Molecular Basis of Carcinogenesis Flashcards
Properties of Malignant Cancer Cells (8)
Altered morphology, contact inhibition, growth without attachment, indefinite proliferation, reduced need of growth factors, high saturation density, increased glucose transport, tumorigenicity
Multi-Step Process of Carcinogenesis
Normal -> increased proliferation -> early neoplasia -> progressive neoplasia -> carinoma -> metastasis
Progressive accumulation of many somatic genetic mutations, early mutations tend to be in tumor suppressors
Two types of genes mutated in cancer
Oncogenes: Qualitative or quantitative change in protein expression. Increase proliferation.
Tumor Suppressors: reduce mutations through DNA repair, cell cycle control, apoptosis. Decrease proliferation.
Cytogenetic Abnormalities Associated with Malignancy
Translocations: activate oncogenes or disrupt tumor suppressors
Loss of Heterozygosity: disruption of tumor suppressors
Aneuploidy: increased aneuploidy has poor prognosis
What causes LOH? (3)
Nondisjunction during mitosis, segregation during recombination, chromosomal deletion
Dominant Cancer Syndrome
Ex Retinoblastoma, FAP, BRCA1&2. Patient inherits one mutated Rb allele. Remaining Rb allele is sufficient to prevent cancer, but there is a greatly increased risk of cancer through sporadic mutation.
Recessive Cancer Syndrome
Xeroderma pigmentosum, Ataxia Telangiectasia, Bloom’s syndrome, fanconi’s congenital aplastic anemia
Retinoblastoma Gene Properties
Inhibits proliferation through sequestration of EF2
Attracts HDACs to reduce chromatin access
Hyperphosphorylated in dividing cells, hypo in non-dividing cells
Rb gene in the cell cycle
Sequesters EF2 TF so cell cannot move from G1 to S phase. Mitogens can cause expression of cyclin-D which activates dormant CDK-4-6 which causes cyclin-E expression which activates CDK2 which phosphorylates Rb and leads to EF2 release.
Hallmarks of a tumor suppressor gene
Reduces cell proliferation. Ex Rb prevents cell movement from G1 to S phase of cell cycle.
APC gene
Tumor suppressor. Binds free beta catenin in the cytosol (not bound to PM by E-cadherin) and prevents its translocation to nucleus. This prevents expression of proliferative protein c-myc
BRCA1
Tumor suppressor gene that regulates DNA checkpoints through DNA damage sensing. It is a scaffold for many DNA repair proteins including BRCA2 and RAD51. Increased DNA repair limits the proliferation of mutations.
BRCA2
Tumor suppressor. Interacts with RAD51 to assist with homologous recombination following DNA damage. Required for RAD51 movement to damage sites.
Why was p53 originally considered an oncogene?
Tumor suppressors mutations tend to homozygous in cancer whereas oncogene mutations tend to be heterozygous. p53 mutations can cause cancer with only 1 copy mutation so it was labeled oncogene.
However, this is due to a dominant negative mutation, where one mutated p53 subunit in tetramer negates function and has increased binding strength and affinity.
Why is p53 the guardian of the genome?
p53 is a transcription factor for 300+ proteins involved in DNA repair and apoptosis. It is mutated in 50% of cancers.
Cellular function of p53
Numerous stressors activate p53 by phosphorylating its N terminus and reducing its degradation. Acts as TF for many important DNA repair and apoptosis proteins. It also upregulates MDM2 which degrades p53
HPV pathogenesis
Increases E7 expression to inhibit retinoblastoma protein and E6 expression to inhibit p53
Discovery of Oncogenes
Peyton Rous and the cancer filtrate that caused sarcoma in chickens.
v-SRC
mutant RTK alters gene expression, causes sarcoma in chickens
v-ERB
mutant protein similar to EGFR, a RTK. Causes avian erythroblastosis.
v-ABL
codes for protein kinase (tyrosine).. Causes mouse Abelson Leukemia
v-MYC
usually fused to gag gene, causes neoplastic transformation
HER2
EGFR mutation in some breast cancers, over-expression. Treated with Herceptin, a MAB for the receptor.
BCR-ABL
Philadelphia chromosome (Chr9-22 translocation), creates fusion protein tyrosine kinase. Causes CML. Treated with Gleevec, a TKI that binds ATP site of BCR-ABL
Bioinformatics in Cancer treatment
Tumor DNA hybridized to standards of common mutations in specific cancer.
Cancer Properties (5)
Uncontrolled proliferation, De-differentiated, Invasive, Metastatic, Clonal Origin
P53 Mutations in Cancer
50%
Most common P53 mutation type?
75% missense
Where is p53 most commonly mutated?
DNA binding domain
Dominant Negative mutation
p53 forms as tetramer, one bad p53 in tetramer prevents function
Mutatnts tend to be more stable than wt p53
Virus Gag gene
Encodes internal virion proteins
Viral Env gene
encodes virus membrane glycoproteins
Viral Pol gene
encodes viral polymerase
EGFR mutation rate in breast cancer?
25%
