(4.8) CANCER GENETICS

Cancer Genetics

• Cancer genetics examines inherited cancer risks, inherited forms of cancers, and hereditary cancer syndromes.
• Cancer development varies between sporadic and inherited forms.
• Hereditary disorders increase cancer risk, while hereditary syndromes are the primary cancer risk.
• Knudson two-hit hypothesis describes how cancer develops due to the loss of gene activity.
• Mutation types include somatic mutations, and loss of heterozygosity.
• Specific cancers have unique genetic changes associated. Examples include retinoblastoma, hereditary breast and ovarian cancer, Fanconi anemia, Xeroderma pigmentosa, and bladder cancer.
• Genes like tumor suppressor genes (Rb, BRCA1) and oncogenes (HRas) affect cancer development.
• Clinical features of hereditary cancers affect age of onset, multifocal/bilateral disease, higher cancer rates, and Mendelian inheritance.

Objectives

• Describe the differences in cancer risk between sporadic and inherited cancers, including clinical differences in presentation.
• Explain hereditary disorders with increased cancer risk and differentiate them from hereditary cancer syndromes.
• Describe the Knudson two-hit hypothesis in relation to cancer development.
• List and explain the mechanisms of gene activity loss following hereditary pathogenic variants.
• Match specific cancers or syndromes to corresponding genetic changes (e.g., Retinoblastoma, hereditary breast/ovarian cancer, Fanconi anemia, Xeroderma pigmentosa, and bladder cancer).
• Evaluate the consequences of gene alterations (tumor suppressor and oncogenes) on cancer development.
• Identify the clinical features of hereditary diseases and relate them to associated gene/pathogenic variant, and cancer risk.
• Compare/contrast BRCA1/2 and FANC mutations in cancer risk.
• List hereditary colon cancer forms, highlighting Lynch syndrome features, including microsatellite instability.
• Compare/contrast genetic and molecular tests in cancer risk assessment and diagnosis.

Sporadic vs Familial Cancer

• Sporadic cancer is most common and not inherited.
• Familial cancer has an increased risk in families, often inherited.

Hereditary Syndromes with Cancer and Hereditary Cancer

• Mutations of a gene can cause a wide range of consequences, including increased cancer risk in specific inherited/genetic syndromes.
• Cancer risk can be a secondary consequence.
• Cancer risk in syndromes are often presented as primary risk.

Features of Increased Cancer Risk/Cancer Predisposition

• Cancer predisposition is an increased risk due to inheritance of a mutation, most commonly associated with tumor suppressor genes.
• Regulatory signals ("STOP" signals) are important.
• Clinical presentations frequently include earlier age of onset, multifocal/bilateral disease cases, increase in rare forms of cancer, and inheritance patterns (typically dominant).

Knudson Two Hit Hypothesis

• Cancer development usually requires mutations in both alleles of a tumor suppressor gene leading to the loss of the function.
• In case of inheritance, the first hit is inherited, meaning the second hit occurs more readily, frequently earlier in life, when compared to sporadic forms.

Mechanism of Loss of Gene Activity

• Loss of heterozygosity
• Somatic Mutations
• Chromosomal rearrangements (breakpoints within genes/positions effects)
• Deletions
• Excessive methylation (promoter).

Tumor Suppressor Genes

• Loss of function in tumor suppressor genes often results in the development of disease.
• Often, additional mutations are required to develop cancer.
• Inherited mutations often represent nearly 100% risk of developing cancer.
• Environmental factors also play roles in the development of cancer.

Retinoblastoma

• Describes a childhood tumor of the retina.
• Inherited form manifests earlier and affects both eyes.
• Sporadic form affects only one eye.

Hereditary Breast and Ovarian Cancer (HBOC)

• 60-75% of inherited breast cancer cases is attributed to BRCA1/2 mutations.
• Multiple breast tumor types (DCIS, invasive ductal, and invasive lobular) can occur.
• Lifetime risk of breast cancer is 50-80% in families with multiple cases before 60.
• Risk is lower if only one family member has been diagnosed before 50.

Genes Associated with Breast Cancer Risk

• Several genes are associated, including BRCA1 and BRCA2.
• Some genes are linked to increased risk for multiple cancer subtypes

BRCA1 and BRCA2 Role in HR Repair

• BRCA1 and BRCA2 play key roles in DNA repair pathways, particularly homologous recombination.
• Defects in these genes are highly associated with increased breast and ovarian cancer risks.

Breast Cancer Subtypes

• Breast cancers are classified based on phenotypic characteristics. Types include luminal A, luminal B, HER2-enriched, basal-like, and triple-negative.
• Various molecular subtypes exist.

Xeroderma Pigmentosum (XP)

• Individuals with XP highly susceptible to UV light.
• Increased risk of skin cancers (basal cell carcinoma, squamous cell carcinoma, and melanoma) and other malignancies.
• Affected children often present with skin changes and eye complications (such as cataracts) by age 15.

Lynch Syndrome

• Affects multiple genes (MLH1, MSH2, MSH6, PMS2, and EPCAM).
• Inherited/autosomal dominant mutation.
• Significantly increased risk of colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, and other cancers.
• Microsatellite instability is often present in Lynch syndrome cases.

Risk of Colorectal Cancer (CRC)

• Risk factors vary based on family history, particular genetic mutations, and individual cases.
• Common mutation types often include HNPCC and/or FAP.
• Rates differ in population and cases.

Colon Cellular Structure

• Description of colon cells, their types, and their function.
• Include descriptions of the protective layer and immune cells.

Colonoscopy and Polyp Removal

• Descriptions of colonoscopy procedures, including the removal of polyps (precancerous growths).

Molecular Profiling

• Provides cancer prognosis by evaluating cancer cell behavior/gene expression.
• Used to predict cancer recurrence, metastatic spread, and effective treatment options for cancer subtypes.

Recent FDA Approved Tests

• New tests use Next Generation Sequencing technology (NGS) to profile tumors.

Cancer Genetic Test Takeaways

• Predictive testing is available for inherited cancer predisposition.
• Not all individuals need the type of genetic testing.
• Defining subgroups/cancer subtypes, and prognostic information is available through cancer cell tests.

This quiz focuses on cancer genetics, exploring the risks of inherited and sporadic cancers, as well as hereditary cancer syndromes. You'll learn about the Knudson two-hit hypothesis, mutation types, and specific genetic changes associated with various cancers. Test your knowledge on cancer-related genes and their clinical implications.