Pre-Cancer: Molecular Basis of Cancer Flashcards
what is the pre-cancerous condition of the stomach that leads to gastric adenocarcinoma?
Atrophic Gastritis of pernicious anemia
what pre-cancerous condition leads to melanoma in the skin?
dysplastic nevus
Barrett esophagus leads to?
Adenocarcinoma of esophagus
H. pylori infection can lead to?
Adenocarcinoma of stomach MALT lymphoma (MALToma)
Chronic ulcerative colitis can lead to?
Adenocarcinoma of colon
Hep B, Hep C, cirrhosis can all lead to?
Hepatocellular carcinoma
Atypical ductal hyperplasia can lead to?
Adenocarcinoma of boob
Lichen sclerosis can lead to?
Squamous cell carcinoma of Vulva
Chronic cystitis can lead to?
Urothelial carcinoma of urinary bladder
RB1- predisposition for?
Retinoblastoma
p53- predisposition for?
Li-Fraumeni syndrome (multiple tumors)
APC- predisposition for?
Familial adenomatous polyposis
NF1, NF2- predisposition for?
Neurofibromatosis 1 Neurofibromatosis 2 (bilateral Schwannoma of acoustic nerve)
BRCA1, BRCA2- predisposition for?
Breast cancer, Ovarian cancer
MEN1, RET- predisposition for?
Multiple endocrine neoplasia 1 and 2
p16INK4A (CDKN2A)- predisposition for?
Melanoma
MSH2, MLH1, MSH6- predisposition for?
Hereditary non-polyposis colon cancer
Retinoblastoma
what is the two hit theory?
What is the MOA behind Retinoblastoma?
What are the clinical signs?
Predisposition for ___ in adolescents?
Loss of RB tumor suppressor gene on chromo 13. It is a malignancy of eye in children
“two-hit theory”
- one gene inactivated in germ cells, the other after birth.
- White pupillary reflex & visual loss
- Predisposition for Osteosarcoma in adolescence
Familial Adenomatous Polyposis (FAP). Leads to development of what?
Inactivation of APC tumor suppressor gene
Development of Colorectal carcinoma from malignant transformation of polyps by age 30
Multiple Endocrine Neoplasia
MEN II –> mutation of rET protooncogene
familial occurence is combination:
- medullary thyroid carcinoma
- bilateral pheochromocytoma
- hyperparathyroidism due to hyperplasia or tumor
Herditary Non-polyposis Colorectal Cancer (HNPCC)
- familial clustering of cancers at several sites
- colon cancers at young age (often R sided)
- DNA mismatch repair (MSH2 and MLH1 and MSH6)
“Cluster of genes, cluster of cancer”
Xeroderma pigmentosum
Mutated Nucleotide Excision Repair (NER) enzymes.
Defect in DNA repair of UV damaged skin
Predisposition to multiple skin cancers- Basal cell carcinoma, squamous cell carcinoma, malignant melanoma
excessive photosensitivity and 2000x increase in skin cancers
Ataxia-telangiectasia
Mutated ATM gene which usually repairs DNA damaged by ionizing radiation
Predisposition to lymphoma, leukemia, breast cancer
Bloom’s syndrome
Mutated BLM gene. DNA helicase family
Predisposition to lymphoma, leukemia
Fanconi’s anemia
Mutated FAC gene
Predisposition to lymphoma, leukemia and bone marrow aplasia
Breast/ovarian cancer
Inactivated BRCA1, BRCA2 genes
Familial melanoma
Mutated p16INK4A gene
Overexpression of PDGFB gene or TGF-alpha
Astrocytoma
Overexpression of HST1 gene
Osteosarcoma
Amplification of FGF3 gene
Stomach
Bladder
Breast
Melanoma
Overexpression of HGF
Hepatocellular carcinoma
Thyroid cancer
amplification of ERBB2 (HER) causes ____ cancer
Breast carcinoma
Point mutation of RET causes ________ cancers
Multiple endocrine neoplasia 2A and B
and
Familial medullary thyroid carcinomas
Translocation on ABL gene
CHRONIC myelogenous leukemia
Point mutation at ABL gene
ACUTE lymphoblastic leukemia
Point mutation at BRAF gene
Melanoma
What causes burkitt lymphoma?
translocaiton on MYC
What causes neuroblastoma?
Amplification of N-MYC
Point mutation in ____ gene is found in 15-20% of all cancers
RAS
t(9;22)
Chronic myeloid leukemia (CML)
ABL, BCR genes- forms Philadelphia chromosome
t(8;14)
Burkitt lymphoma
Overexpression of c-MYC, IGH
(overexpression of proto-oncogene M). You get “starry sky”.
t(14;18)
Follicular lymphoma
Overexpression of BCL2 (anti-apoptosis). results in immortality of B-lymphocytes
t(15;17)
Acute myeloid leukemia
PML and RARA genes
t(11;14)
Mantle cell lymphoma
Cyclin D1 and IGH genes
generalized non-tender lymphadenopathy in elderly male patient
t(11;22)
Ewing Sarcoma
FLI1 and EWSR1 genes
“X-ray tibia, onion-skin pattern, round-dark blue nuclei”
Presence of _____ in >90% of tumors
Telomerase
what skin condition leads to squamous cell carcinoma of skin?
actinic (solar) keratosis
what precancerous condition in the oral cavity leads to oral squamous cell carcinoma?
oral leukoplakia
what cancer is associated with the bronchial mucosa?
squamous cell carcinoma of lung. The precursor lesion is squamous metaplasia –> dysplasia
tubular/villous adenoma can lead to what cancer
adenocarcinoma of colon
endometrial hyperplasia can lead to?
adenocarcinoma of endometrium
a serous borderline tumor of ovary can lead to what?
serous papillary cystadenocarcinoma of ovary
inherited AR syndromes of defective DNA repair (4)
xeroderma pigmentosa
ataxia telangiectasia
bloom syndrome
fanconi anemia
familial cancers (2)
breast and ovarian
what are the 5 categories of oncogenes?
- GF (ex: PDGF, FGF)
- GF receptors (ex: EGF receptor)
- Signal transducers (ex: RAS, B-catenin)
- Cell cycle regulators (Cyclin D, CDK4, Cyclin E)
- transcription factor (i.e. C-MYC or N-MYC)
Point mutaiton of K-RAS causes ____
colon, lung and pancreatic cancers
point mutation of H-RAS causes ____
bladder and kidney tumors
Point mutaiton of N-RAS causes ____
melanomas, hematologic malignancies
List 4 growth factors?
PDGF-beta
FGF
TGF-alpha
HGF
List 4 GF receptors?
ERBB2/HER
RET
PDGFRB
KIT
List 3 signal transducers?
RAS (K, H, and N)
ABL (non-receptor tyrosine kinase)
BRAF (RAS)
List 2 transcriptional activators?
MYC
n-MYC
List 2 cell cycle regulators?
CCNDA1
CDK4
what proto-oncogene causes mantle cell lymphoma?
CCND1
what proto-oncogene causes melanoma?
CDK4
point mutation in BRAF leads to ?
melanoma
point mutation in RET leads to?
MEN 2a and B familial medullary thyroid carcinoma
point mutation in KRAS leads to? (kristen rat sarcoma viral oncogene homolog)
pancreas and colon cancer
RAS proto-oncogene MOA
When RAS is bound to GDP it is “OFF”
GF binds, GDP gets removed –> RAS-GTP = “active” and can send message to nucleus.
“GAP” GTPase associated protein helps shut down active form of RAS by converting back to inactivated RAS-GDP (cuts away phosphate).
in a mutant RAS, phosphate cannot be removed from active RAS by GAP.
APC
function? associated cancer?
prevents nuclear transcription. Tumore supressor gene.
familial polyposis coli (inherited mutation)
and
sporadic colon cancer (somatic mutation)
BRAC1 and BRCA2
function? associated cancer?
regulated DNA repair
breast and ovarian cancer
RB
function? associated cancer?
inhibits G1 to S
retinoblastoma and osteogenic sarcoma
NF-1
function? associated cancer?
encodes neurobromin 1 = GTPase that acts as negative regulator of RAS
neurofibromatosis type I
NF-2
function? associated cancer?
cytoskeleton protein involved in contact inhibition
Neurofibromatosis type II- bilateral Schawannoma of acoustic nerve (hearing disturbances)
P53
function? associated cancer?
inhibits G1 to S, repairs DNA, activates BAX (initiates apoptosis)
50% of all cancers
Li-Fraumeni
Oncogenesis in HPV
VHL
function? associated cancer?
ubiquitin-ligase complex and hypoxia inducible factor 1a (HIF1a)
Von Hippel Lindau disease, hereditary renal cell carcinoma, pheochromocytoma and renal cysts
PTEN
function? associated cancer?
regulates nuclear transcription
cowden syndrome, CARCINOMA OF ENDOMETRIUM, breast and thyroid
WT1
function? associated cancer?
Transcriptional activator of genes invovled in normal development of genitorurinary tissue
Wilms’ tumor
what is the main gene involved in neuroblastoma?
N-MYC
What is Trastumuzab (Herceptin) associated with?
it is monoclonoal Ab against Her-2/Neu for Breast cancer
What is the MOA of APC?
normal function: down-regulates Beta-Catenin and prevents its accumulation.
when APC is lost: B- catenin increases and it travels to nucleus where ther eis continuas WNT signaling causing FAP non-familial colorectal Cancer and sporadic adenoma
What is E-Cadherin?
it is a cell adhesion molecule that keeps eepithelial cells attached to each other.
for tumor to spread locally and metastasize it must detach.
associated with AD familial gastric carcinoma and sporadic carcinomas.
What is CDKN2A? (cycklin dependent kinase inhibitor 2A?
encodes 2 tumor suppressor genes (P16INK4a and ARF)
associated with AD famililal melanoma
what is RB?
tumor suppressor that inhibits movement from G1 to S phase
What is RB associated with?
retinoblastoma, osteogenic sarcoma, soft tissue carcinoma
What is the MOA of RB?
RB “holds” E2F = “hypophosphorylated state” and cell replication is preventated (i.e. cell can’t move from G1 to S).
RB gets phosphorylated by cyclin D/CDK4 which then releases E2F.
If RB gets mutated, E2F is free and cells can easily go from G1 to S and cause tumor.
What is Knudson’s 2 hit hypothesis
Both alleles of RB locus must be inactivaed.
40% of retinoblastoma are familial
1st hit = all somatic cells of body (one defective copy is inherited from affected parent and other copy is normal)
2nd hit =retinal cells (somatic mutation –> loss of normal RB gene –> retinoblastoma)
60% cases sporadic
cells homozygouse for mutant RB –> cancer
Recessive –> heterozygous cells are normal
P53 MOA
inhibits G1 to S, repairs DNA and activates BAX.
how many copies of the P53 must be knocked out for tumor formation?
both
Li-Fraumeni syndrome
increased risk of carcinomas/sarcomas– inherited p53 mutation
what causes oncogenesis in HPV?
viral proteins E6 and E7
bind to inhibit RB and p53
MOA of BCL-2?
stabilizes mitochondrial membrane so cytochome C can’t be released. If it is inhibited, cytochrome C can leak out of mitochondria and activate apoptosis.
Translocation 14:18 overexpresses BCL-2 which prevents apoptosis of B cells and prevents apoptosis of B cells (B cell lymphoma) follicular lymphoma.
Telomerase
limitless replicative potential. Normal somatic cells have 60 to 70 doublings.
telomerase is in over 90% tumors
