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Oncology -Bowel Cancer Family History
I. Recognizable Syndromes & Polyposis:
I. Recognizable Syndromes & Polyposis:
- Increased risk can stem from identifiable syndromes characterized by polyp presence.
- Genetic testing is effective in identifying causative mutations in most cases.
- Key Syndromes & Polyposis:
- FAP (Familial Adenomatous Polyposis): Classically >100 bowel polyps. Autosomal dominant; mutations in the same gene as attenuated FAP, differing in mutation site and phenotype.
- Attenuated FAP: <100 polyps, later onset, high bowel cancer risk, and risk for upper gi malignancy. autosomal dominant, same gene as fap.< />pan>
- MYH-associated polyposis: Autosomal recessive; predisposition to adenomatous bowel polyps; often presents with sibling history of bowel cancer. Testing focuses on two common MYH gene mutations.
- More common than recognizable syndromes.
- Characterized by: Familial aggregation of bowel cancer with fewer polyps.
- Genetic basis: Primarily due to mutations in mismatch repair genes (MLH1, MSH2, MSH6, PMS2). Defective DNA repair leads to increased mutation rates and faster cancer progression.
- Microsatellite instability (MSI): A laboratory finding in tumor tissue indicating a likely mismatch repair gene mutation. Used in risk assessment.
- Family History Assessment: Crucial for determining risk level. Factors considered:
- Low Risk: One affected relative >45 years; two relatives >55 years or on different sides of the family. Reassurance may be appropriate.
- Moderate Risk: One relative <45 years; two relatives (one <55 years); three affected at any age. tumor tissue analysis is warranted.< />pan>
- High Risk (Amsterdam Criteria): At least three individuals with bowel cancer across two generations; at least one affected individual <50 years; familial polyposis excluded.< />pan>
- Tumor Tissue Analysis (for moderate risk):
- MSI testing: Identifies potential mismatch repair gene mutations.
- Loss of expression of mismatch repair proteins: Helps determine which gene to analyze first.
- BRAF V600E mutation testing: Its presence suggests sporadic cancer (not germline mutation) and hypermethylation.
- Genetic Testing: Offered if mutation suspected (moderate or high risk). Guides surveillance strategies.
- Surveillance Strategies:
- Moderate risk: Colonoscopy at presentation and at age 55.
- High risk (known gene carriers): 2-yearly colonoscopies from age 25 or 35 (depending on family history).
- Additional Considerations: Families with known mismatch repair gene mutations should also consider surveillance for endometrial cancer (high risk) and other cancers (e.g., gastric cancer in those >50).
- Autosomal Dominant: One affected allele leads to the condition.
- Autosomal Recessive: Two affected alleles are required.
- Mismatch Repair Genes: Genes involved in DNA repair; mutations increase cancer risk.
- Microsatellite Instability (MSI): A marker of mismatch repair deficiency.
- Germline Mutation: A mutation present in all cells of the body, inherited from parents.
- Somatic Mutation: A mutation acquired during an individual's lifetime, not heritable.
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