Foundations 2 Week 4 part 1
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What is the role of proto-oncogenes?
- Proto-Oncogenes block apoptosis, stimulate proliferation, increase blood supply, and maintain telomeres.
- Gain of function changes (point mutations, gene amplification, chromosome rearrangement) change proto-oncogenes to oncogenes.
How do sporadic tumors come about?
Sporadic cancers occur when a person with two functioning alleles has one cell that loses function in one allele. All of its daughter cells will then have only one functioning copy of the gene (ie, a tumor suppressor gene). Later, one of those cells loses function on the other allele, causing both genes to be abnormal. That cell then proliferates and becomes a tumor.
How do inherited cancers occur?
- Inherited cancers occur when a person is born with one mutated (non functioning) allele in all cells, and then one of those cells loses function in the other allele.
- Inherited cancers are more likely to occur earlier in life and in multiple tissues simultaneously. They may also arise at different times in the same tissue.
What is the Knudson Hypothesis?
The Knudson Hypothesis (two hits theory) states that the genetic code needs to be “hit” twice to disable both alleles. The first hit is intrinsic in all cells in inherited cancers.
What is Familial adenomatous polyposis?
FAP causes 1,000’s of precancerous growths and nearly 100% chance of colon cancer by age 39. It is caused by a mutation in the adenomatous polyposis coli gene (APC). APC binds and degrades ß-catenin (a transcription factor), preventing excessive transcription.
What are case control studies?
- Case control studies compare individuals with a disease to individuals without a disease (rather than exposure vs non-exposure in cohort studies).
- They have no random assignment (individuals or nature chooses exposure).
- These studies have a source cohort (population that give rise to the cases. Ie, if the cases are lung disease in Franklin County, OH, the source cohort is Franklin County, OH).
- In other words, we take a group (source cohort) and after some time split the group into cases and control depending on their outcomes.
Describe the strengths and weaknesses of case-control studies
- Advantages: Inexpensive, only a short time frame is required.
- Disadvantages: Is subject to bias
Explain how incidence and prevalence are involved in case-control studies.
They can be based on incidence or prevalence. Incidence requires waiting for new cases to show up, while prevalence may identify risk factors more related to survival rather than disease development (since patients with the disease are still living while others have died). Hence, incidence is usually used, but it takes more time.
How many controls should a case-control have?
- After having 4-5 controls per case, there is very little statistical advantage.
- Hence the ideal number of controls is # of cases X 4 or 5.
Explain how matching applies to case-control studies.
- Matching is selecting controls that are nearly identical to the cases.
- Individual Matching: aka match pairs. choose a control based on each case (ie, same gender, race, age, and other conditions).
- Group matching: aka frequency matching. Choose controls such that the proportion of characteristics is the same. Ie, same number of males, same age groups, same number of each race. This often requires that all cases are selected first (disadvantage).
- Matching should only be done on a few variables, and overmatching can result in a loss of precision. (disadvantages).
Compare selection bias and information bias in case-control studies?
- Selection bias: Control-selection bias: When the exposure in controls differs from the exposure in source cohorts. Case-selection bias: When the exposure in selected cases differs from the exposure in source cohort (ie, some cases did not arise from source cohort).
- Information bias: recall bias: Occurs when determining exposure is based on interviews or the patient’s memory. interviewer bias: Interviewers may phrase items differently to get different responses.
What is retinoblastoma?
Retinoblastoma is the first described tumor suppressor gene. 60% of retinoblastoma are sporadic (unilateral, onset 24-30 months), 40% are hereditary (unilateral or bilateral, onset 12 months, increased risk for secondary tumors later in life)
What is Familial adenomatous polyposis (FAP)?
Familial adenomatous polyposis (FAP) causes 100’s - 1,000’s of precancerous polyps and nearly 100% chance of colon cancer by age 40. It is caused by an inherited LOF mutation in the adenomatous polyposis coli gene (APC). APC binds and degrades ß-catenin (a transcription factor), preventing excessive transcription.
How does familial cancer work?
- Familial cancer suggests a clustering of cancers that probably occurred by chance due to a combination of genetic and non-genetic (i.e., environmental) factors that contributed to the development of cancers within a family.
- In such instances, where an alteration in a single major gene is not likely or is not identified, individuals may still face elevated risks of cancer.
What is Lynch Syndrome?
- An inherited LOF defect in one or more mismatch DNA repair systems (MSH2, MLH1, MSH6, PMS2).
- It is the most common cause of inherited colorectal cancer (80% risk, compared to normal 5-6% risk). Women are at risk for endometrial cancer.
What is Li-Fraumeni Syndrome?
An inherited LOF defect in the TP53 gene (p53 protein) resulting in tumors of the Brain, Blood, Bone, & Breast (leukemia, sarcoma of the bone/soft tissues, adrenocortical carcinoma). 50% risk of cancer by age 30, 90 % by age 70
What is caused by germline mutations of BRCA1 or BRCA2?
Hereditary breast/ovarian cancer syndrome: Germline mutations of BRCA1 or BRCA2 cause increased risk of breast (including in males) and ovarian cancer.
What is MYCN
A proto-oncogene/transcription factor for neural crest cell proliferation that is amplified in 30% of neuroblastomas.
What is caused by mutations related to the RET gene?
- The RET gene produces a receptor tyrosine kinase.
- LOF mutations cause Hirschsprung disease (an absence of enteric neurons along a variable region of the GI tract).
- GOF mutations cause different forms of Multiple Endocrine Neoplasia 2 (MEN 2A, 2B).
- MEN 2A: Results in a medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperthyroidism. 90% of MEN2
- MEN 2B: Results in earlier onset of MEN 2A features, neuromas of the mouth, and increased intestinal innervation.
What is MTC?
- Medullary Thyroid Cancer: A tumor of calcitonin-producing C cells of the thyroid.
- Remember, calcitonin decreases blood calcium by inhibiting osteoclasts, calcium absorption, and calcium reabsorption.
- Chemotherapy and radiation are ineffective against MTCs once the tumor extends through the capsule of the thyroid gland.
- RET gene testing is important for any individual with MTC, and for their family.
What is caused be HER2 amplification?
- HER2 (an Epidermal Growth Factor receptor, EGF) amplification causes breast cancer to aggressively grow.
- Detected by tissue immunohistochemistry or fish.
- These tumors can be targeted with Herceptin (trastuzumab).
What is the typical cause of Lymphomas and leukemias?
Lymphomas and leukemias are typically caused by an acquired chromosome translocation. The most well known is the Philadelphia Chromosome t(9;22) (BCR/ABL fusion gene) , activating ABL tyrosine kinase, causing common myeloid leukemia (CML).
What are the acronyms discussed in the cultural competency articulate module?
- CLAS standards: Culturally and linguistically appropriate services that are necessary to continue receiving federal funding.
- BATHE: Background, Affect, Trouble, Handle, Empathy
- LEARN: Listen, Explain, Acknowledge, Recommend, Negotiate
- ETHNIC: Explanation, Treatment, Healers, Negotiation, Intervention, Collaboration
What are initiators?
- Initiators are highly reactive electrophiles that attach to DNA nucleosides. When the damaged DNA is replicated, the new changes can be incorporated into the DNA strand and proliferated.
- Initiators can be direct acting compounds or indirect acting compounds (ie, require metabolic conversion in vivo first)
How do you calculate carcinogenic potency?
Carcinogenic potency = inherent reactivity + (metabolic activation / detoxification)
How do metabolic activation and detoxification occur?
Metabolic activation may occur through cytochrome p450 while detoxification may occur through glutathione-S-transferase.
Describe how promoters work and and describe how they work together initiators to cause cancer.
- Promoters induce cell differentiation, but are not mutagenic. Ie, estrogen is a promoter in breast cancer. Sustained proliferation enhances mutagenesis.
- Initiators followed by lots of promoters may result in tumor formation. Initiation or promotion by itself is not typically enough to cause cancer.
How do carcinogens work?
- Chronic exposure to carcinogens causes genetic and epigenetic changes. This can occur through...
- Alkylating agents (weak carcinogens that don’t require metabolic activation),
- polycyclic hydrocarbons (potent carcinogens that are p450-dependent oxidases),
- Nitrosamines (p450 yields highly reactive carbonium ions),
- Aflatoxin (produced by Aspergillus flavus, activated by p450 to produce epoxides. Causes TP53 gene mutation).
Describe the mechanisms by which inflammation is an etiology factor in carcinogenesis.
- Expression of chemokines attract specific WBC populations and promote the natural progression of the inflammatory response.
- Infections and chronic inflammations provide oxidative stress which can lead to initiation.
- COX-2 is overexpressed in multiple components of cancer.
- PGE2, growth factors, and cytokines act as promoters.
- Chronic Ulcerative Colitis causes a 5-7 times greater risk for colon cancer.
- Adenocarcinomas (polyps) indicate greater cancer risk as well.
Describe the mechanisms by which UV and ionizing radiation cause cancer.
- UVB radiation (290-320 nm) causes 6-4 photoadducts (CC → TT) and cyclobutane pyrimidine dimers (CPD)
- UVA radiation (320-400 nm) causes oxidative reactions, indirectly initiating cancer.
- UV is a complete carcinogen, both initiating and promoting.
- Ionizing radiation (x-rays, γ rays, α-particles, ß-particles, protons, neutrons) can cause cancer as well.
What is Xeroderma pigmentosum?
Xeroderma pigmentosum is an autosomal recessive mutation that inhibits UV ray repair and results in extreme UV sensitivity.
Describe Human papilloma virus (HPV).
- Human papilloma virus (HPV) is a DNA oncogenic virus. There are more than 70 types identified.
- Types 1, 2, 4, 7: Benign! associated with benign papillomas
- Types 6 and 11: Low Risk! cervical dysplasia (cervical intraepithelial neoplasia [CIN]) with low risk for developing squamous cell carcinoma
- Types 16, 18: High Risk! High grade dysplasia with high risk for developing squamous cell carcinoma of the cervix and oral cavity (types 16 and 18 with found in 85% of squamous carcinomas of the cervix). Inactivate p53 and Rb proteins.
How do HPV-16 and 18 work?
- HPV-16 and 18 integrate into the chromosome of cervical cells and then produce oncoproteins E6 and E7.
- E6 binds to p53, making it a target for proteasomal degradation.
- E7 attaches to pRB causing degradation as well.
- This prevents tumor suppression and increases the odds of cancer.
How does the Epstein Barr Virus (EBV) work?
- Epstein Barr Virus (EBV) predisposes the infected B cell to rearrange immunoglobulin genes, acquire the t(8;14), and releases cell from normal growth control
- LMP-1 upregulates bcl-2 a activates c-myc growth-promoting pathways
How does hepatitis B work?
- It is thought that hepatitis B viral infections cause chronic liver cell injury and regenerative hyperplasia.
- Another proposed mechanism is that the viral Hbx protein binds to and inactivates TP53.
What is HHV8?
KSHV/HHV8 is a herpesvirus / DNA oncovirus associated with Kaposi’s sarcoma and certain lymphomas in HIV-infected patients
HTLV-1 CD4 T cell leukemia/lymphomaOncogenic RNA virus Endemic in Japan and CaribbeanActivates IL2 and IL2R resulting in initial polyclonal proliferation of CD4 T cells
- HTLV-1 is a RNA virus associated with CD4 T cell leukemia/lymphomaOncogenic.
- It activates IL-2 and IL-2R resulting in initial polyclonal proliferation of CD4 T cells.
What is the effect of hyperplasia?
- Hyperplasia involves an increase in the number of cells, but typically not the size of cells.
- Hyperplasia is associated with an increased risk for neoplastic transformation.
- Hyperplasia key points
- Reversible process that may be physiologic or pathologic in etiology.
- •Hormone mediated
- –Physiologic – endometrial and breast changes
- –Pathologic – prostatic hyperplasia and hyperplasia and fibroadenoma of the breast, hyperplasia of the endometrium
- •Growth factor mediated
- –Physiology – wound healing, liver regeneration
- –Pathologic – immune response, inflammation
What are the effects of metaplasia?
Metaplasia is a reversible processes that is pathological in etiology. It occurs when one type of mature cell is replaced by another, such as when one type of epithelium cell is no longer appropriate for the environment, so it becomes another (eg, simple squamous becomes simple cuboidal).
What is Squamous metaplasia?
When glandular epithelium → stratified squamous epithelium. It can progress to squamous cell carcinoma.
What is glandular metaplasia?
When stratified squamous or transitional epithelium → glandular epithelium. Eg: Barrett’s esophagus, when acid reflux causes goblet cells to appear.
What is dysplasia?
- Dysplasia is an abnormality of development that generally consists of an expansion of immature cells with a corresponding decrease in the number and location of mature cells
- It may or may not progress to cancer. (ie, No invasion through the basement membrane = benign)
- Categorized from low to high grade (mild to severe) depending upon how much of the thickness of the epithelium is replaced by abnormal basal-appearing cells.
- Dysplastic changes that do not involve the full thickness of the epithelium may be reversible following removal of the inciting cause.
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