancer.
• Various examples of environmental agents associated with cancer and epigenetic changes are listed in a table.

Cancer Treatments Aimed at Epigenetic Changes

• Researchers are researching drugs to affect DNA methylation and covalent histone modifications, to inhibit cancer cells.
• 5-azacytidine and decitabine are DNA methyltransferase inhibitors and are effective in diseases such as leukemia. However, mechanisms aren't entirely understood.