Exam #2: Neoplasia V Flashcards

1
Q

What is APC? What are mutations in APC associated with?

A
  • APC is a tumor suppressor gene that prevents nuclear transcription
  • Mutations are associated with familial polyposis coli (adenocarcinoma of the colon)
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2
Q

What is BRCA 1/2? What are BRCA mutations associated with?

A
  • BRCA 1/2 are tumor suppressor genes that regulate DNA repair
  • Mutations are associated with Breast & Ovarian Cancer
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3
Q

What is RB? What are Rb mutations associated with?

A
  • Rb is a tumor suppressor gene that Inhibits G1 to S phase transition
  • Mutations are associated with Retinoblastoma & Osteogenic sarcoma
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4
Q

What is the WNT signaling pathway?

A

This is the signaling pathway that controls cell polarity during embryonic development & self-renewal of hematopoeitic stem cells

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5
Q

What are the function of APC & B-catenin in the WNT signaling pathway?

A

APC= a class of tumor suppressor that generally down regulates growth-promoting signals; mutations lead to “Adenomatous polyposis coli” i.e. APC gene

  • In the WNT signaling pathway, APC causes destruction of B-Catenin
  • WNT binding blocks APC mediated destruction of B-catenin & B-catenin translocates to the nucleus of the cell, upregulating cellular proliferation

Thus, APC mutations cause continuous WNT signaling via B-Catenin

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6
Q

What happens when there is a heterzygous vs. homozygous mutation in APC?

A

Heterozygous= no cancer

Homozygous= cancer
- Constant B-catenin translocation that eventually leads to FAP

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7
Q

What are the cancers associated with Rb gene mutations?

A

1) Retinoblastoma
2) Osteosarcoma
3) Soft tissue sarcoma

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8
Q

What is the two-hit hypothesis?

A

Both alleles of Rb locus must be inactivated i.e. mutated to cause cancer

  • 1 allele= no tumor
  • 2 alleles= tumor
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9
Q

Describe the development to retinoblastoma in familial cases.

A
  • Inherited 1x mutation in Rb gene from parent

- In development, the alternate gene is mutated & leads to the development of retinoblastoma

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10
Q

Describe the development of sporadic retinoblastoma.

A
  • Born normal
  • Acquired mutation in one allele
  • Acquired mutation in the second allele–>disease

**The key here is that the patient is born normal

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11
Q

What is the function of p53?

A

This is a tumor suppressor gene that specifically:

1) inhibits G1–>S phase transition
2) Repairs DNA
3) Activates BAX (anti-apoptotic)

I.e. p53 is “anti-proliferative, pro-apoptotic, and function in repair”

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12
Q

What cancers are p53 associated with?

A

Lung
Colon
Breast
Li-Fraumeni Syndrome

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13
Q

How does p53 mediate cell-cycle arrest?

A
  • p53 prevents the transition from G1–>S phase, by acting via p21
  • p21 inhibits cyclin/CD4
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14
Q

What does DNA damage from carcinogens activate?

A

p53 that binds DNA leading to:

1) Cell cycle arrest via p21
2) DNA repair via GADD45 upregulation

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15
Q

If p53 cannot induce DNA repair, what happens?

A

Upregulation of BAX leading to apoptosis

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16
Q

What are the ultimate effects of a p53 mutation?

A

1) Cell cannot repair damaged DNA
2) Cell cannot induce apoptosis in response to DNA damage that cannot be repaired

*****End result is malignant tumor

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17
Q

What is the mechanism of HPV?

A
  • HPV E6 & E7 inhibit p53

- HPV E7 also inhibits p21

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18
Q

What is the VHL gene?

A

This is a tumor suppressor gene that is located on chromosome 3p

  • Part of the Ub ligase complex
  • Normally regulates a nuclear transcription via HIF-1a
19
Q

What are the diseases associated with VHL gene mutations?

A
  • Hereditary renal cell carincomas
  • Pheochromocytoma
  • Hemangioblastomas of the CNS
  • Retinal angiomas
  • Renal cysts
20
Q

What is the Warburg effect?

A

This is distinct form of metabolism seen in cancer cells:

  • High glucose uptake
  • Increased conversion of glucose to lactose via glycolytic pathway
21
Q

Why is the Warburg effect important?

A

The Warburg effect is how PET scans works:

  • Patient given a glucose analog that radioflouresces
  • Tumor takes up glucose & comes up positive on scan
22
Q

What is the function of telomerase?

A
  • Successive cell division leads to telomere shortening
  • Telmoere shortening eventually results in apoptosis in normal cells
  • Telomerase prevents the shortening of the telomeres
23
Q

How is telomerase implicated in cancer?

A

Upregulation of telomerase ensures that cells avoid apoptosis

24
Q

What are epigenetic changes?

A

Reversible, heritable changes in gene expression that occur without mutation
- Involved post-translational modification of histones & DNA methylation

25
Q

What does DNA methylation result in?

A

Reduction of expression of histone modification and compaction of DNA into heterchromatin

26
Q

What is MicroRNA? Why are they important?

A
  • 19-24 nucleotide family of noncoding RNAs that regulate messenger RNA function at the post-transcription and translational level
  • New evidence suggests that they can be used for diagnostic, prognostic, and therapeutic purposes
27
Q

What are the general categories of carcinogenic agents?

A

1) Chemical carcinogens
2) Radiation
3) Oncogenic viruses & microbes

28
Q

What is carcinogenic in tobacco smoke?

A

Polycyclic hydrocarbons

29
Q

What are chemical carginogens?

A

Highly reactive “electrophiles” that remove electrons from DNA, RNA, or proteins

30
Q

What is the difference between a direct acting and indirect acting chemical carcinogen?

A

Direct= act without modification

Indirect= require metabolic activation

31
Q

What are the steps involved in chemical carcinogenesis?

A

Generally, there are two phases of carcinogenesis:

1) Initiation
- electrophilic intermediate causes DNA damage
2) Promotion
- cell proliferation leads to a preneoplastic clone that then accumulates additional mutations

*****The key point here is that initiation must come before promotion & BOTH phases are required for tumorigenesis

32
Q

What are the direct acting compounds involved in initiation?

A

Chlorambucil
Busuflan
Melphalan

33
Q

What are the indirect compounds involved in initiation?

A

Polycyclic aromatic hydrocarbons

34
Q

What is the source of polycyclic aromatic hydrocarbons?

A

1) Cigarette smoke

2) Smoked meats & fish

35
Q

Where do aromatic amines and azo dyes cause problems?

A

Liver

36
Q

What is B-naphthylamine? What occupations is this associated, and what cancer is it associated?

A

This is a metabolite of aniline dye that works in rubber & textile industries are exposed to
- Causes bladder cancer

37
Q

What is Aflatoxin B1?

A

Fungal toxin produced by Aspergillus flavus in improperly stored corn, rice, and peanuts

38
Q

What cancer is Aflatxoin B1 associated with?

A

Hepatocellular carcinoma due to p53 mutations

39
Q

Nitrosamines & Amines

A

asdf

40
Q

What is asbestos exposure associated with?

A

Mesothelioma
Lung cancer
GI cancers

41
Q

What are chromium and nickel exposure associated with?

A

Lung cancer

42
Q

What is arsenic exposure associated with?

A

Skin cancer

43
Q

What are the promoters of chemical carcinogenesis?

A

Estrogen

High dietary fat & bile acids