Part 2 Flashcards

You may prefer our related Brainscape-certified flashcards:
1
Q

Earliest studies of cancer done in… lead to…

A

sea urchins, the theory that chromosomal aberrations lead to cancer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Categories of genetic alterations in cancer

A

Mutations (point, deletions, translocation), and chromosomal changes (increased copy number)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Categories of epigenetic alterations in cancer

A

DNA methylation, histone modifications, and MicroRNA/NonCoding RNA, deregulation of transcription/translation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Hotspot mutations

A

Common in the activation of oncogenes. Example: V600E in BRAF in Thyroid Carcinoma.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Truncating mutation

A

Common in inactivating a tumor suppressor. Introduction of an early stop codon. Example: Truncating mutations to tp53 in colorectal cancer

Can also activate an oncogene: cycD in Lymphoma. mutation removes PEST sequence, which is an important degratory signal.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Loss of heterozygosity

A

Can be induced by other mutations. RHEB and 4E can induce p53 LOH

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Gene amplification

A

Can occur by double minute or intra-chromosomal amplification

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Chromosomal translocations

A

Induce oncogenic protein fusions or overexpression: Philadelphia chromosome

Frequent in hematological malignancies:

  • Bcl2 deregulated in follicular lymphoma
  • MYC deregulated in Burkitt’s Lymphoma
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Detecting chromosomal changes

A

FISH with different fluorescent markers -> Can see amplifications (more color), deletions (less color), or rearrangements (distance change)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

DNA methylation

A

Methyltransferases methylate C

CpG islands are CG rich regions of DNA that can be highly methylated to suppress transcription

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Measuring DNA methylation

A

Sodium bisulphite modification will change unmethylated C to U, which will be read as T by Taq polymerase. Sequencing original strand will reveal differences.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Histone modifications

A

Methylation regulated by polycomb complexes:
Have readers, writers, and erasers.

Activators: H3 acetylation, H3 K4 trimethylation
Repressors: H3 K9/27 trimethylation, DNA methylation

Regulators of histone methylation (Like EZH2, which is part of a writer complex) are frequently mutated in Cancer. GoF mutation -> repression of transcription

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

ChIP

A

Selection of antibodies allows you to choose which histone modification to screen for.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Types of sequencing

A
  • Targeted: Most manageable in a hospital setting. Applicable to screens.
  • Whole exome sequencing: All coding DNA, most available type of data.
  • Whole genome sequencing: Allows investigation of ncRNA, ncDNA, challenging to interpret, expensive.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Comparative genomic hybridization

A

A method to simultaneously detect chromosomal aberrations across the whole genome

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Role of IDH1 in cancer

A

Cancer-associated mutations produce 2-hydroxyglutarate. Can be used to id patients with IDH1-dependent brain tumor, slowing production of IDH1 can be life-extending for patients.

Accumulation of 2-HG in cells alters DNA methylation, impair TET2.

17
Q

IDH1/2

A

IDH1 is mutated in gliomas, but either can be mutated in Acute myeloid leukemia AML. Both convert α-ketoglutarate to 2HG.

18
Q

Major signaling pathways in cancer

A
  • Ras
  • Akt
  • Notch
  • Hedgehog
  • TGFB
  • Wnt
  • Cell Death
19
Q

Receptor Tyrosine Kinases

A
  • Epidermal growth factor r (EGFR)
  • Fibroblast growth factor r (FGFR)
  • Platelet-derived growth factor
  • Vascular endothelial growth factor
  • Insulin-like growth factor

Downstream:

  • Ras (activated bySOS, activates Raf and PI3K, Ral-GEF)
  • PI3K
20
Q

Ras

A

Oncogene.
Activated by SOS (Guanine exchange factor), having GTP makes it active. inactivated by a GTPase Activating Protein
Hotspot mutation keeps it in a constitutively active form

21
Q

Downstream of Raf

A

MEK, Erk1/2, ( Mnk1 -> elF4E, Ets, Elk-1, SAP-1)

Involved in transcriptional regulation, proliferation, differentiation.
Erk1/2 aka Mitogen-activated protein (MAP) kinase, MEK = MAPKK, Raf = MAPKKK.

22
Q

PI3K pathway

A
  • PI3K phophorylates Inositol-phospholipid -> PIP3
  • PI3K is regulated by PTEN.
  • PIP3 activates AKT
  • PTEN deleted in several cancers.
  • PI3K pathway implicated in protein synthesis and survival
23
Q

Myc

A

myc is a helix-loop-helix leucine zipper protein, frequently overexpressed.
Forms a dimer with max - activates the expression of several genes.
Is translated in burkitt’s lymphoma.

24
Q

Rb pathway

A

CDKN2A/B –| (MDM2 –|tp53, CDK –| RB1)

25
Q

mTOR

A

reactivates AKT

26
Q

How to analyze pathway activity?

A
  • Reporter constructs
  • protein-protein interactions
  • Mass cytometry (Cytof)
  • Y2H, spectroscopy
  • FRET (+ inhibitor: abolishes signal)