Neoplasia topics 2, A60-A71 Flashcards
A/60. Cytogenetic aberrations and the role of telomer in carcinogenesis
What are the major cytogenetic aberrations and how do the form?
Cytogenic aberrations: large scale or karyotypic changes in tumors
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Balanced translocations:
- B lymphocyte translocations generating lymphoma, MYC expression regulated under the Ig heavy chain, and
- B lymphocyte expressing the Bcl-2 antiapoptotic protein under the Ig heavy chain promoter.
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Fusion genes after translocations
- Philadelphia chromosome 9/22 translocation, creating BCR-ABL fusion protein, constituitively active tyrosine kinase activating growth pathways.
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Deletions
- Deleted region contains tumor suppressor genes or DNA repair genes.
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Gene amplifications
- amplification of protoncogenes, anti-apoptotic genes, inhibitors of tumor suppressor genes.
- HER2 estrogen receptor amplification in 30% of breast cancers
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Aneuploidy
- Full chromosome deletion or addition, from chromosomal non-disjunction during mitosis.
- Seen in almost ALL cancers, due to defective checkpoint mechanisms.
- Anaplasia and abberant mitotic spindles, resulting in abnormal numbers of chromosomes being taken to each cell during mitosis
A/60. Cytogenetic aberrations and the role of telomer in carcinogenesis
Telomeres and their role
- Telomeres are long repetitive sequences of DNA at the end of chromosome.
- Normally a peice of it is lost with every cell replication due to the unidirectional synthesis of DNA, and the lack of a primer on the lagging strand.
- Telomeres get progressively shorter, and very short telomeres are recognized by the DNA repair systems as double-stranded DNA breaks, and they induce cell cycle arrest via p53, Rb, and all of its many downstream targets.
- If these systems are inactive, the cell will actually join short teleomeres of two different chromosomes.
- Creating a big chromosome, with two centromeres.
- During mitosis, the centromeres both get pulled apart, and it causes new random breaks and deletions on both of them as they separate, leading to even further genetic instability, and eventual apoptosis with increasing division.
- Tumor cells usually have re-activated expression of telomerase, an embryonic enzyme in germ cells which re-synthesizes the repeitive sequences of the telomeres, preventing this, and immortalizing the cells.
A/61. Epigenetic changes (DNA methylaton, MicroRNAs) and role in carcinogenesis
DNA methylation, Histone modifications, and a few specific examples (of hypermethylated genes)
Cancers are generally characterized by
- Global HypOmethylation, permissive to increase metastatic options, and re-expression of favorable genes. Differentiation generally causes more restricted expression of the genome, Cancerous cells are more undifferentiated. Also contributes to the general chromosomal instability.
- selective hypermethylated, silenced genes. Tumor suppressor genes, DNA repair genes.
Histones:
- Methylation / Demthylation - May be activating or deactivating, but generally Histone methylation lowers the total charge on the hitone, causing looser binding, and more actively available DNA regions for transcription.
- Acetylation / Deacetylation - HATs generally relax the DNA, by adding a negative charge to the histone it binds even weaker, loosening things.
Specific cancers and genes.
- Hypermethylation and silencing of tumor suppressor genes:
- p14/ARF tumor suppressor silencing in stomach and colon cancers
- p16 tumor suppressor silencing seen in many cancers.
- Both are products of different reading frames of the same gene.
- MLH1 mismatch repair gene silencing in colorectal cancer
A/61. Epigenetic changes (DNA methylaton, MicroRNAs) and role in carcinogenesis
MicroRNAs
- Small, non-coding RNA segments.
- Transcribed in the nucleus as the primary transcript, pri-miRNA
- Processed in the nucleus to form pre-miRNA
- Transported to the cytoplasm, where it is cleaved by Dicer, generating mature double stranded miRNA that is 21-30 nucleotides long.
- The strands are separated and single strands are incorporated into RISC complexes. RNA-Induced Silencing Complex.
- They then bind their target mRNA, and with the RISC comlpex either cause cleavage of the mRNA or modification in a way to prevent mRNA transcription (covalently)
Oncogenes can activate the expression of miRNAs that will inhibit tumor suppressor genes.
A/62. Inherited cancer syndromes (autosomal dominant, recessive and familiar)
Autosomal dominant cancers: Deletions/defects of tumor suppressor genes.
Inhereitance of one defective gene, is an inherited Loss of Homozygocity, (LOH) means child only needs one more spontaneous hit to obtain the full inactivation and is drastically predisposed to cancers.
- APC, Adenomatous polyposus coli.
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Hereditary non-polyposis colon cancer syndrome.
- From defective mismatch repair systems.
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Rb gene, retinoblastoma, defective G1/S checkpoint.
- Retinoblastoma’s develop, often multiple loci, and bilaterally.
- At age 3-6.
- Also strongly increased risk of Sarcomas.
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P53 gene defects
- Increases general risk of all tumors by 50 times.
- Causes a wide spectrum increase of cancers that can be developed.
Autosomal recessive cancer syndromes:
- Xeroderma pigmentosa:
- Defect in Nucleotide Excision repair system.
- Increased risk of skin cancers caused by sun exposure
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Ataxia teleangiectasia:
- ATM gene defects,
- Part of the homologous repair system,
- Part of the activating system for p53.
- Causes Ataxia
- Increases susceptibility to breast cancers, lymphoma, hepatocellular carcinoma.
Familial cancers:
There are virtually familial forms of every single type of cancer, with many different specific genetic or epigenetic mechanisms involved. These are usually devined by early age onset. High concordance between siblings, and often cause bilateral or multifocal tumors.
Are probably caused by multifactoral gene defects.
A/63. Viral and microbal oncogenesis
Describe the oncogenic RNA virus example
Describe the general mechanisms by which DNA viruses can be oncogenic.
Oncogenic RNA viruses: HTLV1. Human T cell Leukemia Virus 1.
- A retrovirus with a single stranded RNA genome. (HIV also has two copies of single stranded RNA genome).
- Similar to HIV, it specifically targets T-cells, and its genome is incorporated into their own.
- Expression of the TAX viral gene, causes increased expression in an array of cytokines and cytokine receptors, via its interactions on NF-KB and other major transcription factors
- This generates autocrine signaling loops that are sufficient to stimulate polyclonal T cell proliferation
- The increased proliferation causes secondary mutations, that generate a monoclonal population of neoplastic T-cells (the first clone that obtained sufficient secondary mutations to become cancerous).
Oncogenic DNA viruses. HPV, EBV, Kaposi sarcoma herpes virus. Hepatitis B Virus.
Methods of viral genes causing cancer:
- Viral genome contains a direct oncogene
- Viral gene incorporates into the genome and either up regulates a host oncogene/proto-oncogene, or inhibits a tumor suppressor gene.
- Viral DNA does not integrate, but creates and Episome within the cell, and Episomal transcription occurs, generating the viral proteins that may be oncogenes or may activate/inhibit oncogenes in the host cell.
- The viral may have no direct oncogenic effect, but the chronic infection it presents generates lots of immune damage, DNA damage, and cell regeneration, increasing the accumulation of mutated cells.
Human Papilloma Virus, Epstein-Barr Virus. EBV.
A/63. Viral and microbal oncogenesis
What are the oncogenic DNA viruses?
HPV, EBV, Hepatitis B and C, and Kaposi Sarcoma herpes virus.
HPV:
- If it remains episomal, it will create benign squamous papillomas, (warts)
- If the DNA becomes integrated, it increases teh risk for cervial cancer, as well as oral, rectal cancer.
- HPV has 2 major oncogenic genes.
- E6, Inhibits p53 and also promotes BAX1 antiapoptotic gene
- E7 inhibits Rb, which thus disinhibits the transcription factor E2F, promoting cyclin E. It also stimulates CDK1 expression
EBV Epstein Barr virus.
- Burkitt’s lymphoma, Hodgkins lymphoma, Nasopharyngeal carcinoma
- Is also a herpes virus
- EBV integrates to the genome
- Has its LMP-1 viral oncogene, activates NFkB and JAK/STAT pathways
- Activates BCL-2 expression, inhibiting apoptosis
- Its EBNA-2 viral oncogene activates cyclin D and src transcription factor expression
- Expresses a viral cytokine that inhibits macrophage and monocytes activation.
- it is not sufficient to induce oncogenesis on its own, requires other mutations, but it increases cancer risk.
Hepatits B and C.
- oncogenic due to chronic infection and inflammation.
Kaposi Sarcoma
- Herpes simplex virus 8.
- Viral encoded G protein induces VEGF production, promoting vasculogenesis to the site.
- It also synthesizes a viral homolog of cyclin D, and inhibits p53
A/63. Viral and microbal oncogenesis
Microbial oncogenesis
H. Pylori infections
Increase risk of gastric adenocarcinomas and gastric MALT lymphomas. Due to the chronic inflammation again, damaged stomach lining and repair.
Increased aciditiy promoting metaplasia of the esophagus/duodenum.
Its viral CagA protein activates growth factor pathways.
A/64. Chemical and radiation carcinogenesis
Chemical carcinogenesis, types, stages
Chemical carcinogenesis.
The example of scrotal cancer in chimney sweeps at the period of he industrial revolution, chemicals accumulating in the pubic hair and causing cancer. Dr. Pott.
A huge number of chemicals are now designated as carcinogenic.
Ame’s test is used to screen for them. Uses special strains of Slamonella that require specific gene mutations to re-activate their ability to synthesize histidine and grow on a selective medium.
2 groups of chemical carcinogens:
1) Direct carcinogens
- These are usually weaker carcinogens
- They are used in chemotherapies
- They are: Alkylating agents, Bi-valent metal ions.
2) Indirect carcinogens
- Require metabolic processing to become more toxic/carcinogenic.
- By the P450 enzymes of the liver, individual gene polymorphisms make a person more or less susceptible to indirect carcinogens.
- Polyaromatic hydrocarbons/polycyclic hydrocarbons in cigarette smoke and smoked meat are indirect carcinogens.
Chemical carcinogenesis is a multi step process:
- Initiation - DNA mutation occurs
- Promotion - some environmental or signaling stimulus has to actually promote the proliferation of the cells, and stimulating the activation of the mutated/dysregulated pathway.
- Progression - Autonomous growth occurs, independent of the signaling.
A/64. Chemical and radiation carcinogenesis
Radiation carcinogenesis
Radiation carcinogenesis comes from either Ionizing or Non-ionizing radiation.
Ionizing: X, gamma, particle rays: Cause point mutations or strand breaks. The homologous repair system is crucial to fixing this damage, as is the mismatch repair.
Non-ionizing: UV-rays. These generate thymidine dimers, and the base-excision repair system is critical for fixing these mutations.
Non-melanoma skin cancers arise from chronic skin exposure, while melanoma is associated with individual instances of very severe sun damage.
A/65. Tumor antigens
how does the degree of tumor immune cell infiltration affect the prognosis?
High neutrophil and immune cell infiltration = better prognosis
Less = worse.
A/65. Tumor antigens
What are the major classes of tumor antigens? (6)
Tumor Specific antigens
- Do not exist in normal genome.
- BCR/ABL
- Immunogenic
Tumor Associated antigens
- Normal proteins expressed very highly in tumor cells,
- Can be associated with specific tumors.
- PSA. prostate specific antigen
- HER2 receptor
- MAGE1, an oncospermatogonal antigen. Since sperm dont have MHC1, these oncospermatogonal proteins are not processed and displayed by the MHC1 system, and these ones are not immunogenic either.
Oncofetal protein - alpha fetoprotein
- Proteins normally just expressed in development, but reactivated by the tumor cells.
- Alpha-fetoprotein
Virus associated antigens
- Protein products of viral infected cells, displayed by MHC1.
Cell differentiation antigens
- Surface markers used to identify the tumor’s origin.
- CD3,–> T cells
- CD20, B cells
Cell surface glycoproteins
- MUC-1 in breast cancers.
A/66. Tumor immunity and immune surveillance
Tumor immunity mechanisms of killing tumor cells
Antitumor immunity
Cytotoxic T lymphocytes: MHC1 presentation of abnormal tumor proteins
- TNF receptors and FasL expression by the T cells.
- perforin
- granzyme
NK cells:
- Respond to the absense of MHC1.
- Respond to Stress-Induced Antigens - expressed by cells with DNA damage.
- Cytotoxic granule release, also have perforin and granzyme
- other lytic enzymes
Macrophages and Neutrophils.
- IFN-gamma released by the T cells and NK cells, stimulates macrophages to release ROX and TNF-alpha cytokines.
- DAMPS expressed by the tumor cells also activate them.
Humoral mechanisms: are NOT a part of the endogenous anti-tumor response.
But synthetic monoclonal antibodies are useful medications against tumors, blocking specific tumor receptors important for their proliferation, such as recombinant anti-CD20 inhibiting B cell lymphomas.
A/66. Tumor immunity and immune surveillance
Mechanisms of immune system avoidance by tumor cells (5)
Natural selection of clones which do not express immunogenic antigens.
Reduced or lost MHC1 expression
Masking of antigens - High expresion of glycoproteins that can bind to or obscure the tumor antigens.
Expresion of anti-inflammatory cytokines, TGF-beta, IL-10
Expressing FAS-ligand and inducing T-cell apoptosis of activated T cells that are expressing the Fas-receptor.
A/67. Epidemiology of neoplasms
Worldwide rankings of mortality
Epidemiology of cancer types in men.
Worldwide mortality ranks: 1) infections 2) cardiovascular disease 3) tumors
Us/Europe 1) cardiovascular disease 2) tumors
Men: Highest morbidity
- Prostate
- Lung
- GI tract
Men: Highest Mortality
- Lung
- Prostate
- GI tract
Lung** incidence is **decreasing**. It is almost totally related to **smoking.
Prostate is slowly starting to decrease**, due primarily to **increased screening and early treatment.
Stomach cancer has dropped sharply over the last 50-60 years, mostly due to refridgeration, and meats no longer being preserved by smoking them.
