Summary - Class notes - MOD2

• 1508882400 Theme IA LT1-7

• What are the macroscopical aspects of cancer?

  Benign: small sometimes, well demarcated, slow growing, noninvasive, nonmetastatic, well differentation
  
  Malignant: large, poorly demarcated, rapidly growing with hemorrhage and necrosis, locally invasive metastatic, poorly differentiated
• Waarin verschillen normale cellen van kanker cellen?

  grote hoeveleheid ovan irregulair gevormde delende cellen
  Grote, variablee gevormde ncuclei
  Relatief klein cytoplasma 
  Variatie in celgrootte en vorm
  Verlies van normale gespecialiseerde cel eigenschappen
  Disorganized arrangement of cells
  poorly defined tumor boudnary
• What is HER2?

  HER2 is a protein that is presence in the membrane of breast cancer cells.
• What information gives immunochemistry?

  prognostic information of cancer (biomarkers)
  predictive information of cancer (biomarkers)
  both
• Immunochemistry, tumor typing, keratin

  epithelial lineage
• Immunochemistry, tumor typing, desmin

  myogenic tumors
• Immunochemistry, tumor typing, S100/Melan-A

  melanoma
• Immunochemistry, tumor subtyping, P40

  squamous differentaiton
• Immunochemistry, tumor subtyping, TTF-1

  thyroid tumors, adenocarcinoma of the lung
• Immunochemistry, tumor subtyping, OC125

  Ovarian tumors
• Immunochemistry, tumor subtyping, GATA-3

  Breast and urothelial tumors
• What is fine needle aspiration?

  cytology
  You make a cell analysis, used in cancer diagnostics. 
  It is easily done. 
  You can stick a needle in the swelling and you can analyze the cells quite easily and rapidly. 
  
  You can see size and shape of the nucleus and the amount of cytoplasm, but you can't see any detailed information about the proteins. 
  
  Palpable mass (eg thyroid, breast, skin, lymph node)
  Rapid, only cellular information
  DD reactive vs cancer
  Mostly followed by biopsy
• What is molecular pathology

  Recognition of the chromosomes in the cells. 
  Duplication of chromosomes is a general feature of cancer cells. 
  Chromosome instability will lead to genes which are neede dto grow
• Wat is HER2? hoe kun je dit voorkomen?

  HER2 receptoren op cellen. HER2 genen worden in grote hoeveelheiden geactiveerd in cancer cellen. Je kunt binding van deze groeifactoren voorkomen met behulp van trastuzumab.
• What is prefereable way in cancer diagnostics?

  histology
• What does sustaining proliferative signaling mean?

  Tumor cells are able to constantly signal themselves that they have to proliferate.
• What are agents of carcinogenesis?

  - Aging (more indolent behaviour)
  - Exogenous (enviironmental) factors
  - Chronic inflammation -> risk factor to cancer development
  - Viruses -> if we can't clear the infection, they can develop malignant transfomrmation
  - genetics
• What are exogenous factors in scrotal cancer?

  Soot. Not completely burned wood waste.
• What are environmental factors in cancer?

  Smoking <- increase in risk for many cancers: mouth, pharynx, larynx, oesophagus, pancreas, bladder , lung
  
  alcohol consumption: oesophagus, HCC, upper respiratory tract, pancrease
  
  DIet: colorectal and stomach cancer
  
  Obesity and hormones: breast and endometrial cancer
  
  Radiation
  
  Sun: skin cancer
• What kind of cancer can sun exposure cause?

  UV light is dangerous
  
  Basal cell carcinoma and squamous cell carcinoma are the most common cancer types. 
  Melanoma accounts for less than 1% of skin cancer cases, but the vast majority of skin cancer leads to death.    
  
  UV causes DNA damage in making a pyrimidine dimer.
• What are the risks of asbest?

  vezels hopen zich op in de narrow branhces of de longen en zorgen voor inflammation en scarring van de airways. Dit geeft een chronische hoest en pijn op e borst
  
  - longkanker of mesothelioma
  
  - pleural lining, plaque builds up and may restrict breathing
  
  het heeft een latente periode van 20 jaar
• Hoe werkt viral carcinogenesis?

  Invloed op de celcyclus en apoptosis door:
  
  - coderen voor eiwitten die de progressie van de celcyclus beïnvloeden
  - integreren dichtbij cellulaire genen die de celcyclus progressie controleren.
• Wat zijn de meest voorkomende oncogenic viruses?

  HPV (cervical, vulva, penile, anal cancer)
  Hepatitis B/C (liver)
  EBV (hogdkin lymphoma, naso-pharyngeal cancer)
  Human herpes virus     (Kaposi sarcoma)
• What are central items of viral carcinogenesis

  Host susceptibility factors are important determinants
  Viruses are seldom carcinogenic on their own
  Viral infections are far more common than viral cancers
  Prolonged periods are usually required
  Viral strains may be different in their capcaity to cause cancer
  Can be used for both preventive and therapeutic vaccination
  One virus species can be associated with multiple tumor types
• What are the most common types in HPV?

  16 and 18, cause cervical cancer
• What do HPVE6?

  E6 binds to TERT -> increased telomerase expression, zodat tumorcellen oneindig kunnen blijven delen
  
  E6 binds to p53 -> inhibition of P53
• What does HPV E7?

  E7 binds to p21, inhibtion of P21, dat zorgt voor increased CDK4/cyclin D
  E7 binds to RB-E2F -> inhibition of RB-E2F
• How does a EBV carcinogenesis exist?

  Latent infection with EBV
  
  Polyclonal B cell expansion
  
  Increased MYC protein because of DNA breaks
  
  Outgrowth of neoplastic clone: burkitt lymphoma
• What are proto-oncogenes?

  promote tumor development, you don't have these genes in the genome, they have a role in embryogenesis and repair
  
  they only become oncogenes, if they have tumor context, very much related to the hallmark of cancer, sustaining proliferative signals
• What are tumor suppressor genes?

  Gate keepers, they prevent that cells with damage survive. so they do cell cycle arrest and apoptosis
  
  loss of expression
  inactivting mutations
  chromosomal loss -> los of genetic material
• What do oncogenes?

  Oncogenes are for proliferation and cell surivval
  
  - increased expression
  - activating mutations
  - chromosomal gains
• You have a proto-oncogene, which mutations can occur?

  Translocation or transposition: new promoter: -> normal grwoth stimulating protein in ecess
  
  Gene amplificiation: normal growth stimulation protein in excess
  
  Point mutation: within a control element of an oncogene -> normal growth stimlating protein in ecess
  
  Point mutation: within the gene: hyperactive or degradation resistant protein
• Which chekpoints do you have in the cell cycle (amongst others)

  After G1: G1/S checkpoint, check for DNA damage
  Before mitosis: G2/M  checkpoint, check for damaged or unduplicated DNA
• What is TP53?

  Central monitor of stress in the cell. 
  Can be activated by anoxia, DNA damage or inappropriate signaling by mtuated oncoproteins. 
  P53 is involved in cellcycle arrest, DNA repair, cellulair senescence and apoptosis. 
  If DNA damage is not successful, p53 induces apoptosis or senescence. 
  P53 can be inactivated by bi-allellic loss of functio TSG or by binding of viral oncoproteins, HPV E6
• What stages of development are there from normal to neoplastic tissue with many non-malignant intermediate stages?

  Normal epithelium
  Proliferation
  Local invasion
  Lymph node invasion
  Distant metastases
• What kind of chromosome mutations are there?

  chromosome losses/gains
  translocations
  multi-locus deletions
• What kind of gene mutations are there?

  deletions/insertions
  base pair substituions
  frameshifts
• What are multi-locus deletions?

  Part of chromosome is lost. All the genes present on the deleted part are lost. 
  If this occurs on a chromosome you have two copies. 
  
  Leads to loss of function of the deleted alleles
  Deletion on an autosomal chromosome: hemizygosity for multiple genes
• Wat houdt truncation van the gene in?

  Het eiwit kan door delete kleiner zijn, maar je hebt geen veranderend reading frame. Het eiwit is dan nog functioneel. 
  
  Een andere optie is dat je wel veranering in reading frame hebt. 
  Dan heb je een truncated protein en is je gen warschijnlijk niet meer functioneel.
• Wat gebeurt er met gen mutatie in de promotor?

  transcriptie efficiente beïnvloeden,
• Op welke plekken kunnen gene mutations plaatsvinden?

  intron: most often no effect on the function of the gene
  
  promoter: may affect transcription efficiency
  
  splice site: may affect splicing (eg exon skipping),   nucleotides are 100% conserved, if you get a mutation in the intron this will cause skipping of the exon, and this can lead to loss of function
  
  exon: may affect protein composition
• Welke soorten mutaties kunnen optreden?

  -1 frameshift: protein trunctation, er kan een stopcodon worden ingebouwd, geeft (partial) loss of function
  
  nonsense mutation: er wordt een andere base ingebouwd, protein truncation: partial loss of function, kan een stopcodon geven  
  
  missense mutation: non-synonymous amino acid change: partial loss of function, maar hoeft niet, er wordt een andere aminozuur ingebouwd, kan nog steeds dezelfde functi hebben
• What are SNP?

  single nucleotide polymporphisms.
  originally a sequence variant found in > 1 % within a population
  common SNP; in 10% of all individuals
  Will mostly not affect biological function, because if they would effect it, there would bes seltion
  frequency is 1/100 bp, dus  million SNP
• Whate are SNV?

  Differences in the DNA sequence between individuals (or within the human reference genome)
  Does not need to affect biological function
  Frequency ~1 /300 BP
• How much mutations before a malignant tumor?

  6-7 mutations
• How do you get oncogene activation?

  Coding mutation: amino acid will change, this will lead to abnormal protein which is always actiated .
  
  Regulatory mutation: excessive amount of protein
  
  Translocation: fusion in gene which will produce novel proteins
  
  Gene ampfliciation: instead of one allele you might have multiple alleles, so excessively amount of protein. 
  
  So either you produce aprotein which is always active, or you produce way too much of the normal proteins         
  
  It always leads to gain of function
• Hoe werkt de activatie van RAS?

  GEF uitwisselaar van GDP naar GTP
  
  GAP: verhoogt GTP ase activiteit, Pi wordt van GTP los gekoppeld
• What can go wrong in gene amplification?

  Double minutes (specules next to the normal chromosomes)
  Homogenously staining regions (HSR) -> amplifcation on a normal chromosomal location
• Leg aan de hand van Burkitt Lymphoma hoe overproductie van een normaal eiwit kan plaatsvinden.

  ~85% van de gevallen van Burkitt lymphoma is er een t(8;14) (q24;q32) translocation. 
  Hierbij komt MYC aan IGH vast te zetten
  dit zorgt voor een up-regulated expression of structurally normal MYC protein (exon 1 is non-coding)
• Wat is fusion genes?

  mRNA with part of the BCR gene and part of the ABL gene. 
  

  • you get fusion protein which is constantly active and cannot be switched off