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Nutrition > Cancer > Flashcards

Cancer Flashcards

1
Q

What is the most common pathway of spreading of carcinomas and sarcomas?

A

Carcinoma : lymphatics
Sarcomas : hematogenous (small veins -> liver, lungs)

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2
Q

How can chronic inflammation predispose to cancer?

A

Increase pool of tissue stem cells (susceptible to transformation)
Immune cells produce ROS -> damage DNA -> promote cell survival even with genomic change

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3
Q

4 target genes (general) of cancer-causing mutations

A

1) growth-promoting oncogene
2) growth-inhibiting tumor suppressor gene (both allele must be damaged)
3) gene regulating apoptosis
4) genes responsible for DNA repair

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4
Q

What are driver mutations?

A

Initiating mutations (phenotypic atributes) -> acquisition of cancer hallmarks

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5
Q

What are passenger mutations?

A

Loss-of-fct mutations in gene that maintain genomic integrity -> more risk for driver mutations
Mutations w/o phenotypic consequences

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6
Q

8 cancer cellular hallmarks

A
  1. Self-sufficiency in growth signals (oncogene activation)
  2. Insensivity to growth inhibition signals
  3. Altered cellular metabolism (aerobic glycolysis)
  4. Evasion of apoptosis
  5. Limitless replicative potentital (avoid senescence)
  6. Sustained angiogenesis
  7. Ability to invade/metastasis
  8. Ability to evade host immune response
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7
Q

Role of transcription factor MYC

A

Induced by RAS/MAPK
Active expression of genes involved in cell growth (D cycline, rRNA)
Upregulates expression of telomerase
Many SNP flank MYC

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8
Q

G1/S checkpoint

A

GAIN OF FCT = mutations D cyclin (1 à 3) and CDK4 (promote progression in cell cycle)
LOSS OF FCT = CDK inhibitors (p16, RB, p53)

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9
Q

Function of CDK4 and D cyclins

A

Form a complex that phosphorylates RB = allow cell to progress through G1

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10
Q

Function of cell cycle inhibitors : CIP/KIP, p21, p27

A

Block cell cycle by binding cyclin-CDK complex
P21 induced by p53
P27 responds to growth suppressor TGFB

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11
Q

Function of cell cycle inhibitors : INK4/ARF

A

P16/INK4a binds cyclin D-CDK4 = promotes inhibe effects of RB
P14/ARF increase p53 by inhibiting MDM2 activity

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12
Q

Main function of RB

A

Tumor suppressive protein that binds E2F transcription factors in hypophospgorylated state = prevent G1/S transition
Interacts with transcription factors that regulate differenciation
Mutation requires mutations of BOTH alleles

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13
Q

Main function of p53

A

Tumor suppressor altered in majority of cancer
Induced by DNA damage
Causes cell cycle arrest by upregulating CDK inhibitor p21
Induces apoptosis by upregulating BAX and other pro-apoptotic genes

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14
Q

Effect of high levels of CD4K/cyclin D CDK6/cyclinD and CDK2/cyclin E on RB

A

Hyperphosphorylated state of RB = release E2F transcription factor = progress to S phase

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15
Q

Function of genes : INHIBITORS OF MITOGENIC SIGNALING PATHWAYS
1. APC
2. NF1
3. NF2
4. PTCH
5. PTEN
6. SMAD

A
  1. APC = inhibe WNT signaling
  2. NF1 = inhibe RAS/MAPK
  3. NF2 = Hippo pathway signaling
  4. PTCH = inhibe hedgehog signaling
  5. PTEN = inhibe PI3K/AKT signaling
  6. SMAD = component of TGFB signaling, repressor of MYC and CDK4, inhibe CDK expression
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16
Q

Function of genes : Inhibition of pro-growth
1. VHL
2. STKI I
3. SDHB, SDHD

A
  1. VHL = inhibe hypoxia-induced transcription factor (HIF)
  2. STKI I = active AMPK, suppress cell growth
  3. SDHB, SDHD = TCA cycle, oxidative phospho
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17
Q

Function of gene :
1. CDH1 (E-cadherin)
2. TP53 (p53)
3. BRCA1 et 2
4. MSH2 et 6, MLH1

A
  1. CDH1 (E-cadherin) = cell adhesion, inhibe cell motility
  2. TP53 (p53) = cell cycle arrest and apoptosis
  3. BRCA1 et 2 = repair of double stranded breaks in DNA
  4. MSH2 et 6, MLH1 = DNA mismatch repair
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18
Q

How does DNA damage and hypoxia affect p53
Oncogenic stress?

A

Damage -> ATM and ATR initiator phosphoryle MDM2 et p53 to disrupt degradation
Oncogenic stress -> active RAS protein -> pro-growth (MAPK, PI3K, AKT) -> p14/ARF binds MDM2 -> active p53 -> cell cycle arrest, senecsence or apoptosis
1. Cell cycle arrest : transient if GADD45 protein enough to repair DNA
2. Senescence = permanent cycle arrest
3. Apoptosis = promote transcription of proapopto gene (BAX, PUMA)

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19
Q

Mechanisms used by tumor cells to escape cell death

A

1 = loss of p53 fct (mutation or antagonism of MDM2)

  1. Reduced egress of cytochrome C by upregulation of antiapoptotic factors that stabilize mito membrane (BCL2, MCL-1)
  2. Less common = upregulate membors of the inhibitory of apoptosis family (IAP) = inhibe caspase 9
  3. Deficiency of growth factor and survival signals (BAX/BAK)
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20
Q

3 mechanisms to allow limitless replicative potential

A

1) evasion of senescence (w/o p53 or INK4/p16 = RB hypophospho = no cycle arrest)
2) evasion of mitotic crisis (shortening of telomeres)
Normal cell end of telomeres = p53 arrest growth
Dysfct of p53 = join naked ends of 2 chromosomes = dicentric chromosomes -> mitotic catastatrophe OR telomerase reactivation
Telomere resistance in cancer = expression of telomerase
3) capacity for self renewal = cancer stem cells

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21
Q

Proangiogenic factors

A
  1. Hypoxia -> stabilize HIF1a -> activate VEGF + bFGF
  2. Driver mutations and oncogenes -> loss of p53 -> less thrombospondin-1 (antiagniogenic)
    Gain of fct of RAS and MYC = more VEGF
  3. Proteases -> release bFGF from ECM -> release angiostatin and endostatin from plasminogen and collagen
22
Q

Steps of metastatic cascade

A
  1. Clonal expansion, growth, diversification, angiogenesis of primary tumor
  2. Metastatic subclone
  3. Adhesion and invasion of basement membrane
  4. Passage through ECM
  5. Intravasion
  6. Interaction with host lympho cells
  7. Tumor cell embolus
  8. Adhesion to basement membrane
  9. Extravasion
  10. Metastatic deposit -> angiogenesis -> growth
23
Q

Steps to invade the ECM

A
  1. Loosening of cell-tumor interactions = loss of E-cadherins fct (mutation or silenced by epithelial-mesenchymal transition)
    EMT transition controlled by SNAIL and TWIST
  2. Degrade of ECM (MMP, cathepsin D, urokinase)
    MMP9 cleave collagen IV = release VEGF + offer binding sites to tumor cells
  3. Attache to ECM by other integrins
  4. Migration and invasion (autocrine motility factor, fibronectin, stromal cell paracrine factor HGF)
24
Q

What is needed for extravasation?

A

Adhesion molecules = integrins, laminin-R
Proteolytic enzymes
Chemokines

25
Q

Immune antitumor mechanisms

A
  1. Mutated self proteins recognized by CD8+ CTL
  2. Overexpressed or aberrantly expressed self protein (tyrosinase) killed by CTL
  3. Oncogenic virus recognized by CTL
26
Q

Mechanisms of immune evasion of tumor cells

A
  1. Selective outgrowth of AG-negative variants (similaire mechanisme atbresistance)
  2. Loss or reduced expression of CMH (escape CTL may trigger NK)
  3. Engage pathway inhibing LT activation
    A) promote CTLA-4 = binds/remove ligand B7 from APC = unresponsive tumor Sp-LT
    B) upregulate PDL1 et 2 (oncogene)
  4. Secretion of immunosuppressive factors (TGFB, IL10, PGE2, VEGF)
  5. Induction of Treg
27
Q

Chromosomal changes leading to cancer

A
  1. Chromosomal translocation (most common)
    DNA break à deux places
  2. Deletions (common, loss of tumor suppressor genes ex : RB)
  3. Gene amplification (small extrachromosomal structures = double minutes)
  4. Chromosomal rearrangement
28
Q

Epigenetic changes leading to cancer

A

Histone modification
Silencing tumor suppressor genes by methylation of DNA

29
Q

Definition of chemical carcinogenesis :
1. Initiation
2. Promoters
3. Direct acting

A
  1. Exposure to sufficient dose leading to permanent DNA mutations
  2. Can induce tumors to arise from initiated cells (not tumorigenic themselves), pass DNA mutations to daughter cells
  3. Do not require metabolic conversion to become carcinogenic
30
Q

Events of chemical carcinogenesis

A
  1. Carcinogen
  2. Metabolic activation
  3. Electrophilic intermediates
  4. Binding to DNA (adduct formation)
    -DNA repaire, cell death or :
  5. Cell proliferation, altered differenciation
  6. Preneoplastic clone
  7. Additional mutations, prolif
  8. Malignant neoplasm
31
Q

By what are metabolized most carcinogens?

A

Cytochrome P450

32
Q

Mechanism of UVB carcinogenesis

A

Cause pyrimidine dimers to form DNA -> distort helix -> prevent proper pairing of dimers = error in DNA

33
Q

What are the steps in neoplastic transformation?

A
  1. Initiation = irreversible alteration of genetic material
  2. Promotion = selective outgrowth of initiated cells to form benign tumor = REVERSIBLE
  3. Progression = gradual development of features of malignancy resulting from combination of genetic and epigenetic changes = REVERSIBLE ET IRREVERSIBLE
34
Q

How are methylated CpG islands in normal and tumor cells? Impact on transcription

A

Normal tissu : CpG site in promoter region of genes and first exon = UNMETHYLATED and in the body of the gene = METHYLATED
Cancer : reverse, 5’ CpG island = HYPERMETHYLATED, body = HYPOMETHYLATED
Unmethylated 5’ CpG = active transcription
Methylated 5’ CpG = transcriptional repression

35
Q

Histone acetylation impact on transcription

A

DNA wound around histones
Ac group on histones = RELAXED = allow transcription
Remove Ac = closed transcription = prevent gene transcription

36
Q

Difference between a conservative and non conservative missense mutation

A

Conservation = a.a substituted by a similar one
Non conservative = different family of a.a

37
Q

What is a nonsense mutation?

A

Change aa codon to stop codon

38
Q

Gene defect in Marfan syndrome

A

Genes : FBN1 et 2 (+++missense mutations)
Inherited defect in EC glycoprotein fibrillin-1
Fibrillin = major component of ECM (aorta, ligaments, lens)

39
Q

How is TGFB affected in Marfan syndrome?

A

TGFB bioavailability controlled by fibrillin = excessive activation = inflamm, increase activity of MMP (loss of ECM)

40
Q

Mutations in familial hypercholesterolemie + 5 class

A

Autosomal dominant = gene encoding LDL-R, ApoB, PCSK9
PCSK9 = inhibe recycling of LDL-R
Class 1 = mutation in synthesis in RE
Class 2 = mutation in transport to Golgi
Class 3 = mutation of binding apoprotein ligand
Class 4 = mutation of clustering in coated pits
Class 5 = mutations in recycling endosomes

41
Q

Pathogenesis of primary and secondary lysosomal storage disease

A

Primary :
Stored nonmetabolized products -> defective fusion of autophagosome and lysosome -> defective degradation of IC organelles ->
A) Accumulation of toxic proteins -> inducing cell damage -> cell death -> secondary storage dz
B) Accumulation of aberrant mitochondria -> generation of ROS -> cell death -> secondary storage dz

42
Q

What is Klinefelter syndrome?

A

Male hypogonadism
X = 2 ou +
Y = 1 ou +
Reduced spermatogenesis, male infertility

43
Q

What is Turner syndrome?

A

Complete or partial monosomy of X = hypogonadism female

44
Q

What is the hallmark of trinucleotide repeat mutation dz?

A

Accumulation of aggregated mutant proteins in large intranuclear inclusions

45
Q

What are the single gene disorders with nonclassic inheritance?

A
  1. Trinucleotide repeat mutations
  2. Mutations in mitochondria genes
  3. Genomic imprinting (maternal imprinting = silence maternal allele) = occurs before fertilization
  4. Gonadal mosaicism (phenotypically normal parents in autosomal dominant disorders) = mutation during embryonic development
46
Q

Utility of restriction fragment lenght analysis

A

Molecular dx when mutations always occurs at one nucleotide position

47
Q

Utility of FISH

A

Used to detect numeric abnormalities, subtle microdeletions, translocations and gene amplification
Need prior knowledge of region suspected

48
Q

Utility of cytogenomic array technology

A

Don’t need prior knowledge of localisation

49
Q

Utility of single nucleotide polymorphism genotyping arrays (SNP)

A

Uncover copy number anomalies when karyotype is normal but structure anomaly is suspected

50
Q

How can we detect DNA methylation

A

Treat genomic DNA with sodium bisulfite = converts unmethylated cytosine to uracil = acts like thymine in reaction

51
Q

Utility of doing RNA analysis

A

Because most translocation occurs in scattered locations = need very large DNA PCR amplification
Introns are removed by splicing during mRNA formation = PCR possible if RNA first converted to complementary DNA by reverse transcriptase

Nutrition (13 decks)

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