Hereditary Cancer Syndromes - Lecture 7

Question 1

Types of genes responsible for cell division

Answer 1

• Tumor suppressor genes - stops tumor growth (cancer results from both copies being mutated)
• Oncogenes - accelerates cell division (tumors arise when these genes are constitutively active, single mutation sufficient to cause disease)
• DNA damage response genes - “spell checkers” (tumors arise when both genes fail due to accumulation of mutations in other important genes)
• Proto-oncogenes - regulate cell division, cell cycle, and cell differentiation (oncogenes are active form of proto-oncogenes, mutations may cause proto-oncogenes to become constitutively active)

Question 2

Multiple Endocrine Neoplasia Type 2A

Answer 2

MEN2A
-RET proto-oncogene, chromsome 10, exons 10 and 11
-codes for membrane spanning tyrosine kinase receptor
High phenotypic heterogeneity
-Medullary thyroid cancer (very rare, very aggressive; 95% lifetime risk)
-Pheochromocytoma - often benign
-Hyperparathyroidism

Question 3

Multiple Endocrine Neoplasia Type 2B

Answer 3

MEN2B (up to 50% of mutations de novo)
-RET gene, exons 15 and 16
-childhood onset medullary thyroid cancer
-pheochromocytoma
Developmental abnormalities
-upturning of eyelids
-neuromas on tongue
-full lips
-mega colon
-Marfanoid phenotype

Question 4

Hirschprung disease

Answer 4

RET gene innervates the intestines/colon

• lack of innervation leads to intestinal block, poorly working colon
• 30% penetrance

Question 5

Familial Medullary Thyroid Carcinoma (FMTC)

Answer 5

RET gene - Exons 13, 14, and 15
Criteria:
-4 or more family members with medullary thyroid cancers
-NO pheochromocytoma or parathyroid disease
-Late age of onset

Question 6

Two hit hypothesis

Answer 6

In tumor suppressor genes, two mutated copies are required for tumor formation. The two hit hypothesis suggests that one copy is herditarily mutated and the other copy will be mutated by an environmental factor
-Cancer won’t typically be seen at birth in these genes, but will have an onset typically before 50

Question 7

Familial Adenomatous Polyposis (FAP)

Answer 7

APC - Chromosome 5q (up to 30% are de novo, most families have unique mutations, most mutations are protein truncating)
-Multi-step process to colon cancer formation
-Early polyps lead to mutations that cause colon cancer if not removed
-90% penetrance for adenomas
Symptoms:
-Adenomatous polyps
-Risk of extra-colonic (GI, desmoid, osteoma, papillary thyroid, brain) that don’t respond well to chemo and are more likely to recur with surgery
-CHRPE (congenital hypertrophy of the retinal pigment epithelium) may be present
-Untreated polyposis leads to 100% risk for cancer

Question 8

Gardener’s Syndrome

Answer 8

Symptoms of FAP plus extra-intestinal lesions

• Jaw osteomas
• Desmoid tumors
• Supernumerary teeth

Question 9

Attenuated FAP

Answer 9

• NO CHRPE
• Later age of onset for colorectal cancer
• Fewer adenomas
• Associated with mutations in 5’ and 3’ ends

Question 10

Li-Fraumeni Syndrome

Answer 10

TP53, Chromosome 17p

• 50% risk of cancer by age 35
• 90% lifetime risk for cancer for women
• 70% lifetime risk for cancer for men
• Sarcomas, brain, breast, leukemia, adrenocortical tumors account for 75% of all Li-Fraumeni cancers
• Can also get just about any cancer

Question 11

PTEN Hamartoma Tumor Syndrome

Answer 11

PHTS, PTEN, Chromosome 10
-90% penetrance by age 20
Cowden Syndrome:
-Cancers: Breast, uterine, follicular thyroid
-Macrocephaly
-Autism
-Mucocutaneous lesions (papillomas on face, lips, tongue)

Question 12

Von-Hippel Lindau Syndrome

Answer 12

VHL, Chromosome 3p

• 20% are de novo
• Retinal or CNS hemangioblastomas
• Pheochromocytomas - usually benign but because adrenal can cause high BP, panic attacks
• Renal, pancreatic, and epididymal cysts
• Abnormal growth of blood vessels
• Renal tumors

Question 13

HNPCC - Lynch Syndrome

Answer 13

Mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM)
-Microsatellite instability from template slippage
-IHC staining - stain only adheres when protein is expressed
Amsterdam criteria:
-3 or more relatives with an HNPCC tumor in family (one case must be first degree relative of the other)
-Two or more affected generation
-One CRC by age 50
-FAP EXCLUDED
Syptoms:
-CRC tumor by age 50
-Tumor is right-sided, ascending (proximal colon)
-May also see endometrial, skin, ovarian, or bile duct cancers
-Polyps have a faster pathway to cancer