Week 10: Genes and Cancer

Week 10: Genes and Cancer

• Cancer is a phenotype resulting from both environmental and genetic factors.
• Cancer is a group of diseases affecting multiple cells and tissues.
• Two key characteristics of cancer:
  • Uncontrolled cell division
  • Ability of cells to spread (metastasis)
• Improvements in medical treatments have increased life expectancy but also increase cancer risk.
• Cancer is a major cause of death in developed countries, with around 30% of deaths attributed to it in Australia.
• Age is the biggest risk factor for developing cancer.
• Risk increases with age, and early diagnosis leads to better treatment and outcomes.

What Causes Cancer?

• Cancer has a variety of causes, including:
  • Genetic predisposition
  • Mutagenic chemicals
  • Some viruses
  • Chromosomal changes
  • Environmental factors
  • Time (accumulation of mutations over time)
• Mutations are the starting point for all cancers.
• Most cancers are sporadic, arising from the accumulation of mutations over time, though environmental factors can accelerate this process.
• More than two mutations are typically required to develop cancer.

Some Cancers are Familial

• Some cancers run in families.
• These familial cases have identified cancer genes.
• These cases often involve inheritance of one mutated gene, with the normal gene mutating later—a process called loss of heterozygosity (LOH).
• Other mutations are also often needed for cancer to develop.

Inheritable Susceptibilities

• Specific genes associated with various cancers and their chromosomal locations are presented in a table. (The exact table is not provided)

Progression of Cancer

• Cancer starts in a single cell.
• Mutations accumulate over time.
• Cancer cells repeatedly divide.
• Cancer cells become more aggressive.
• Cancer cells can spread to new locations.

Types of Cancer

• Carcinoma affects tissues lining internal organs.
• Sarcomas affect connective or supportive tissue.
• Leukemia affects blood and blood-related cells.
• Lymphomas and myelomas affect the immune system.
• Brain and spinal cord cancers affect the central nervous system.
• Cancer types are also classified by location.

Some Mutations Disrupt the Cell Cycle

• Many cancers originate in epithelial cells, which are constantly renewed.
• Mutations can disrupt the regulation of the cell cycle, leading to uncontrolled cell division.

Cell Cycle Checkpoints

• Checkpoints ensure proper cell cycle progression, checking for internal and external conditions, size, nutrients, growth factors, and DNA quality.
• A primary checkpoint occurs early in the cell cycle determining whether to enter or halt in a state of inactivity (GO).
• DNA copy integrity and protein production are further assessed at other checkpoints.

Checkpoint Regulation Genes

• Tumor suppressor genes decrease or stop cell division, working mostly during G1/S or G2/M phases.
• Mutations in tumor suppressor genes can result in uncontrolled cell division.
• Proto-oncogenes start or maintain cell growth/division and are normally activated by signals—in cancer, these are often permanently switched on.

Retinoblastoma

• Retinoblastoma 1 (RB1) is a tumor suppressor gene.
• Mutations can lead to several different cancers, including retinal, bone, lung, and bladder cancers, and is commonly diagnosed in children between 1 and 3 years of age.

Retinoblastoma

• RB1 is on chromosome 13q1.
• Codes for pRB, a protein binding to transcription factor E2F.
• pRB activity regulates the cell cycle.
• Its inactivation allows cells to progress through the cell cycle even with DNA damage.

Ras Proto-oncogenes

• A family of proto-oncogenes that code for signal transducers.
• The RAS protein is important in cell signaling.
• Activating mutations in RAS lead to cancer.
• A single base mutation in the protein can cause cancer.

DNA Repair and Genome Stability

• Cancer often results from genomic instability, such as aneuploidy, loss of chromosomes, duplication, deletions, etc.
• Loss of DNA repair capacity leads to a progressive increase in mutations throughout the life cycle of a cancer.

DNA Repair Problems

• Damaged DNA repair genes can lead to uncontrolled cell growth and development.
• The accumulation of mutations within DNA affects the genetic stability of the cells.

Breast Cancer and DNA Repair Genes

• Mutations in BRCA1 or BRCA2 increase the risk of breast and ovarian cancer in females and prostate cancer in males.
• BRCA1 and BRCA2 are DNA repair genes, crucial for repairing double-strand breaks in DNA.

BRCA1 and BRCA2 DNA Repair Mechanisms

• Detailed descriptions of the mechanisms BRCA1 and BRCA2 use for DNA repair are given. (The description is too complex to fit a single bullet point.)

BRCA Mutations

• BRCA mutations account for a significant portion of hereditary breast cancers (15-20%) and a smaller portion of all breast cancers overall (5-10%).
• Frequency of BRCA mutations varies across different types of cancer (breast, ovarian, prostate). (Exact figures are presented in a table).

The Pathway to Colon Cancer

• Several mutations are required to develop colon cancer.
• Genetic and environmental factors are significant.
• Much of colon cancer is sporadic, though around 5% results from hereditary transmission.
• Key hereditary forms, including Familial Adenomatous Polyposis(FAP) and Hereditary Nonpolyposis Colon Cancer (HNPCC), are discussed.

FAP (Familial Adenomatous Polyposis)

• Accounts for around 1% of all colon cancers.

• Inheriting one mutated APC gene leads to a 100% lifetime risk of colon cancer.

• The APC gene is a critical tumor suppressor gene.

• Multiple polyps commonly appear from adolescence, and their accumulation and growth contribute to the development of colon cancer.

• Detailed description of FAP progression is given

• Mutations in additional genes beyond APC and KRAS are implicated.

HNPCC (Hereditary Nonpolyposis Colon Cancer)

• Mutation carriers of HNPCC genes have a high lifetime risk of developing colon cancer; diagnosis typically occurs between 40-50 years.
• HNPCC results from mutations in DNA repair genes.
• Yearly colonoscopies, genetic screening of family members, and early detection are key measures for managing individuals with HNPCC.

Chromosomal Rearrangements and Cancer

• Several cancers have linked translocation events involving different chromosomes.
• Translocations involving ABL and BCR, for example, are implicated in Chronic Myelogenous Leukemia (CML).
• Specific chromosome translocations are associated with several cancers. A table linking them is not included.

Chronic Myelogenous Leukemia (CML)

• Translocation between chromosomes 9 and 22 occurs.
• This forms the Philadelphia chromosome.
• The translocation leads to uncontrolled cell division.

Cancer is a Genomic Disease

• DNA sequencing, family studies, and genome-wide association studies (GWAS) identify cancer-driving genetic alterations.
• The goal is to compile a comprehensive cancer mutation catalog.

Better Identification of Cancer Genes

• Cancer gene identification in typical tissues allows for comparison with cancerous tissues.
• Studies have shown an average of 90 differences in gene mutations between normal and cancerous tissues.

Epigenetics and Cancer

• DNA and histone modifications can lead to cancer development.
• Epigenetic factors (e.g., methyl groups) influence gene activity.
• These factors can affect cell cycle control and contribute to uncontrolled and/or damaged cell proliferation.

Historical Cancer Therapy and Modern Approaches

• Historical methods included chemotherapy and radiation therapy, which were nonspecific and could harm normal cells.
• Modern approaches include focused therapies, such as immunotherapy and targeted therapy, as well as personalised medicine.
  • Immunotherapy helps the immune system recognize and attack cancer cells.
  • Targeted therapies use drugs to directly target specific cancer cells.
• These approaches provide a more personalized and efficacious approach to treatment.

Personalized Cancer Therapy

• Personalised cancer treatment aims to tailor medical interventions to individual patient needs based on genetic and molecular characteristics.

Targeted Therapy for CML

• The drug Gleevec targeted the BCR-ABL fusion protein preventing cell division in CML.

Zero Childhood Cancer

• A national clinical trial focused on childhood cancers in Australia.
• This initiative aims to identify and monitor minute information about tumors.

Environmental Effects on Cancer

• Environmental elements (e.g., viruses, chemicals, radiation, diet, smoking, sun exposure) can damage DNA, which can be harmful.

Viruses and Cancer

• Some viruses cause 15% of cancers.
• HPV viruses are linked to cervical cancer.

Other Environmental Agents (Smoking)

• 75-85% of smokers develop cancer, with tobacco significantly increasing cancer risk.

Other Environmental Agents (Sunlight)

• Exposure to sunlight, including tanning beds, is a major risk for skin cancer, particularly for those with fair skin.

Reducing Cancer Risks

• Lifestyle modifications, such as avoiding tobacco, consuming a balanced diet, managing obesity risk, staying active, and minimizing environmental exposure are important in preventing many types of cancer.