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Renal System > Genetics of Bladder Carcinoma > Flashcards

Genetics of Bladder Carcinoma Flashcards

1
Q

What does the term urological cancer refer to?

A

It is a broad term that involves cancer of the male and female urinary tacos and male reproductive organs

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2
Q

What s the most common urologic cancer?

A

Bladder cancer

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3
Q

What is the male to female ratio of bladder cancer?

A

4:1

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4
Q

What are the two unique phenotypes of bladder cancers?

A

Urothelial (noninvasive)
Invasive beyond te urothelial layer

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5
Q

What are the risk factors of urothelial carcinomas?

A
  1. Smoking
  2. Long-term exposure to chemicals
  3. Chronic urinary tract inflammation
  4. Genetic predisposition –> mutation in the RB1, TP53, or PTEN genes
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6
Q

How do environmental factors interact with genetic predisposition to influence bladder cancer risk?

A

Exposure to carcinogens, such as arsenic, activates the signaling pathway that may contribute to tumor development

Lifestyle factors like smoking and dietary habits have also been associated with bladder cancer risk

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7
Q

What % of bladder cancer cases have been attributed to genetic factors?

A

Approximately 30%

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8
Q

Single nucleotide polymorphisms in what kind of genes have been associated with an increased risk of bladder carcinomas?

A

Genes involved in chemical carcinogenesis, DNA repair and cell cycle regulation

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9
Q

What genetic syndromes have been linked to an increased risk of bladder cancer?

A

Lynch syndrome, particularly in carriers of MSH2 mutations

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10
Q

Mutations in the TP53 gene are frequently observed in what kind of bladder tumors?

A

High-grade bladder tumors, indicating their role as early events in tumorigenesis

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11
Q

What is p53?

A

The guardian of the genome, a tumor suppressor gene

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12
Q

What is the importance of p53 and retinoblastoma pathways? What happens to them in cancer?

A

They are critical tumor suppressor mechanisms that regulate the cell cycle, maintain genomic stability, and prevent tumorigenesis.

Both pathways are frequently altered in various cancers, leading to uncontrolled cell proliferation and malignancy

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13
Q

Which chromosome is p53 encoded on?

A

Chromosome 17p13.1

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14
Q

What are the function of p53?

A
  1. It is sensing DNA damage
  2. Cell cycle arrest: activates a protein called p21 that inhibits the cyclin-dependent kinase, which normally drives a cell through the G1 checkpoint
  3. Promotes apoptosis: activation of Bax gene
  4. DNA repair
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15
Q

Is DNA damage indicative of cancer?

A

Not necessarily, DNA damage could be due to stress, toxins, poor diet, fast foods, or even radiation

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16
Q

What happens in response to DNA damage?

A

The p53 pathways gets activated

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17
Q

What is the DNA repair pathway?

A

GADD45: p53 upregulates GADD45, which plays a role in DNA repair processes.
If the DNA damage is repairable, GADD45 facilitates the repair, allowing the cell to continue its normal function.

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18
Q

When does p53 cause the cell cycle to stop? (3)

A
  1. p53 upregulates P21, which acts as a CDK inhibitor (Cyclin-Dependent Kinase inhibitor).
  2. P21 stops the progression of the cell cycle at the G1/S checkpoint, allowing time for DNA repair.
  3. If damage cannot be fixed, the cell does not progress further –> leads to apoptosis of the cell
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19
Q

What is the apoptosis pathway that is activated by p53? (3)

A
  1. p53 upregulates apoptotic genes that initiate cell death.
  2. This prevents the propagation of damaged cells that could lead to cancer.
  3. Apoptosis ensures the elimination of cells that might become malignant.
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20
Q

What controls the regulation of the p53 activity?

A

Tightly controlled by the MDM2 protein, which promotes p53 degradation through ubiquitination

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21
Q

How does MDM2 control p53 regulation?

A

MDM2 sends a negative signal to stop p53 from being continuously active

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22
Q

What happens if there is an overexpression of MDM2?

A

In the case of overexpression of MDM2, it will constantly send negative feedback to p53 to be inhibited –> p53 cannot regulate and check the cell cycle and thus cause apoptosis to damaged cells or tumor cells when needed

–> In this case, there is no mutation affecting the p53, the mutation is on the MDM2 –> constantly suppressing a normally functioning p53

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23
Q

What primarily activates the p53 pathway?

A

Primarily activated in response to cellular stress, such as DNA damage, hypoxia, or oncogenic signals.

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24
Q

Upon activation, what does the p53 pathway function as?

A

Functions as a transcription factor that regulates the expression of numerous target genes involved in cell cycle arrest, apoptosis and DNA repair

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25
Q

How does the p53 pathway trigger apoptosis?

A

Apoptosis through the upregulation of pro-apoptotic factors such as PUMA and NOXA, thus eliminating damaged cells

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26
Q

What do mutations of the p53 often lead to?

A

Production of a dysfunctional p53 protein that loses its tumor-suppressive functions, allowing for unchecked cell proliferation and survival

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27
Q

What do point mutations often lead to?

A

Increased protein half-life

28
Q

How can you dtect a mutant p53?

A

By immunohistochemistry or by DNA sequencing
–> Negative detection or < 10% detection of p53 protein in nuclei of transitional cell carcinomas of the bladder –> negative

29
Q

What is a nuclear accumulation of p53 highly correlated to?

A

Highly correlated with mutations in the TP53 gene

–> Mutation in the TP53 gene –> advanced tumor stage and high histological grade of bladder cancer

30
Q

What is the Rb protein?

A

Crucial cell cycle regulator primarily binds to E2F transcription factors, inhibiting their activity and preventing the transcription of genes required for S phase entry

31
Q

What happens when cyclin-CKD complexes phosphorylate Rb?

A

When that phosphorylation reaction happens during the G1 phase, they release E2F, allowing the transcription of genes that promote cell cycle progression

32
Q

What is RB pathway?

A

This pathway is a critical checkpoint in the transition from the G1 to S phase

33
Q

What do mutations in the RB1 gene or alterations in upstream regulators lead to?

A

Lead to the loss of Rb function, resulting in the unregulated activation of E2F and subsequent cell cycle progression

34
Q

What is the relationship between the p53 and Rb pathways?

A

Rb inactivation can activate p53 as a compensatory mechanism to prevent tumorigenesis

35
Q

What happens to Rb pathway if there is a mutation in the p53?

A

If p53 is mutated, Rb may also become dysregulated, leading to enhanced cell proliferation and tumor growth

36
Q

What is the relation between RB gene mutations and bladder cancer?

A

RB gene mutations have been implicated in low-grade, high-grade and invasive cancers

37
Q

What is the role of the signaling pathway from tyrosine kinase receptors o AKT/PIK3?

A

It would play a role in carcinogenesis and development of bladder cancer and other cancers (PTEN)

38
Q

What is FGFR3?

A

It is an oncogene
It belongs to the fibroblast growth factor receptor family, its extracellular portion interacts with other growth factors and conducts downstream signals

39
Q

What is the function of FGFR3?

A

Cell proliferation, differentiation and angiogenesis

40
Q

What is the effect of mutated FGFR3 in bladder cancer?

A

Mutated FGFR3 or truncated receptors trigger downstream signaling even in the absence of ligand binding –> no ligands, they are always active, downstream signaling will constantly be active

41
Q

In what % of bladder cancer cases is there a mutation in FGFR3?

A

17% –>more favourable prognosis and may be targetted therapeutically

42
Q

What is HRAS?

A

HRAS mutation is common in bladder cancer

43
Q

When is HRAS gene expression significantly greater?

A

Significantly greater in bladder urothelial carcinoma as compared to normal bladder sample –> HRAS oncogene is important in the tumor progression of urinary tract cancers

44
Q

WHhat happens when GDP gains an extra phosphate?

A

The conversion to GTP allows it to constnatly be active –> downstream signal is continuous which helps the cells survive (RAS activation)

45
Q

Which regions of chromosomes are believed to play a role in bladder carcinogenesis?

A

3q26.2
11p15.5
6q22.3
9p21.13

46
Q

What is the importance of 9p21 loci, including CDKN2A and CDKN2B? What is its role?

A

It is a critical genomic region implicated in various cancers, including bladder cancer.

It is known for its role in cell cycle regulation by producing tumor suppressor proteins that inhibit CDKs, thereby controlling cell proliferation and promoting cell cycle arrest

47
Q

What does CDKN2A code for?

A

It is agene whch codes for 2 proteins:
p16INK4A and p14ARF

48
Q

WHat is the function of P16INK4A?

A

Primarily functions as an inhibitor of CDK4 and CDK6, preventing phosphorylation of the Rb protein and thereby blocking progression from the G1 phase to the S phase

49
Q

What is the function of the p14ARF protein?

A

Involved in the p53 pathway, stabilizing p53 by inhibiting its negative regulator, MDM2

50
Q

What does the CDKN2B gene encode for?

A

p15INK4B

51
Q

What is the function of p15INK4B?

A

Inhibits CDK4 and CDK6, reinforcing the cell cycle control mechanisms initiated by p16INK4A

52
Q

What happens if there is a loos of activation in the CDKN2A and CDKN2B genes?

A

This leads to uncontrolled cell vision and tumor progression

53
Q

What is the effect of deletions of the 9p21 locus in bladder cancer?

A

Usually occurs in conjunction with other genomic alterations, contributing to the aggressive nature of the disease

54
Q

What is the prognosis of cancers involving loss of function mutations of CDKN2A and CDKN2B?

A

Associated with poorer prognosis and resistance to therapies, particularly immune checkpoint inhibitors

55
Q

What are the function of 9q-?

A

Controls p53 and p16
Helps the next phases of invasion by helping the tumor become more invasive

56
Q

What is the increase in risk for people who smoke vs people who do not smoke for bladder cancer?

A

Increase in risk up to 5 times

57
Q

Why is smoking such a risk for bladder cancers?

A

It contains numerous carcinogens, including nitrosamines, which are directly linked to bladder cancer development

58
Q

How are processed meats a dietary risk for bladder cancer?

A

They contain heterolytic amines and polycyclic aromatic hydrocarbons formed during high-temperature cooking and are known carcinogens

59
Q

What is the management of genetic bladder cancer?

A

Involves a multifaceted approach that integrates understanding genetic predispositions, lifestyle modifications, and advanced therapeutic strategies

60
Q

How can individuals at higher risk be identified?

A

Through genetic testing and next-generation sequencing

–> Prognostic markers
–> Predictive biomarkers
–> Precision medicine

61
Q

What do microarrays look for?

A

Look at the presence of DNA/SP in whole genome testing for structural variants such as translocation and CNV

62
Q

What is PCR used for?

A

Used for conformatory testing

63
Q

What is next generation sequencing?

A

Massively sequencing of nearly all protein-coding portions of the genes

64
Q
A
65
Q
A

Renal System (24 decks)

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