Biology Chapter 10: Genes and Cancer

What is Cancer?

• Cancer is a phenotype produced by the environment and a person's genotype.
• It is a group of diseases affecting many different cells and tissues in the body.
• Two main characteristics of cancer:
  • Uncontrolled cell division.
  • Ability of cells to spread (metastasis).

Causes of Cancer

• Several different causes:
  • Genetic predisposition.
  • Mutagenic chemicals.
  • Some viruses.
  • Chromosomal changes.
  • Environmental factors.
  • Time.
• Mutation is the starting point for all cancers.

Sporadic vs Familial Cancers

• Most cancers are sporadic (accumulation of mutations over time).
• Environmental factors can speed up the process.
• At least two mutations are required.
• Some cancers are familial (e.g., inherited breast cancer).
  • These have helped identify cancer genes.
  • Inherit one mutated gene, then the normal gene mutates too (Loss of Heterozygosity, LOH).

Inheritable Susceptibilities

• Examples of inherited cancer genes:
  • BRCA1 and BRCA2 (breast cancer).
  • FAP1 (familial adenomatous polyposis).
  • MSH2 (Lynch Syndrome I).
  • LFS1 (Li-Fraumeni Syndrome).
  • MEN1 (multiple endocrine neoplasia type I).

Progression of Cancer

• All cancers start in a single cell.
• Mutations accumulate over time until the cell becomes cancerous.
• Once formed, cancer cells divide continuously.
• Further mutations accumulate, making the cancer more aggressive.
• Cancer cells become invasive and can colonize new areas.

Types of Cancer

• Classified by:
  • Tissue or organ of origin (e.g., carcinoma, sarcoma, leukaemia).
  • Location (e.g., skin, lung, colon).

Cell Cycle Checkpoints

• G1/S Checkpoint: checks internal and external conditions.
• G2/M Checkpoint: checks that all DNA has been copied and any mistakes have been repaired.
• M Checkpoint: checks that chromosomes are lined up correctly.

Tumour-Suppressor Genes and Oncogenes

• Tumour-suppressor genes: decrease or stop cell division (e.g., RB1).
• Oncogenes: drive cell division in response to signals received (e.g., Ras).

DNA Repair and Genome Stability

• All cancers result in some form of genomic instability.
• Aneuploidy, loss of chromosomes, duplications, deletions, inversions, etc.
• Result from a loss of the ability to repair DNA damage.

Genes and Cancer

• Examples of genes involved in cancer:
  • Retinoblastoma (RB1).
  • Ras.
  • BRCA1 and BRCA2.
  • p53.

BRCA-Related Genome Instability

• BRCA1 and BRCA2 mutations account for 15-20% of hereditary breast cancers.
• Associated with increased risk of breast, ovarian, and prostate cancer.

The Pathway to Colon Cancer

• >6 mutations required to form cancer.
• Genetic and environmental factors.
• Mostly sporadic, ~5% inherited.

Familial Adenomatous Polyposis (FAP)

• Accounts for ~1% of all colon cancers.
• 100% lifetime risk of developing colon cancer.
• Associated with chromosomal instability.
• Requires 5-7 mutations.
• Order of mutations is important.

Hereditary Nonpolyposis Colon Cancer (HNPCC)

• Mutations in 7 different genes lead to HNPCC.
• Mutations in MSH2 and MLH1 cause 90%.
• Associated with increased risk of colon, stomach, pancreas, endometrial, and ovarian cancer.

Chromosomal Rearrangement and Cancer

• Several cancers are associated with translocations (e.g., Chronic Myelogenous Leukaemia (CML)).

Cancer is a Genomic Disease

• Accumulation of mutations throughout the genome.
• DNA sequencing, family studies, and GWAS are helping identify cancer-causing changes.

Better Identification of Cancer Genes

• Genes in normal tissue can be compared to genes in cancerous tissue.
• Identifies which mutations have occurred.

Epigenetics and Cancer

• DNA and histone modifications can lead to cancer.
• Allows cells to proceed through the cell cycle with damaged DNA.

Targeted Cancer Therapy

• Affects only cancer cells.
• Selectively blocks oncogenes and slows cell division.
• Two types of drugs – small molecules and monoclonal antibodies.

Environmental Effects on Cancer

• Viruses, chemicals, radiation, diet, smoking, sun exposure, etc. can all damage DNA.

Viruses and Cancer

• 15% of cancer associated with viruses.
• Examples: HPV16 and HPV18 causing cervical cancer.

Other Environmental Agents

• Smoking: 75-85% of smokers develop cancer.
• Sun exposure: 95-99% of skin cancers.

Reducing Your Risks

• Various ways to reduce the risk of cancer.