Neoplasia Coursework Materials

What is cancer characterised by? abnormal and uncontrolled growth What is the balance of cell growth and uncontrolled cell growth or loss of a cell's cell death disrupted by? ability to undergo apoptosis most cancers result from mutations in In what cells can mutations result in can- somatic cells cer? some cancers are caused by mutations in germline cells What is cancer caused by? genetic mutations affecting genes such as proto-oncogenes, oncogenes, and tumour suppressors Describe malignant tumours. life-threatening fast growing capable of spreading by invasion and metastasis Describe benign tumours. slow growing less likely to come back do not spread to other parts of the brain or spinal cord What are the four stages of the cell cycle? G1 S G2 M What happens in G1? growth What happens in S? DNA synthesis What happens in G2? growth and preparation for mitosis What is a proto-oncogene responsible for? for making a protein involved in cell growth, division, regulation of programmed cell death, and inhibition of cell differentiation cell growth and development and for maintaining healthy tissues and organs How do proto-oncogenes cause cancer? a mutation occurs in the gene and it turns into an oncogene 1/9 it becomes permanently turned on What happens when a mutation occurs (gain-of-function mutation) in a proto-oncogene? the gene will then start to make too much of the proteins that code for cell growth What kind of mutation is a gain-of-function mutation? dominant means that only one copy of the gene needs to be mutated in order to start cancer What is a point mutation? this mutation alters, inserts, or deletes only one or a few nucleotides in a gene sequence, in effect activating the proto-oncogene What is a gene amplification mutation? this mutation leads to extra copies of the gene What is a chromosomal translocation mutation? this is when the gene is relocated to a new chromosomal site that leads to higher expression Are most mutations that cause cancer acquired or inherited? acquired Name examples of proto-oncogenes. Ras HER2 Myc Cyclin D What does Ras do normally? encodes an intracellular signal-transduction protein Ras is transiently activated and recruits Raf, to activate the MAP-kinase pathway to transmit growth-promoting signals to the nucleus What does Ras do when mutated? it leads to continuous stimulation of cells without any external trigger causing an uncontrolled growth-promoting signal What type of cancer does a point mutation in the Ras gene cause? pancreatic 2/9 What does HER2 normally do? this gene makes protein receptors that are involved in the growth and division of cells in the breast What mutation do many people with breast cancer have? gene amplification mutation in their HER2 gene, also known as HER2-positive breast cancer Burkitt's lymphoma What type of cancer does a mutation in occurs when a chromosomal translocathe Myc gene cause? tion moves a gene enhancer sequence near the Myc proto-oncogene What does Cyclin D normally do? to make a protein called Rb tumour suppressor protein inactive What cancer is usually associated with Cyclin D? tumours of the parathyroid gland Cyclin D is activated due to a mutation as a result, it can no longer do its job What happens when Cyclin D is mutatof making the tumour suppressor protein ed? inactive this causes uncontrolled cell growth a mutated form of a proto-oncogene which is more active than normal or has too many copies What is an oncogene? encode proteins that are receptors for seWhat do tumour suppressor genes do? creted hormones that function to inhibit cell proliferation Describe tumour suppressor gene mutations. usually loss of function recessive the loss of function of one or more tuWhat is the transformation of a normal mour suppressor genes and both gene cell to a cancer cell accompanied by? copies must be defective in order to promote tumour development Describe the p53/MDM2/p14ARF pathway. decreased apoptosis increased proliferation Describe the p16INK4a/CDK4/RB1 pathway. loss of cell cycle control 3/9 Describe the EGFR/PTEN/Akt/mTOR pathway. increased proliferation cell migration and invasion Describe the Platelet Derived Growth Factor and Receptor Pathway. increased proliferation What chromosome is p53 tumour suppressor gene located on? 17p13.1 Describe the p53 tumour suppressor gene. highly conserved gene containing 11 exons encoding 53kDa protein involved in many human tumours such as colon, breast, bladder, brain, etc renders it unable to signal and activate Describe inactivation of the p53 tumour the cell's apoptotic machinery resulting suppressor gene. in increased survival of cancer cells What does p53 induce transcription of? MDM2 p21 Gadd45 CD45 Bax What does p53 prevent transcription of? p14ARF Bcl-2 When is p53 induced? in response to DNA damage Describe the process of functional p53. DNA damage accumulation of p53 in nucleus G1 arrest DNA repair and apoptosis Describe the process of inactivated p53. DNA damage no G1 arrest replication of damaged DNA genomic instability What are the stages of carcinogenesis? malignant transformation invasion of neighbouring tissues metastasis What do the stages of carcinogenesis comprise of? a series of genetic alteration of cells affecting specific genes that are involved in regulating cell properties relevant for the individual stage 4/9 Describe the main components of cancer. self-sufficiency in growth signals insensitivity to anti-growth signals tissue invasion and metastasis limitless replicative potential sustained angiogenesis evading apoptosis What is senescence and what cells undergo it? irreversible inhibition of replication normal mammalian somatic cells What is the enzyme responsible for maintaining telomeres at the ends of chromosomes? telomerase 90% of human tumours consist of cells that contain an active telomerase enzyme What do cancer cells spread to distant sites in the body via? the blood stream and lymphatics Describe metastatic cells. less adhesive than normal cells able to degrade and penetrate tissue barriers such as the extracellular matrix of surrounding connective tissue and the basement membrane of blood vessels can invade normal tissue at various sites in the body forming secondary colonies Describe the metastasis cascade. acquisition of local invasiveness invasion of the cell into blood/lymph vessels (intravasation) transport through the blood/lymph vessels to distant tissue sites escape of the cancer cells from circulation (extravasation) ability to adapt to the local tissue environment and to proliferate What is aneuploidy? the presence of an abnormal number of chromosomes in a cell What cancers are associated with aneuploidy? prostate neuroblastoma brain colon 5/9 Name cancers associated with chromosomal changes such as an increase in DNA copy number. bladder cancer endometrial cancer brain tumours cervical cancer Why do tumours have a high degree if genetic abnormalities? due to the lack of p53 protein, and the ability of cancer cells to avoid cell death through apoptosis What is loss of heterozygosity? cross chromosomal event that results in loss of the entire gene and the surrounding chromosomal region What is microsatellite instability? this is a phenomenon often seen in colorectal cancer cells with defective DNA mismatch repair system What are microsatellites? regions of repetitive DNA sequences in the genome that are prone to shortening or extension if the mismatch repair enzymes are defective What are chromosomal anomalies? anomalies that affect autosomes and the 2 sex chromosomes What are autosomes? the 22 paired chromosomes that are alike in males and females What are the two major categories of chromosomal anomalies? numerical structural What are the types of numerical chromosomal anomalies? trisomy (an extra chromosome) monosomy (a missing chromosome) translocations (a whole chromosomes or segments of chromosomes inappropriName the types of structural chromosoately join with other chromosomes) mal anomalies. deletion duplication if they activate or inactivate genes that How do chromosomal anomalies cause result in a proliferative advantage over cancer? normal cells 6/9 1. cell enters S phase and replicates its DNA despite unrepaired strand break 2. one daughter cell inherits chromosome lacking telomere 3. cell enters S phase and replicates its DNA How does replication of damaged DNA 4. sister chromatid ends that lack telomlead to chromosome abnormalities? eres fuse 5. fused sister chromatids are pulled apart at mitosis, creating breakage ate new site 6. one daughter cell inherits chromosome with duplicated genes but again lacking telomere What is epigenetics? the study of stable changes in cell function that do not involve alterations in the DNA sequence What is hypermethylation? transcriptional silencing that can be inherited by daughter cells following cell division What enhances basal mutation rate in humans? exposure to chemical mutagens, radiation, and tumour viruses What are chemical mutagens? can modify DNA through alkylation or deamination of DNA bases, or through intercalation between base pairs and formation of aromatic compounds Give examples of alkylating agents. ethyl methyl sulphate nitrogen mustards mitomycin Give examples of DNA-intercalating agents. acridine orange ethidium bromide proflavine formation of thymidine dimers, which How can UV radiation cause skin canmay escape excision and re-synthesis of cer? a normal DNA strand 7/9 What may accidental/occupational ionising radiation and exposure to therapeutic irradiation lead to? leukaemia breast cancer sarcomas What are aromatic amines a carcinogen for? bladder cancer What is arsenic a carcinogen dor? lung and skin cancer What is benzene a carcinogen for? leukaemia What are asbestos, chromates, and diesel exhaust a carcinogen for? lung cancer What is formaldehyde a carcinogen for? leukaemia and nasal cancer What do oral contraceptives increase the risk of? breast cancer What does oestrogen used for HRT increase the risk of? uterine cancer What do combined oestrogen and progesterone increase the risk of? breast and ovarian cancer What does long term use of anabolic steroids increase the risk of? liver cancer also accelerates prostate cancer What does a diet high in fat increase the risk of? colon, breast, and prostate cancer What does large alcohol consumption increase the risk of? head, neck, and oesophageal cancer What does a diet high in smoked and pickled foods increase the risk of? stomach cancer Name some known cancer-associated immune disorders. ataxia-telangiectasia wiscott-aldrich syndrome X-linked agammaglobulinemia insertion of a strong promoter in the vicinity of a host cell proto-oncogene What do oncogenic viruses use to stim- expression of proteins that neutralise ulate proliferation of their host cells? host cell tumour suppressor proteins expression of proteins that prevent or delay apoptosis 8/9 tumour viruses often establish persistent What are the characteristics of viral carinfections in the human host cinogenesis? host factors are important determinants What bacteria increases the risk of cancer? helicobacter pylori infection What parasite causes chronic inflammation and fibrosis of the bladder which may lead to cancer? schistosoma haematobium What parasite has been linked to carcinoma of the pancreas and bile ducts? opisthorchis sinensis What do DNA repair systems do? fix damage that may have occurred to DNA What are some of the principal DNA repair mechanisms? mismatch repair base and nucleotide excision repair repair of depurinated site repair of double-strand breaks What is the underlying basis for the genomic instability in hereditary cancers? mutations in DNA repair genes 9/9