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Chromosomes Exam 2 > 10/24 - Hereditary Cancer Syndromes (Darcy) > Flashcards

10/24 - Hereditary Cancer Syndromes (Darcy) Flashcards

1
Q

The Human Genome and Cancer

A
  • 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
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2
Q

List of common Dominantly Inherited Cancer Syndromes

A
  • 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
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3
Q

Most cancer susceptibility genes are dominant with incomplete penetrance

A
  • Penetrance is often incomplete
  • May appear to “skip” generations
  • Individuals inherit altered cancer susceptibility gene, not cancer
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4
Q

Genes Associated with Cancer Predisposition

A
  • Tumor Suppressor Genes
  • Oncogenes
  • DNA-Damage Response Genes (e.g. Mismatch Repair)
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5
Q

Tumor Suppressor Genes

A
  • 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
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6
Q

Oncogenes

A
  • 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
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7
Q

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

A
  • Repair DNA

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

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8
Q

The Cell cycle and cancer predisposition genes

A
  • Oncogenes (between G1, cell growth, and G1, resting or S, synthesis)
  • Tumor Suppressor genes; step before Synthesis
  • DNA repair genes: between synthesis and G2
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9
Q

Proto-oncogenes

A
  • highly conserved and tightly regulated genes that function to regulate the cell cycle progression, cell division and differentation
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10
Q

Oncogenes are activated ______________

A
  • are activated proto-oncogenes which act through signal transduction or blunted apoptosis. Dominant at the cellular level
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11
Q

Mechanisms for Proto-Oncogene Activation

A
  • Regulatory mutation
  • Mutation
  • Chromosome translocation, retroviral insertion or gene amplification
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12
Q

Examples of Chromosome translocation, retroviral insertion or gene amplification

A
  • Chimeric protein (CML) t(9;22)

- Downstream of a strong promoter (Burkitt Lymphoma) t(8;14)

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13
Q

Genetics of MEN2 Syndromes

A
  • RET proto-oncogene on chromosome 10
  • Autosomal dominant transmission
  • Mutated RET gene remains activated (stuck in the “on” position), leading to tumorgenesis
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14
Q

RET proto-oncogene on chromosome 10

A
  • 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
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15
Q

Features of Multiple Endocrine Neoplasia Type 2A (MEN2A)

A
  • Lifetime risks in patients who manifest clinical disease: Medullary thyroid carcinoma (95%), pheochromocytoma (~50%), hyperparathyroidism (20-30%)
  • Skin lesions in some families
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16
Q

Features of MEN2B

A
  • Early onset and aggressive MTC
  • Pheochromocytoma
  • Developmental abnormalities (mucosal neuormas, ganglioneuromatosis, marfanoid phenotype, megacolon)
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17
Q

Clinical Presentation of MTC

A
  • 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
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18
Q

Hirschsprung Disease

A
  • 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
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19
Q

Features of Familial Medullary Thyroid Carcinoma (FMTC)

A
  • 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
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20
Q

MEN2 Syndromes: key points

A
  • 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
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21
Q

The Two-Hit Hypothesis

A
  • Tumor Suppressor genes

- First hit in germline; second hit = tumor

22
Q

Genetics of FAP

A
  • 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
23
Q

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

A
  • 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)
24
Q

Multi-Step Carcinogenesis (Colon Cancer)

A
  • 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
25
Q

Clinical Features of FAP

A
  • 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
26
Q

Gardner’s Syndrome: A variant of FAP

A

Features of FAP plus extraintestinal lesions:

  • Desmoid tumors
  • Osteomas
  • Supernumerary teeth
  • CHRPE
  • Soft tissue skin tumors
27
Q

Attenuated FAP

A
  • 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
28
Q

FAP: Key points

A
  • 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
29
Q

Li-Fraumeni Syndrome

A
  • 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
30
Q

Classic tumor spectrum: Li-Fraumeni Syndrome

A
  • Sarcoma
  • Breast
  • Brain
  • Leukemia
  • Adrenocortical carcinoma
31
Q

Other tumors found in Li-Fraumeni Syndrome

A
  • Colon
  • Lung
  • Melanoma
  • Ovary
  • Thyroid
  • Prostate
  • Pancreas
32
Q

PTEN Hamartoma Tumor Syndrome (PHS)

A
  • Incidence ~1/200,000
  • Penetrance >90% by the late 20s
  • PTEN gene mutations (chromosome 10q)
33
Q

PTEN gene mutations

A
  • chromosome 10q
  • Autosomal dominant tumor suppressor
  • Present in most cell types
  • signals apoptosis
  • evidence to suggest protein aids cell migration, adhesion and angiogenesis and may play a role in maintaining genomic stability
34
Q

PHTS

A
  • Cowden syndrome
  • Bannayan-Riley Ruvalcaba syndrome
  • PTEN-related Proteus syndrome
  • Proteus-like syndrome
  • phenotypic heterogeneity
35
Q

Cowden Syndrome Diagnostic Criteria

A
  • Two or more major criteria, one of which is macrocephaly or LDD
  • One major and three minor criteria criteria
  • Four minor criteria
36
Q

Cowden Syndrome: Pathgnomonic Features

A

Mucocutaneous lesions:

  • Facial trichilemmomas
  • Papillomas of face, lips, tongue, oral mucosa
  • Acral keratoses
37
Q

Cowden Syndrome: cancer risks

A
  • Perhaps as high as 85% lifetime risk for breast cancer with average age of diagnosis between 38 and 46
  • 35% thyroid cancer (follicular, rarely papillary and not medullary)
  • Uterine cancer not well defined (maybe 28%)
  • Skin cancers, renal cell carcinomas, and brain tumors are occasionally seen (male breast cancer has been reported)
  • colorectal cancer risk is thought to be somewhat increased
  • 85% of patients meeting clinical criteria will have a mutation identified
38
Q

Von Hippel Lindau (VHL) Genetics

A
  • VHL gene on chromosome 3p25 (forms a complex to aid in protein degradation)
  • Tumor Suppressor gene
  • Autosomal dominant inheritance
  • 20% of cases result from de novo mutations
  • ~100% mutation detection
  • Genotype/phenotype correlations
39
Q

VHL: Clinical diagnosis

A
  • Isolated case with 2 or more characteristic lesions present
    (2 or more hemangioblastomas of the retina or brain or a single hemangioblastoma with cysts in kidneys, pancreas, renal cell carcinoma, or pheochromocytoma)
  • An asymptomatic individual with a + family history of VHL
40
Q

VHL manifestations

A
  • CNS hemangioblastoma
  • Retinal hemangioblastoma
  • Pheochromocytoma
  • Cysts/tumors of kidney
  • Pancreatic cysts
  • Epididymal cysts
41
Q

VHL: Hemangioblastomas

A
  • Abnormal growth of blood vessels, may cause weakening and bleeding
  • Can grow in the eye (retinal): may be initial symptom, may be asymptomatic, sometimes causes vision loss
  • Can grow in the brain (80%)/spinal cord: can cause problems due to size - headache, vomiting, dizziness, balance; exert pressure on brain, spinal cord
42
Q

VHL: Adrenal glands

A
  • Pheochromocytoma
  • Rarely cancerous (1%)
  • Produce stress hormones (adrenaline and noradrenaline that help body respond to stress)
  • Symptoms include high BP, irregular heartbeat, panic attacks, fear
  • Should be removed
43
Q

VHL: Kidney symptoms

A
  • Usually VHL pts have multiple cysts
  • Tumors can be present (Renal Cell Carcinoma) ~40% of patients
  • Usually asymptomatic therefore screening necessary
44
Q

VHL: Other manifestations

A
  • Pancreatic cysts: rarely show symptoms, usually benign, may become very numerous
  • Endolymphatic sac tumors: tumor of the inner ear, can cause deafness of varying degress
  • Epididymal cysts: common in males, rarely cause problems
45
Q

VHL: Phenotypic Variation

A
  • Type 1: Retinal angioma, CNS hemangioblastoma, renal cell carcinoma, pancreatic cysts an neuroenocrine tumors
  • Type 2A: Pheochromoctoma, retinal angiomas and CNS hemangioblastoma; low risk for renal cell carcinoma
  • Type 2B: Pheochromocytoma, retinal angioma, CNS hemangioblastomas, pancreatic cysts and neuroendocrine tumor with a high risk for renal carcinoma (~70%)
  • Type 2C: Risk for pheochromocytoma only
46
Q

Mismatch repair genes

A
  • repair mismatches between complimentary DNA. Mutations in these genes result in increased point mutations and DNA instability of simple sequence repeats (microsatellite polymorphisms)
47
Q

Genetic Features of HNPCC

A
  • Autosomal dominant inheritance
  • Penetrance ~80%
  • Genes belong to DNA mismatch repair (MMR) family
  • Genetic heterogeneity (MLH1, MSH2, MSH6, PMS2, EPCAM)
48
Q

Immunohistochemistry staining for Lynch syndrome

A
  • Stains can be performed on tumor tissue for the four MMR gene proteins
  • Loss of protein expression can suggest a germline mutation and direct gene testing
49
Q

Amsterdam Criteria II (used for HNPCC)

A
  • 3 or more relatives with verified HNPCC tumor in family
  • One case a first-degree relative of the other two
  • Two or more generations
  • One CRC by age 50
  • FAP excluded
  • (failure to meet these criteria does NOT exclude NHPCC)
50
Q

What is key to diagnosing HNPCC?

A

Family history

51
Q

Clinical Features of HNPCC

A
  • Early but variable age at CRC diagnosis (~45 years)
  • Tumor site in proximal colon predominates
  • Extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous skin tumors
52
Q

HNPCC: key points

A
  • Genetic testing in HNPCC can identify mutation carriers
  • Genetic heterogeneity sometimes requires additional screening tests
  • Colonoscopic surveillance can improve survival in at-risk individuals
  • Noncarriers can be spared anxiety and the need for increased surveillance

Chromosomes Exam 2 (11 decks)

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