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Questions and Answers
Which human tissue is considered the most sensitive to radiation exposure?
What significant pattern was observed in cancer incidence following the Chernobyl disaster?
Which of the following therapies is based on the principle that radiated cancer cells cannot divide?
What was a notable health outcome for individuals involved in the early use of x-rays?
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What is a consequence of normal cells being included in the radiation field during therapy?
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What result can DNA hypermethylation lead to in critical tumor suppressor genes?
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Which enzyme is primarily responsible for demethylation of cytosine nucleotides?
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How does histone acetylation affect chromatin structure?
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What is the consequence of aberrant methylation changes during stem cell division?
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What percentage of CpGs are typically methylated in human adult cells?
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Which statement is true regarding post-translational histone modifications?
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What factor plays a role in the increase of tumor-cell heterogeneity in cancers?
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What is the primary physiological function of DNA methylation in gene expression?
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Which statement about microRNAs is true?
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Which of the following is classified as an initiator in the context of chemical carcinogens?
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What characterizes direct-acting carcinogens?
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Which of the following best explains the role of promoters in chemical carcinogenesis?
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Which mutation is characteristic of aflatoxin B1 exposure leading to hepatocellular carcinoma?
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Chemical carcinogens primarily contribute to cancer through which mechanism?
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What is the primary function of microRNAs in gene regulation?
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Which of the following scenarios exemplifies the concept of chemical initiation in carcinogenesis?
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Which statement is true regarding mutational hotspots in cancer?
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What distinguishes indirect-acting carcinogens from direct-acting carcinogens?
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Which infectious agent is associated with an increased risk of gastric adenocarcinoma?
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What consequence does immunodeficiency have on immune surveillance?
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Which of the following cancers is NOT caused by chronic viral infections?
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In which type of cancer is the Class I MHC antigen processing pathway particularly critical?
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Which of the following conditions is associated with an increased risk of cancer due to immunosuppression?
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What is a predominant effect of chronic inflammation in the context of cancer development?
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Which type of lymphoma is notably associated with chronic H. pylori infection?
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What is the main mechanism by which Hepatitis B and C contribute to hepatocellular carcinoma?
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What is the background radiation exposure equivalent for a full mouth series of dental x-rays?
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Which HPV type is primarily classified as high-risk for cancer causation?
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Which statement about the HPV vaccine is true?
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What is the primary mechanism by which high-risk HPV E6 contributes to cancer development?
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Which statement about EBV is accurate?
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What percentage of cancer cases caused by dental radiography could potentially be reduced by proper selection criteria?
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Which of the following types of cancer is NOT associated with HPV?
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How many different types of HPV have been described?
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Which is a consequence of HPV integrating into the host DNA?
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What is the translocation associated with Burkitt lymphoma?
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Study Notes
DNA methylation and demethylation
- Can cause aberrant silencing of tumor suppressor genes or overexpression of oncogenes
- Cytosine nucleotides can be covalently modified by adding a methyl group
- CpG = cytosine-phosphate-guanine
- TET2 enzyme → demethylation
- More potent in hyperglycemia
- Links higher cancer susceptibility in patients with diabetes to high blood glucose levels
Histone modifications
- Post-translational histone modifications can open chromatin for gene expression or close it for gene silencing
- Lysine rich histone ‘tails’ are a frequent site of post-translational changes
- Histone acetylation → open, active chromatin state
- Histone methylation → more diverse, complex effects
MicroRNAs
- Small RNA molecules (20-23 nucleotides in length) that act as post-transcriptional regulators of gene expression
- Base-pairing with complementary sequences of mRNA
- Silenced mRNA molecule → impaired translation into protein (e.g., tumor suppressor)
Carcinogens and their cellular interactions
- Chemical carcinogenesis
- Radiation carcinogenesis
- Microbial carcinogenesis
Chemical Carcinogenesis
- Mutations are generally random
- Mutations in RAS, TP53, or other important genes give the cell:
- Potential selective growth advantages
- Higher risk for malignant transformation
- Cigarette smoke is a major cancer risk factor: huge mutational potency
- Lung cancers in smokers -- 10x higher mutational burden than in non-smokers
- Accelerated rate of mutations → higher risk of acquiring driver mutations
Targets of chemical carcinogens
- Some carcinogens, because of their chemical structure, interact with particular DNA sequences/bases
- Mutations are clustered at ‘hotspots’
- Aflatoxin B1
- Produced by some strains of Aspergillus (mold)
- Common food contaminant in parts of Africa and Far East
- Results in increased risk of hepatocellular carcinoma in these regions
- Hepatocellular carcinoma worldwide: p53 mutations are generally uncommon
- Aflatoxin B1- associated hepatocellular carcinoma: Characteristic p53 R249S mutation (arginine in place of serine)
Chemical Carcinogens: Initiators and Promoters
- Chemical carcinogens may directly damage DNA or enhance proliferation of cells
- Initiation: genetic alteration of a cell exposed to sufficient dose of chemical carcinogen
- Permanent and irreversible
- Necessary for tumor formation
- Not sufficient for tumor formation
- Promotion: stimulation and alteration of an already initiated cell by a chemical carcinogen
- Cellular changes are reversible
- Not carcinogenic if the cell is not initiated
Chemical Carcinogens: Initiators
- All initiating chemical carcinogens are highly reactive electrophiles
- Electron-deficient chemicals that are attracted to electrons
- Electrophiles harvest electrons from (and mutate) nucleophiles in a cell: DNA, RNA, proteins
- Direct and indirect initiators:
- Direct-acting carcinogens don’t require metabolic conversion to become carcinogenic
- Indirect-acting carcinogens require metabolic conversion of pro-carcinogen to become carcinogenic
- Direct and indirect initiators:
Ionizing Radiation
- Electromagnetic (x-rays, γ rays) and particulate (α-particles, β-particles, protons, neutrons) radiation is carcinogenic
- Oxygen free radicals damage DNA
- Radiated cancer cells cannot divide → die
- Basis of radiation therapy
- Normal cells included in radiation field cannot divide → die
- Basis of side effects
- Some normal cells may incidentally acquire cancer-promoting DNA damage
- e.g., post-radiation sarcoma following radiation for breast cancer
- Radiated cancer cells cannot divide → die
Radiation Carcinogenesis
- Certain human tissues are more sensitive to radiation than others
- Bone marrow is most sensitive
- Thyroid is sensitive in young people
- Breast, lungs, salivary glands have intermediate sensitivity
- Any cell exposed to enough radiant energy can be transformed into a cancer cell
- Marie Curie and her daughter both died of leukemia
- Many individuals pioneering use of x-rays developed cancer
- CT scans
- 3x higher risk of leukemia in children after 2-3 scans
- 3x higher risk of brain tumors in children after 5-10 scans
Dental and maxillofacial X-rays
- Single PA/bitewing = 6 hrs of background radiation
- Full mouth series = 4.3 days of background radiation
- Panoramic Xray = 1.7 days of background radiation
- CBCT = 8 days of background radiation
- Approximately 330 million radiographs are taken annually in US
- 95 million FMX
- 19 million BWX
- Approximately 1000 cancer cases caused by dental radiography annually
- Proper adherence to selection criteria and use of collimation could reduce this number by 75%
Microbial Carcinogenesis
- Only a few potentially oncogenic DNA viruses, RNA viruses, bacteria
Human papillomavirus (HPV)
- Ubiquitous DNA virus infecting exclusively humans
- 120 different HPV types described
- Affects epithelial surfaces of skin and mucosa
- Verruca vulgaris
- Condyloma acuminatum
- Oropharyngeal cancer
- Cervical cancer
Human papillomavirus (HPV)
- HPV consists of a double-stranded, circular DNA genome containing 8 genes: E1, E2, E4, E5, E6, E7, L1, L2
- Certain ‘high-risk’ HPV types integrate into host DNA
- Instead of remaining in cytoplasm as an episome
- To integrate: circular DNA breaks → HPV integrates as a linear strand
- Breaks at part of DNA that encodes E2 → leads to viral overexpression of E6/E7, since E2 regulates E6/E7 expression
High-risk HPV E6:
- Degrades p53
- Stimulates TERT
High-risk HPV E7:
- Binds and inactivates Rb,
- Allowing progression through cell cycle
Human papillomavirus (HPV)
- HPV types (strains) are classified based on relative carcinogenic potential:
- High-risk: HPV-16, HPV-18, a few others
- Low-risk: all others
- High risk HPV causes essentially all cervical and most oropharyngeal cancers
HPV vaccine
- If the virus can’t enter a cell, it can’t cause cancer
- 3 vaccines approved by FDA to prevent HPV infection:
- Cervarix (HPV-16, -18)
- Gardasil (HPV-16, -18, -6, -11)
- Gardasil 9 (HPV-16, -18, -6, -11, -31, -33, -45, -52, -58)
- CDC recommends that 11-12 year olds receive two doses of HPV vaccine 6-12 months apart
Epstein-Barr virus (EBV)
- EBV associated with several cancers:
- Burkitt lymphoma (African form)
- B-cell lymphomas in immunosuppressed patients
- Some Hodgkin lymphomas
- NK/T cell-lymphoma
- Nasopharyngeal carcinoma
- EBV appears to act as potent mitogen
Burkitt lymphoma:
- t(8:14) translocation
Hepatitis B and C viruses (HBV, HCV)
- 70-85% of worldwide hepatocellular carcinoma is caused by HBV, HCV
- HBV is endemic in Far East and Africa
- Far East and Africa have highest rate of hepatocellular carcinoma
- Dominant oncogenic effect seems to be immunologically mediated chronic inflammation and liver regeneration
Helicobacter pylori
- Chronic H.pylori infection presents predominantly as antral gastritis
- Patients are at increased risk for:
- Duodenal or gastric ulcers
- Gastric adenocarcinoma
- MALT lymphoma
- Chronic inflammatory state → pro-carcinogenic effect
Cancer and Immunosuppression
- Immunodeficiency states are associated with increased cancer frequency:
- AIDS
- Immunosuppressed transplant recipients
- Patients on long-term pharmacologic immunosuppression
- Congenital immunodeficiency
- Immunodeficient patients have decreased immune surveillance
Cancer and Immunosuppression
- Immune surveillance: constant scanning of body for abnormal cells and their destruction
- Natural function of intact immune system
- Immunodeficiency → immune surveillance is not intact
- In immunosuppressed host, antigens (such as those found in tumor cells) don’t elicit appropriate immune response
- Favorable environment for infection
- Favorable environment for tumorigenesis
Cancer and Immunosuppression
- Class I MHC antigen processing pathway is critical in immune surveillance
- All nucleated cells express MHC I antigens on cell membrane
- Present endogenous/self antigens: Normal peptides, Viral peptides if cell is infected by virus, Abnormal/mutant proteins if DNA is mutated
- CD8+ (cytotoxic) T-cells bind MHC I
- Trigger apoptosis if endogenous/self antigens abnormal
- All nucleated cells express MHC I antigens on cell membrane
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Description
Explore the intricate relationships between DNA methylation, histone modifications, and microRNAs in the context of cancer biology. This quiz covers how these molecular processes influence gene expression and contribute to carcinogenesis. Test your knowledge on the role of these mechanisms in tumor suppression and oncogene activation.
