Carcinogenesis

Question 1

Properties of transformed cells

Answer 1

Altered morphology
Loss of contact inhibition
Anchorage independence
Immortalization
Reduced requirement for mitogenic growth factors
High saturation density
Increased transport of glucose 
Sustained angiogenesis

Question 2

Phenotype of malignant cancer cells

Answer 2

Unresponsive to normal signals for proliferation control
De-differentiated
Invasive
Metastatic
Clonal in origin (derived from a single cell)

Question 3

Autosomal dominant cancer susceptibility - 5 examples

Answer 3

Familial Adenomatous Polyposis (FAP-APC gene)
Familial Retinoblastoma (RB gene)
Familial Breast and Ovarian Cancer (BRCA1 and BRCA 2)
Wilms Tumor Syndrome
Von Hippel-Lindau Syndrome (VHL gene)

Question 4

Autosomal recessive cancer susceptibility - 4 examples

Answer 4

Xeroderma pigmentosa (XP genes)
Ataxia-telangiectasia (AT gene)
Bloom’s Syndrome
Fanconi’s congenital aplastic anemia (FA genes)

Question 5

Familial Retinoblastoma

Answer 5

Autosomal dominant cancer susceptibility resulting from inherited heterozygosity in the RB tumor suppressor gene on 13q14, followed by LOH of RB gene in a single cell; often presents as bilateral retinal tumors and affected individuals are at high risk of recurrent cancers because every somatic cell has lost 1 copy of RB

Question 6

Normal function of RB

Answer 6

RB is an inhibitor of cell cycle progression. Growth factors activate TM growth factor receptors (EGFR) which stimulate production of cyclin D; cyclin D binds CDK4,6 which activate production of cyclin E; cyclin E binds CDK2, which phosphorylates RB, inhibiting it and activating progression from G1 to S phase.

In retinoblastoma, there is no RB present to inhibit the cell cycle so proliferation occurs independently of cell-signaling.

Question 7

Loss of Heterozygosity

Answer 7

Results from duplication of an inherited mutant tumor suppressor gene during S phase, followed by a rare mitotic cross-over event between homologous chromosomes during M phase; in some cases, one daughter cell will end up with both functional allele copies and one daughter cell will end up with NO functional tumor suppressor alleles - this cell may become tumorigenic

Question 8

HPV

Answer 8

HPV is a small DNA virus that encodes several proteins including E6 and E7, which inhibit p53 and Rb, respectively

Question 9

Adenomatous Polyposis Coli

Answer 9

Results from inheritance of one defective copy of APC tumor suppressor gene on 5q22 followed by LOH; 90% of affected will develop colon cancer by age 50

Question 10

Wnt2-APC signaling pathway

Answer 10

Normally, WNT growth factor binds Frizzled cellular receptor and signals APC to release B-catenin in the cytoplasm; once released, B-catenin is translocated into the nucleus and binds TCF which signals transcription of c-myc, a TF that promotes cellular proliferation (oncogene)

In APC, APC protein is absent; as a result, B-catenin is constitutively active in the nucleus, promoting overexpression of the c-myc oncogene

Question 11

Familial Breast Cancer

Answer 11

Caused by inherited heterozygosity in BRCA1 or BRCA2 genes followed by LOH through mutation; normally, BRCA1 and BRCA2 function in the ATM/CHK2 DNA-damage check point & repair system

Question 12

p53

Answer 12

P53 is a tumor suppressor gene that is up-regulated in response to DNA damage; ATM/CHK2 phosphorylate p53 in response to cellular damage, activating p53 to bind DNA and promote transcription of p21, which inhibits progression of the cell cycle by inactivating S-CDK complexes

Missense mutation in p53 gene codes for a mutant protein that disrupts the normal tetramer structure of p53; tetramers with even 1 mutant subunit have decreased funciton in their DNA-binding domains

Question 13

Retroviral carcinogenesis

Answer 13

Retroviruses are ds RNA viruses that usually encode gag, env, and pol genes that code for viral proteins; retroviruses that contain an extra v-onc gene (ex: v-src in RSV) can transform normal cells

Question 14

3 examples of v-onc genes

Answer 14

V-SRC (found in Rous Sarcoma Virus) codes for a membrane-bound tyrosine kinase

V-ERB (found in avian erythroblastosis virus) codes for a tyrosine kinase protein that is similar in structure to EGFR

V-ABL (found in Abelson Leukemia virus) codes for a tyrosine kinase that is similar in structure to c-ABL, found in the BCR-ABL translocation in CML

Question 15

erbB2

Answer 15

ErbB2 encodes an integral membrane protein kinase and is amplified in about 20% of breast cancers; Herceptin is a monoclonal antibody specific for the overexpressed product of the ErbB2 oncogene

Question 16

CML

Answer 16

Caused by the BRC-ABL translocation (Philadelphia chromosome) resulting in constitutive activation fo the ABL tyrosine kinase; ABL can be inhibited by Gleevac, an ATP analogue.

Question 17

Phenotypic tumors of VHL

Answer 17

Hemangioblastoma (CNS or retinal angiomas)
Renal Cell Carcinoma
Pheochromocytoma

Question 18

VHL Mechanism

Answer 18

Under normal conditions, VHL binds hypoxia-inducible factor (HIF) subunit alpha and ubiquinates it for proteolysis; under conditions of hypoxia (or VHL absence) VHL does not ubiquinate HIF-a, which binds HIF-Beta and translocates into the nucleus to affect transcription of VEGF and PDGF

Question 19

Targeted therapies for VHL

Answer 19

VEGFR tyrosine kinase inhibitors

Sunitinib
Sorafenib

Question 20

Li-Fraumeni Syndrome

Answer 20

Caused by an inherited mutation in the p53 tumor suppressor gene, which predisposes the affected to many types of cancer which occur as a result of various LOH mechanisms

Diagnostic criteria:

1. Sarcoma diagnosed before 45 years old
2. 1st degree relative with any cancer under 45 years old
3. 1st or 2nd degree relative with any cancer under 45 years old or a sarcoma at any age

Question 21

Fanconi’s Anemia (FA)

Answer 21

Autosomal recessive disorder caused by homozygous loss of function in any of ~15 DNA repair genes, including BRCA2.

Pts present with progressively abnormal hematological findings, including thrombocytopenia, leukopenia, and bone marrow failure. Pts are also susceptible to many cancers, especially AML.