Cancer Biology Flashcards
Which genetic alteration is pancreatic cancer commonly a/w?
K-RAS at codon 12
Mnemonic: Pankreas
Which genetic alterations are cutaneous melanomas commonly a/w?
BRAF
Which genetic alterations are basal skin carcinoma and medulloblastoma commonly a/w?
PTCH
Mnemonic: BiTCcH
Which genetic alterations are thyroid cancers commonly a/w?
RET proto-oncogene
Which genes are a/w HNPCC?
- Mismatch repair genes (most common ones in bold)
– MLH1
– MSH2, MSH3, MSH6
– PMS1, PMS2
How does APC lead to polyps?
During differentiation from stem cells to crypt cells, APC-gene (aka β-catenin) gets turned on. This leads to a progenitor-like phenotype, causing abnormal, continued proliferation → polyp formation
Which famous syndrome is a/w p53 mutation?
- Li Fraumeni syndrome
– a/w breast, lung cancers, brain tumors, sarcomas
What is APC gene?
It is a tumor suppressor gene a/w colon (FAP), stomach, and intestine tumors.
Which CDKs phosphorylate RB1 protein?
CDK4/6
What other cancers are patients with familial retinoblastoma at risk for?
- Osteosarcomas
- Lung Ca
- Kidney Ca
- Bladder Ca
Is p53 inactivated by mutations only?
- No, it can be inactivated in two other ways:
– Viruses with proteins that inactivate p53
– Deletion in INK4A-ARF locus (common in cancers). The ARF (aka p19) region makes proteins that control p53 activation through MDM2 inactivation.
Where on DNA does p53 bind?
It binds to single-strand regions generated in damaged DNA, including those at telomeres.
Is p53 activated or inactivated by DNA damage?
Activated
Which downstream proteins does p53 activate?
p21, GADD45A, Bax, MDM2, PCNA, NFκB, and others.
How does p53 cause apoptosis?
It activates BAX, BID, and PUMA.
What is the function of MDM2?
- Negative self-regulator of p53
– Produced by p53 itself
– MDM2 binds to p53 to cause p53 degradation
What’s the first step for ATM after radiation damage to DNA?
- Auto-phosphorylation
- It then Phosphorylates a number of effector proteins
What is the function of ATM as it related to DNA repair?
It coordinates DNA repair by activating repair enzymes, including p53 through phosphorylation.
How does CHK2 interact w/ CDC25C to regulate the cell cycle?
- ATM activates CHK2
- CHK2 phosphorylates CDC25C phosphatase, inactivating it and inhibiting cell cycle
– CDC25C phosphatase normally removes inhibitory phosphates from cyclin-CDK complexes promoting cell cycle progression
How does p53 affect the G2-M transition?
p53 inhibits CDC25C → prevents G2-M transition.
What is the main mechanism of lymphoma cell death following radiation?
- p53-mediated apoptosis
- p53 mutations make them radioresistant
How do p53 mutations affect lymphocyte and thymocyte radiation sensitivity?
This mutation makes them more radioresistant.
What is the function of p53?
It is a tumor suppressor gene and plays a role in cell cycle regulation and apoptosis.
It also plays a vital role in DNA damage surveillance and almost all forms of DNA repair, including NHEJ, HRR, MMR, BER, and NER.
What is the function of BRCA1/2?
- Tumor suppressor genes.
- Play a role in homologous recombination.
Which cancer is a/w ABL1 mutation?
CHRONIC myeloid leukemia
What is the function of ABL?
It is an oncogene activated through chromosome translocation, forming BCR-ABL (9:22)
What’s the function of the PI3K-Akt-mTOR pathway? What’re the steps?
- Function:
– Anti-apoptosis
– Pro growth
– Pro angiogenesis
– Pro ribosome biogenesis - Some activators:
– VEGF
– IGFR
– HIF1 - Steps:
What is the function of PTEN?
- Tumor suppressor gene
- Counteracts PI3K
– PI3K: PIP2 → PIP3
– PTEN: PIP3 → PIP2
What’re some drugs that target the mTOR pothway?
- Everolimus
- Temsirolimus
What is the function of NF1?
It is a tumor suppressor gene a/w neurofibroma, and sarcoma.
What is the function of WT1?
- Tumor suppressor gene and a transcription factor
- When mutated or absent, it leads to the development of Wilms tumor.
Which main proteins regulate p53?
- ATM
- ATR
- DNA-PK
Approximately what % of cancers have p53 inactivation?
≥ 50%
Which domain of the p53 protein is acted on by viral inactivating proteins?
DNA-specific binding domain, the same region affected by mutations in the majority of cancers.
Which domain of the p53 protein is mutated in the majority of cancers?
DNA-specific binding domain
Which viruses contain proteins that inactivate p53?
- HPV (E6)
- Adenovirus (E1B55K).
- SV40 (large T)
Such proteins are absent in EBV virus.
Mnemonic: HAS proteins
Which kind of viruses contain proto oncogenes?
Retroviruses contain altered/mutated proto-oncogenes, usually acquired through their vertebrate hosts.
They were instrumental in the study of oncogenes.
What are exons? What are introns?
Exons → coding regions
Introns → non-coding regions
What are the most common ligands for EGFR?
- EGF
- TGF-α
What is EGFR? What are the different types of EGFR, its ligands, and its function?
- Cell surface tyrosine kinase receptor family. Members:
– EGFR (Her1; ErbB)
– EGFR2 (HER2; ErbB2)
– EGFR3
– EGFR4 - Activated by the epidermal growth factor (EGF) ligand and TGF-α.
- Enhances cell proliferation
– Pathway: See figure
What’re the molecules involved in the EGFR pathway?
- In order:
– EGFR
– Ras/Raf
– MAPKK (Mek)
– MAPK (Erk) - Figure:
Does EGFR exist as a homo or a heterodimer?
Homodimer
What mechanism normally inactivates tumor suppressor genes?
Loss of heterozygosity, since they act in a recessive manner.
Also inactivated by epigenetic silencing
What mechanism(s) activate oncogenes?
- Deletion
- Point Mutation
- Retroviral integration
- Gene amplification
- Chromosome rearrangement
What is the function of the promoter region?
Determines whether a gene is transcribed or not.
What is the function of BRCA1/2?
They are tumor suppressor genes.
They play a role in homologous recombination.
Why are levels of p16 elevated in HPV-driven cancers?
- Normal p16 negative feedback loop fails
– RB is inactivated by E7 and becomes insensitive to p16 levels
Which cancers are a/w p16-INK4A mutations?
- Pancreatic
- Esophageal
- Malignant Melanomas
PEMs
What is the role of p16-INK4A?
- Protein product of the p16 tumor suppressor gene
- Inhibits CDK 4/6:cyclin D/E complex
- Prevents RB phosphorylation
- Limits cellular proliferation
How is p53 usually modified?
- Phosphorylation
- Acetylation
What is the role of p14-INK4A?
- Inhibits MDM2-mediated degradation of p53
- ↑ p53 → cell cycle inhibition
Which cancer is a/w ALK translocation?
NSCLC
Which cancer is a/w amplified C-MYC?
- Burkitt Lymphoma
- Leukemias
Which cancer is a/w amplified L-MYC?
SCLC
Which cancer is a/w mutated Notch1?
T cell acute lymphoblastic leukemia
Which cancer is a/w KIT and/or PDGFR receptor kinase activations?
≥ 90% gastrointestinal stromal tumor (GIST)
Which drug targets the KIT and/or PDGFR receptor kinase activations?
Imatinib (Gleevac)
What is the oncogene addiction model?
Some tumors rely on the continued activity of a single oncogene for growth and survival.
Inactivation of this gene can halt the progression of such cancer.
What kind of enzymatic activity does telomerase exhibit?
- Reverse transcriptase.
- Telomerase complex has an RNA template from which a repeating TTAGGG sequence is reverse transcribed and added to the ends of the DNA.
- Mnemonic: Telomere adds TAGs to chromosome ends
Do all tumor cells have deficiences in DNA repair?
No
Why are levels of p16 elevated in HPV-driven cancers?
The p16 negative feedback loop fails. RB is inactivated by E7, and becomes insensitive to p16 levels.
Which notable chromosomal instability disorder is not a/w cancer?
Cockayne’s syndrome: stunted growth, impaired nervous system development, photosensitivity, and premature aging.
What causes Cockayne’s syndrome?
Deficiency in nucleotide excision repair, akin to what happens in XP.
Which cancer is a/w Bloom’s syndrome?
- Leukemia
- Lymphoma
Mnemonic: Bloom’s
Which cancer is a/w Fanconi’s anemia?
Leukemia
Which cancer is a/w Nijmengen breakage syndrome?
Leukemia
Which cancers are a/w ataxia telangiectasia?
- Leukemia
- Lymphoma
How is ATM activated following radiation?
- Autophosphorylation
– Inactive dimer to an active monomer
How does ATM interact with MDM2?
It phosphorylates MDM2, preventing it from inhibiting p53.