Path: Carcinogenesis 2 Flashcards
Describe initiation in carcinogenesis.
exposure to a carcinogen that causes permanent DNA damage/mutations; this process is rapid, irreversible, and necessary but not sufficient for tumor formation
Describe promotion in carcinogenesis.
process of exposure to agents (promoters) that can induce tumors to arise from initiated cells by enhacning the proliferation of initiated cells; these changes don’t affect DNA directly and are reversible
What features do all initiating chemical carcinogens share?
they are highly reactive electrophiles that target DNA, RNA, and proteins; in some cases they can cause cell death
Describe the “memory” that initiated cells can have.
since initiated cells are those with nonlethal yet permanent DNA mutations, they will pass the mutations on to the daughter cells
Chemicals that can cause initiation of carcinogenesis can be classified into two categories; what are they and what is the difference between them?
direct acting and indirect acting; difference is that indirect acting carcinogens require metabolic conversion to their carcinogenic state
Name two categories of some very potent indirect chemical carcinogens and where they are commonly found.
- polycyclic hydrocarbons (fossil fuels, cooked fats, and smoked meat/fish)
- benzo[a]pyrenes (cigarettes)
True or false: most chemical carcinogens are direct chemical carcinogens.
False - most are indirect because most require metabolic activation
Most known carcinogens are metabolized by what enzyme?
CYP450-dependent monooxygenases
How do polymorphic genes contribute or form the basis of individual variation in metabolism?
polymorphic genes means that the metabolic enzymes they produce can have inherently different levels of inducibility and activity; this can vary into higher/lower susceptibility to cancer based on the rate at which different enzymes catalyze the conversion of carcinogens to ultimate carcinogens
What is CYP1A1 a good illustrative example for?
this CYP metabolizes polycyclic aromatic hydrocarbons, such as the benzo[a]pyrene found in cigarette smoke; smokers with a highly inducible version of this gene have a greatly increased risk of cancer over other smoker without the polymorphism
Aspergillus produces what infectious toxin?
aflatoxin B (also a carcinogen)
What is the connection between aflatoxin B and hepatocellular carcinoma?
aflatoxin B is associated with a unique mutation (G:C–>T:A transversion, arginine to serine substitution) in TP53 that leads to hepatocellular carcinoma; this particular mutation is rarely seen in liver cancers in places where aspergillus food contamination doesn’t occur
How are nitrites associated with cancer?
they are used to preserve food, and cause nitrosylation of amines in the food; the amines formed are suspected to be carcinogenic
What are the high-risk strains of HPV and what are they associated with higher risk of?
16 and 18; higher risk of SCC of cervix, anogenital region, and H&N
Which HPV types cause benign squamous papillomas, otherwise known as warts?
1, 2, 4, 7
Which are low-risk HPVs and what diseases are they associated with?
6, 11; genital warts
True or false: warts have high malignant potential
False (generally)
What is the genetic difference between benign warts and malignant cancers caused by HPV?
in benign warts the HPV genome is maintained in non-integrate, episomal form; in cancers the HPV genome is integrated into the human genome (this suggests integration is important for malignant transformation)
In what manner is HPV genome integrated into host chromosomes? How is the pattern of integration described?
the manner is random and the pattern in clonal
Cells in which the HPV genome has integrated show significantly more ____ ____ in the host DNA.
genomic instability
How does integration of the HPV genome lead to the overexpression of viral proteins E6 and E7?
integration interrupts the viral DNA within the E1/E2 open reading frame, leading to loss of the E2 repressor and subsequent overexpression of E6 and E7
Describe the activity of HPV viral protein E6 and how it explains the cancer HV causes.
E6 binds/degrade p53 and stimulates TERT; because there are polymorphisms in p53 - some are more susceptible to degradation than others; additionally some HPV strains’ E6 has higher affinity for p53 and that’s what makes them high risk
Describe the activity of HPV viral protein E7 and how it explains the cancer HV causes.
E7 binds RB and releases E2F, promoting progression through the G1/S checkpoint and the cell cycle; E7 also inactivates the CDKIs p21 and p27
What makes an HPV strain “high-risk”?
that HPV strain’s viral proteins have a higher affinity for the targets; for example: high-risk HPV E6 has higher affinity for p53 and degrades it more, hence higher risk for developing cancer from that strain
True or false: Infection with HPV itself is not sufficient for carcinogenesis.
True - other genetic co-factors and environmental factors are key players as well
The genetic damage that causes cancer can be big or small; describe the small and the big changes that can occur.
subtle may be point mutations; large may involve segments of chromosomes large enough to be detected in a routine karyotype.
Of the potential chromosome rearrangements, what is the most common?
chromosomal translocation
What are the two ways in which translocations can activate proto-oncogenes?
- promoter or enhancer substitution (typically with one that is highly expressed, so the protooncogene is now highly expressed)
- formation of a fusion gene that encodes a novel chimeric protein that has oncogenic properties
Deletions of chromosomal regions are associated with loss of TSGs, but how can they be associated with activating oncogenes?
could be a deletion that produces a fusion protein (ex: EML4-ALK –> lung cancer)
Where is the RB gene locus and what does RB deletion lead to?
13q14; retinoblastoma
Where is the VHL gene and what does VHL deletion lead to?
chromosome 3p; Von Hippel Lindau syndrome –> RCC
Amplification of an oncogene may produce up to how many copies of the oncoprotein in the tumor cell?
several hundred
What are two mutually exclusive patterns of gene amplification/expression?
- double minutes - extrachromosomal DNA
2. homogenous staining regions - amplified genes inserted into different chromosomal locations
The most important amplifications are ____ in neuroblastoma and ____ in breast cancers.
n-MYC; ERB-B2
The nuclei of cancer cells display abnormal morphologies that may take the form of…? (histologically)
- hyperchromasia
- chromatin clumping
- chromatin clearing (so-called vesicular nuclear chromatin)
Some cancer cells exhibit selective hypermethylation of the promoters of ________ that results in their transcriptional silencing.
tumor suppressor genes
CDKN2A is an example of a TSG hypermethylated in several cancers. Name the 2 tumor suppressors it encodes and their functions.
- p14/ARF –> enhances p53
- p16/INK4a –> enchances RB
Tumors commonly exhibiting abnormal DNA methylation might have mutations in genes encoding what proteins/enzymes?
DNA methyltransferases or other factors that influence DNA methylation
Describe the genetic basis of the changes in histones sometimes seen in some tumors.
As with changes in DNA methylation, the changes may be attributable to mutations in protein complexes that “write”, “read” and “erase” histone marks, or that position nucleosomes on DNA
The lineage-specificity of certain oncogenes and tumor suppressor genes has an ____ basis.
epigenetic
What does it mean for a cancer cell to be lineage-restricted?
that cell is expressing genes within epigenetic contexts to produce a pattern of expression that characterizes that particular cell type
Inhibitors of histone deacetylases (chromatin erasers that remove acetyl groups from histones) are approved for use in certain ____ tumors, and DNA methylation inhibitors are now being used to treat ____ tumors.
lymphoid; myeloid
What is the series of morphologically identifiable stages that most colon carcinomas evolve through?
colon epithelial hyperplasia; formation of adenomas; progressive enlargement of adenomas; malignant transformation of adenomas
What is the series of molecular identifiable stages that most colon carcinomas evolve through?
inactivation of APC TSG; activation of Ras; loss of TSG on 18q; loss of TP53
