Neoplasia 4 Factors Leading to Cancer/Carcinogenic agents Flashcards
chromosomal changes
chromosomal translocations
chromosomal rearrangement that activate proto-oncogenes? in what 2 ways?
ex disease? what is rearranged?
how does a translocation occur?
CML?
acute promyelocytic leukemia?
An exception with important clinical consequences is found in a form of leukemia called acute promyelocytic leukemia (APML). APML is virtually always associated with a reciprocal translocation between chromosomes 15 and 17 that produces a PML-RARA fusion gene (Fig. 7-41). How this fusion gene functions is now reasonably well understood.
- The fusion gene encodes a chimeric protein consisting of part of a protein called PML and part of the retinoic acid receptor-α (RARα). Normal RARα binds to DNA and activates transcription in the presence of retinoids. Among the RARα responsive genes are a number that are needed for the differentiation of myeloid progenitors into neutrophils.
- The PML-RARα oncoprotein has diminished affinity for retinoids, such that at physiologic levels retinoids do not bind to PML-RARα to any significant degree. In this “unliganded” state, it retains the capacity to bind DNA, but instead of activating transcription, it inhibits transcription through recruitment of transcriptional repressors. This interferes with the expression of genes that are needed for differentiation, leading to a “pile-up” of proliferating myeloid progenitors that replace normal bone marrow elements.
- When given in pharmacologic doses, all-trans retinoic acid binds to PML-RARα and causes a conformational change that results in the displacement of repressor complexes and the recruitment of different complexes hat activate transcription. This exchange overcomes the block in gene expression, causing the neoplastic myeloid progenitors to differentiate into neutrophils and die, clearing the marrow over several days and allowing for recovery of normal hematopoiesis. This highly effective therapy is the first example of differentiation therapy, in which immortal tumor cells are induced to differentiate into their mature progeny, which have limited life spans. It has also spurred efforts to develop drugs that target other nuclear oncoproteins, despite the inherent difficulty of the problem.
Deletions
associated with loss of?
gene amplification
leads to? result from? two mutually exclusive patterns seen?
2 important ex of amplifications?
chromothrypsis
what is it?
key concepts of genetic lesions in cancer?
epigenetic changes
important role in?
epigenetic alterations in cancers? 3
epigenetic.
what has an epigenetic basis?
therapeutic target why?
cancer exhibit what epigenetics?
noncoding RNAs and cancer
what is a miRNA? in cancer?
whats an onco-mIRs? important for? incancer
tumor suprresive miRs in what specific cancers?
tumor suppressive properties of mIR processing factors? important protein?
other noncoding RNAs?
molecular basis of multistep carcinogenesis
how do cancers get all of their hallmarks?
how many?
in experiment what ar ethe 5 mutations needed? (epithelial cells)
steps precancerous v?s adenocarcinomas
steps of mutations in colorectal cancer through adenoma-carcinoma sequence
steps in chemical carcinogenesis
3
i- results from? what happens
above causes what damage? this causes?
p- do what?
what if promoting agent comes first?
carcinogens are what type of molecule? targets are?
initiation types?
experimental data of initiators and promoters that will and wont cause tumors
Direct acting carcinogens
what are they?
strength? some important because they are? causes?
indirect acting carcinogens
what are they? other name? strength? ex?
most chem carcinogens require what to turn?
most are metabolized by?
example of susceptibility of a P-450 gene? protein involved? at risk for? other influences?
molecular targets of chem carcinogens.
cancer initiation how would this happen?
is there preference?
ex?
promotion of chem carcinogenesis
promoters are chem agents that cause what?
initiator as promoter?
classically?
Radiation carcinogenesis
what is it?
UV rays
who more at risk? type of cancer?
nonmelanoma cancer associated with? melanomas?
which UV is shitty? why not the other one?
carcinogenicity of this light is due to? leads to? repaired by?
disease if that is faulty?
ionizing radiation
what are these?
CT scans?
most likely cancers?
oncogenic RNA virus
what type of virus? what does it cause? location?
major target cell? infection via?
what leads to opportunistic infections?
does the virus have oncogene? what gene alows transforming activity? allows what? what hallmarks gained?
Oncogenic DNA viruses
what 5?
HPV what are the high risk types? types of cancer?
HPV genes go where? this interrupts what? where? loss of this leads to overexpression of?
oncogenic potential largely explained by?
oncogenic activities of E6? E7?
