Genes and Cancer - Part 1 Notes

Cancer as a Disorder of Somatic Cells

• Cancer is a disorder of somatic cells, which are all body cells except gametes (eggs and sperm).
• Cancer involves malignant tumors that invade other tissues and can be fatal.
• Malignant means "bad" in several languages.
• Age is a primary risk factor for cancer, as mutations accumulate over time.
• Heritable predispositions to cancer often show dominant inheritance patterns, where inheriting a mutated gene involved in cell cycle control can lead to cancer development.

Age and Cancer Risk

• The risk of cancer increases with age, particularly after age 30-35.
• Cancer death rates per 100,000 individuals are relatively flat until around age 30.
• Significant increases in cancer risk are observed in older age groups (e.g., 45-54, 55-64).

Characteristics of Cancer

• Uncontrolled Cell Growth:
• Benign tumors are non-invasive, encapsulated, slow-growing, and do not spread. They can often be surgically removed.
• Malignant tumors are cancerous, non-encapsulated, fast-growing, and can metastasize.
• Metastasis:
• Metastasis involves the spread of cancer cells from the primary tumor to other parts of the body via the circulatory or lymphatic systems.
• Metastasis is a sign of advanced cancer and makes it harder to control.

Causes of Cancer

• Mutations:
• Cancer is caused by mutations, which can arise from:
• Heritable predispositions:
• Inherited mutations in genes involved in cell cycle control or DNA repair.
• Spontaneous mutations:
• Errors during DNA replication by DNA polymerase.
• Environmental and behavioral factors:
• Exposure to toxins and behaviors like smoking.
• Inheritable vs. Sporadic Cancers:
• Most cancers are sporadic, resulting from accumulated mutations over time.
• Heritable cancers involve inherited mutated genes that predispose individuals to cancer.
• Mutations accumulate in somatic cells, with each cell division potentially introducing new mutations.

Accumulation of Mutations

• Normal cell divides, mutation occurs, daughter cells inherit mutation.
• Second mutation occurs later, subsequent cells inherit both mutations.
• Heritable predispositions mean inheriting one mutated gene involved in cell cycle control or repair.

Examples of Cancers with Heritable Predispositions

• Early Onset Familiar Breast Cancer:
• Mutations in BRCA1 and BRCA2 genes (DNA repair genes).
• Hereditary Nonpolyposis Colorectal Cancer:
• Inherited colon cancer requiring multiple mutations to manifest.
• Retinoblastoma:
• Cancer behind the eye due to a mutation in a tumor suppressor protein.

Cancer Cells vs. Healthy Cells

• Cancer cells exhibit uncontrolled cell division and odd shapes.
• Healthy tissues eliminate damaged cells through apoptosis (cellular suicide).
• Apoptosis involves chemical signals that cause a damaged cell to change shape, die, and be engulfed by macrophages.
• In cancer cells, this elimination process fails, leading to uncontrolled growth and mutated offspring cells.

Cell Behavior In Vitro

• Normal cells require growth factors to divide in a tissue culture flask.
• They grow and cover the bottom of the flask and stop in one layer.
• Cancer cells divide regardless of the presence of growth factors.

Tumor Suppressor Genes

• RB (mutated in 48% of cancers) and p53 (mutated in 50% of cancers) are tumor suppressor genes.
• They suppress the cell cycle and tumorous growth.
• They work inside the nucleus.

Proto-oncogenes

• Proto-oncogenes promote the cell cycle.
• Examples include RAS proteins (activated by mutations in 20-30% of cancers) and SOK kinase.
• RAS protein is normally active and inactive as part of cellular growth.

Cell Cycle Regulation

• Tumor suppressor proteins (RB, p53) regulate the cell cycle.
• Checkpoints:
• G1 checkpoint: determines if DNA should be duplicated; cells can exit into G0 phase if something is wrong.
• G2 checkpoint: between G2 and mitotic phase; prevents cell division if something is wrong.
• Mitotic checkpoint: ensures chromosomes are properly separated.
• Tumor suppressors act like brakes, stopping the cell cycle.

Role of p53

• p53 is a tumor suppressor activated by DNA damage, hypoxia, nutrient deprivation, oxidative stress, and oncogene expression.
• It can induce cell cycle arrest or apoptosis.
• p53 is involved in DNA repair, metabolism, and senescence.

Retinoblastoma (RB)

• RB mutation can lead to malignant eye tumors. Predisposition exists if a child inherits a mutated RB protein.
• Genetic checks can identify family history and probability of retinoblastoma.
• Early detection allows for eyeball removal or tissue treatment to restore eyesight.
• Hereditary vs. Sporadic Retinoblastoma:
• Hereditary retinoblastoma involves inheriting one mutated RB gene.
• Sporadic retinoblastoma requires two mutations over a longer time.
• The RB gene is on chromosome 13 (Q arm) and is often caused by deletion.

RB Gene Function

• RB protein inhibits transcription factor E2F from binding to DNA and facilitating transcription.
• If RB is phosphorylated, it releases E2F, allowing transcription to proceed and initiating cell division.

Overview of Cell Growth Regulation

• Growth factors (e.g., PDGF) bind to receptors on the cell surface.
• This initiates a cascade of events involving RAS protein.
• RAS activates kinases, which phosphorylate and activate other proteins.
• In the nucleus, RB binds to E2F, inhibiting transcription.
• RAS and kinase cascade lead to RB phosphorylation, releasing E2F and activating transcription.
  (Growth\,Factor + Receptor \rightarrow RAS \,Activation \rightarrow Kinase\,Cascade \rightarrow RB\,Phosphorylation \rightarrow E2F\,Activation \rightarrow Transcription)

Proto-oncogenes and Oncogenes

• Proto-oncogenes (like RAS) are like gas pedals, promoting cell cycle.
• Tumor suppressors are like brakes, inhibiting cell cycle.
• Normal RAS can be turned on and off, but mutant RAS is often always on.
• Normal growth is controlled via proto-oncogenes; RAS can be activated and inactivated.
• Mutant RAS is constantly active, leading to uncontrolled growth.

Mutations in RAS Protein

• Mutation at position 12 or 61 leads to mutant RAS protein remaining active.
• Neither mutant protein can be turned off, resulting in uncontrolled cell growth.

Anchorage Dependence and Density-Dependent Inhibition

• Anchorage dependence: cells must adhere to the bottom of the dish to grow.
• Density-dependent inhibition: cells stop dividing when they sense neighboring cells.
• Cancer cells ignore these rules and pile up on each other.

DNA Repair Genes

• Factors causing DNA damage: radiation, aging, UV light, chemicals, DNA polymerase errors.
• DNA repair enzymes fix errors and eliminate mutated base pairs.
• If DNA repair mechanisms fail, mutations accumulate, leading to uncontrolled cell growth.

BRCA1 and BRCA2

• BRCA1 and BRCA2 are DNA repair genes.
• Mutations lead to breast and ovarian cancer.

Development of Breast Cancer

• Initial abnormal growth in milk duct (benign tumor, encapsulated).
• Cancer cells invade neighboring tissue (malignant).
• Metastasis via circulatory or lymphatic system.