Molecular Basis of Cancer Flashcards
four classes of normal genes that are the principal targets of genetic damage
growth-promoting oncogenes
growth-inhibiting tumor suppressor genes
genes that regulate apoptosis
genes involved in DNA repair
mutator phenotype
a propensity to mutations, possibly due to damage in DNA repair genes
eight essential alterations for malignant transformation
self-sufficiency in growth signals
insensitivity to growth-inhibitory signals
evasion of apoptosis
defects in DNA repair
limitless replicative potential
sustained angiogenesis
ability to invade and metastasize
ability to evade the immune system
insertional mutagenesis
viral DNA is inserted near a protooncogene inducing a change in this cellular gene converting it into a cellular oncogene
herceptin
a monoclonal antibody drug that targets breast tumors which overexpress HER-2/neu
imatinib mesylate (Gleevec)
treatment for chronic myeloid leukemia, targets fusion protein BCR-ABL tyrosine kinase
ras oncogenes
most common abnormality of dominant oncogenes in human tumors
normally involve codons 12, 59, or 61
carcinomas have KRAS
bladder tumors have HRAS
hematopoietic tumors have NRAS
MYC oncogene
commonly found in tumors
dysregulation in Burkitt lymphoma
amplification in breast, colon, lung carcinomas
N-MYC amplification in neuroblastomas
tumor suppressor genes
proteins that regulate growth inhibition
both copies need to be lost for cancer to develop, so these are recessive cancer genes
INK4a/ARF in familial melanomas
TGF-beta in HNPCC
NF1 and 2 in neurofibromatosis types 1 and 2
VHL on chromosome 3 in renal cell cancers
PTEN on chromosome 10q23 in endometrial carcinomas and glioblastomas
WT-1 gene on chromosome 11p13 in Wilms tumor
DCC gene on chromosome 18q21 in colon and renal carcinomas
Cadherin family in breast, esophagus, colon, ovarian cancer
“two-hit” hypothesis
two mutations are necessary for cancer to develop, the first hit can be in genetically inherited mutations
the second hit happens in one of these mutant cells to generate cancer
common tumor suppressor genes
RB gene on chromosome 13q14, loss or mutation predispose it to the development of retinoblastoma and osteosarcomas
WT-1 gene in Wilms tumor on chromosome 11, vonHippel Lindau (VHL) gene in celar cell renal carcinoma
About how many genes have to be mutant before the malignant process begins?
loss of normal cell cycle control along with at least four regulators of the cell cycle
p53 gene
“guardian of the genome”, located on chromosome 17p13.1 and mutated in more than 50% of human tumors
acts as a “molecular policeman” and leads to cell-cycle arrest and initiation of apoptosis in response to DNA damage
tumors with intact p53 respond very well to radiation and chemotherapy
APC/beta-catenin pathway
individuals with mutated APC on chromosome 5q21 develop thousands of adenomatous polps in their colon at a very early age
bcl-2
anti-apoptotic gene, overexpressed in B-cell follicular lymphomas
in some cancers such as lymphomas, bcl-2 on 18q21 is translocated to the immuoglobin heavy-chain locus in 14q32, causing it to become overexpressed
angiogenesis
formation fo blood vessels around a tumor
stimulates tumor growth by secreting factors such as PDGF
tumor blood vessels differ from normal vessels in that they are tortuous and leaky
angiogenic switch
essential for tumor growth, involves increased production of angiogenic factors or loss of angiogenic inhibitors
area of targeteed treatment using inhibitors of angiogenesis such as endostatin
metastasis signature
tumor cells need the right combination of gene products to complete all the seps involved in metastasis
two phases of the metastatic cascade
invasion of the ECM and vascular dissemination
homing of tumor cells
invasion of the ECM
detachment of tumor cells from each other
attachment to matrix components
degradation of ECM
migration of tumor cells
attachment of tumor cells to laminin and fibronectin
protease degradation
escape from immune system by forming platelet aggregates in blood
“homing” of tumor cells
adherence of the migrating tumor cell to the endothelium and going through the basement membrane
CD44 adhesion molecule important
proteases also important for integration of the cell
chemokines and cytokines are important for location
important types of defeccts of DNA repair
mismatch repair, nucleotide excision repair, recombination repair
BRCA-1 and BRCA-2 genes
two genes associated with the development of breast and ovarian cancer
60-85% lifetime risk of development of breast cancer,a nd 15-40% lifetime risk for the development of ovarian cancer
gene is important for homologous recombination leading to DNA repair
adenoma-carcinoma sequence of colorectal cancers
the best example of a molecular model for multistep carcinogenesis
the buildup of mutations and lack of suppression leads to carcinoma
gatekeeper genes
oncogenes and tumorsuppresssor genes
caretaker genes
genes that do not directly control tumor growth bt affect genome stability such as repari genes
RET protooncogene
associated with MEN type IIA and IIB, familial medullary thyroid carcinoma and Hirschsprung disease
hereditary nonpolyposis cancer syndrome (HNPCC)
a condition of familial cancers of the colon that results from defects in DNA mismatch repair genes
hallmark of defective mismatch repair
microsatellite instability
diseases arising from defects in DNA repair by homologous recombination
ataxia-telangiectasia syndrome, Bloom syndrome, and Fanconi anemia
