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

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Other tumors found in Li-Fraumeni Syndrome

- Colon
- Lung
- Melanoma
- Ovary
- Thyroid
- Prostate
- Pancreas


PTEN Hamartoma Tumor Syndrome (PHS)

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


PTEN gene mutations

- 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



- Cowden syndrome
- Bannayan-Riley Ruvalcaba syndrome
- PTEN-related Proteus syndrome
- Proteus-like syndrome
- phenotypic heterogeneity


Cowden Syndrome Diagnostic Criteria

- Two or more major criteria, one of which is macrocephaly or LDD
- One major and three minor criteria criteria
- Four minor criteria


Cowden Syndrome: Pathgnomonic Features

Mucocutaneous lesions:
- Facial trichilemmomas
- Papillomas of face, lips, tongue, oral mucosa
- Acral keratoses


Cowden Syndrome: cancer risks

- 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


Von Hippel Lindau (VHL) Genetics

- 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


VHL: Clinical diagnosis

- 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


VHL manifestations

- CNS hemangioblastoma
- Retinal hemangioblastoma
- Pheochromocytoma
- Cysts/tumors of kidney
- Pancreatic cysts
- Epididymal cysts


VHL: Hemangioblastomas

- 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


VHL: Adrenal glands

- 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


VHL: Kidney symptoms

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


VHL: Other manifestations

- 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


VHL: Phenotypic Variation

- 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


Mismatch repair genes

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


Genetic Features of HNPCC

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


Immunohistochemistry staining for Lynch syndrome

- 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


Amsterdam Criteria II (used for HNPCC)

- 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)


What is key to diagnosing HNPCC?

Family history


Clinical Features of HNPCC

- 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


HNPCC: key points

- 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