10/24 - Hereditary Cancer Syndromes (Darcy) Flashcards Preview

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The Human Genome and Cancer

- All cancer arises form genetic alterations
- Tumorgenesis is a multistep process
- Most cancer is NOT inherited
- About 5-10% of cancer is due to an inherited predisposition


List of common Dominantly Inherited Cancer Syndromes

- Von Hippel Lindau: VHL
- Familial Adenomatous polyposis: APC
- Hereditary nonpolyposis colorectal cancer (Lynch): MLH1, MSH2, MSH6, PMS2
- Multiple Endocrine Neoplasia Type 2: RET
- Cowden: PTEN
- Li-Fraumeni: TP53


Most cancer susceptibility genes are dominant with incomplete penetrance

- Penetrance is often incomplete
- May appear to "skip" generations
- Individuals inherit altered cancer susceptibility gene, not cancer


Genes Associated with Cancer Predisposition

- Tumor Suppressor Genes
- Oncogenes
- DNA-Damage Response Genes (e.g. Mismatch Repair)


Tumor Suppressor Genes

- The cell's brakes for tumor growth
- Cancer arises when both copies of the gene are mutated
- Control cell growth
- Loss of function can result in uncontrolled or abnormal cell growth or faulty apoptosis.
- Recessive at the cellular level



- Accelerates cell division or apoptosis fails
- Tumors arise when the gene is stuck in the "on" mode
- A single gene mutation is sufficient to cause tumorgenesis


DNA-Damage Response Genes (e.g. Mismatch Repair)

- Repair DNA
- Cancer arises when both genes fail due to accumulation of mutations in other important genes


The Cell cycle and cancer predisposition genes

- Oncogenes (between G1, cell growth, and G1, resting or S, synthesis)
- Tumor Suppressor genes; step before Synthesis
- DNA repair genes: between synthesis and G2



- highly conserved and tightly regulated genes that function to regulate the cell cycle progression, cell division and differentation


Oncogenes are activated ______________

- are activated proto-oncogenes which act through signal transduction or blunted apoptosis. Dominant at the cellular level


Mechanisms for Proto-Oncogene Activation

- Regulatory mutation
- Mutation
- Chromosome translocation, retroviral insertion or gene amplification


Examples of Chromosome translocation, retroviral insertion or gene amplification

- Chimeric protein (CML) t(9;22)
- Downstream of a strong promoter (Burkitt Lymphoma) t(8;14)


Genetics of MEN2 Syndromes

- RET proto-oncogene on chromosome 10
- Autosomal dominant transmission
- Mutated RET gene remains activated (stuck in the "on" position), leading to tumorgenesis


RET proto-oncogene on chromosome 10

- 21-exon gene codes for membrane-associated tyrosine kinase receptor
- Protein spans the cell membrane allowing it to interact with specific factors outside the cell and to receive signals that help the cell respond to its environment


Features of Multiple Endocrine Neoplasia Type 2A (MEN2A)

- Lifetime risks in patients who manifest clinical disease: Medullary thyroid carcinoma (95%), pheochromocytoma (~50%), hyperparathyroidism (20-30%)
- Skin lesions in some families


Features of MEN2B

- Early onset and aggressive MTC
- Pheochromocytoma
- Developmental abnormalities (mucosal neuormas, ganglioneuromatosis, marfanoid phenotype, megacolon)


Clinical Presentation of MTC

- Sporadic: unilateral MTC, no familial pattern, no associated abnormalities
- MEN2A: Bilateral MTC, familial pattern present, pheo & HPT are associated abnormalities
- MEN2B: Bilateral MTC, can have familial pattern or not, and associated abnormalities are mucosal neuormas, ganglioneuromatosis, marfanoid phenotype, megacolon)
- FMTC: Bilateral MTC, familial pattern present, no associated abnormalities


Hirschsprung Disease

- Autosomal dominant, recessive or sporadic
- 1 in 5000 live births
- Congenital lack of enteric innervation resulting in blocked intestines
- 30% penetrance
- 10-40% of patients have RET mutations
- Mutations cause inactivation or loss of RET function


Features of Familial Medullary Thyroid Carcinoma (FMTC)

- 4 or more family members with MTC
- No pheochromocytoma or parathyroid disease
- Later age at onset and indolent course
- Associated with specific mutations in RET gene


MEN2 Syndromes: key points

- MEN2 is a well-defined hereditary syndrome associated with RET gene mutations
- Benefit of testing: Prophylactic thyroidectomy in RET mutation carriers is thought to substantially reduce morbidity and mortality and identifies non-carriers in affected family
- Limitations: no detectable mutation in some families


The Two-Hit Hypothesis

- Tumor Suppressor genes
- First hit in germline; second hit = tumor


Genetics of FAP

- Autosomal dominant inheritance
- Caused by mutations in APC tumor gene on chromosome 5q
- Up to 30% of patients have de novo germline mutations
- Most families have unique mutations
- Most mutations are protein truncating
- Genotype/phenotype relationships


Important points on mutations in APC tumor gene on chromosome 5q

- helps control how often a cell divides
- how it attaches to other cells within a tissue
- helps ensure that the number of chromosomes in a cell is correct following cell division
- The APC protein associates with other proteins especially those that are involved in cell attachment and signaling (beta catenin)


Multi-Step Carcinogenesis (Colon Cancer)

- Normal epithelium and then the loss of APC
- to Hyperproliferative epithelium
- to Early adenoma
- Activation of K-ras
- to intermediate adenoma
- Loss of 18q
- to Late adenoma
- Loss of TP53
- to Carcinoma
- and other alterations to metastasis


Clinical Features of FAP

- Estimated penetrance for adenomas > 90%
- Risk of extracolonic tumors (upper GI, desmoid, osteoma, thyroid, brain, other)
- CHRPE may be present
- Untreated polyposis leads to 100% risk of cancer


Gardner's Syndrome: A variant of FAP

Features of FAP plus extraintestinal lesions:
- Desmoid tumors
- Osteomas
- Supernumerary teeth
- Soft tissue skin tumors


Attenuated FAP

- Later onset (CRC ~age 50)
- Few colonic adenomas
- Not associated with CHRPE
- UGI lesions
- Associated with mutations at 5' and 3' ends of APC gene


FAP: Key points

- CRC risk is virtually 100% in untreated FAP patients
- Genetic testing identifies most APC mutation carriers
- Endoscopic surveillance and prophylactic colectomy can improve survival in at-risk patients
- Noncarriers can be spared anxiety and the need for increased surveillance


Li-Fraumeni Syndrome

- Rare autosomal dominant syndrome caused by germline mutations in TP53 gene on chromosome 17 (critical role in determining whether DNA will be repaired or if the cell will undergo apoptosis. p53 is essential for regulating cell division and preventing tumor formation, "guardian of the genome")
- 50% risk of cancer by age 35
- Lifetime risk of cancer ~90% for women; ~70% for men
- Risk for multiple primary tumors


Classic tumor spectrum: Li-Fraumeni Syndrome

- Sarcoma
- Breast
- Brain
- Leukemia
- Adrenocortical carcinoma