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Aberrant gene expression in cancer biology Flashcards

1
Q

A nucleosome is an octomer made up of which 4 histones?
1. H2A, H2B,H3,H4
2. H1,H2A, H2B, H3
3. H1A, H2B, H3A, H4B
4. H1, H2, H3, H4

A

H2A, H2B, H3, H4

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2
Q

The first highly recurrent non-coding somatic even observed across multiple cancer types was:
1. Mutations within the promoter of the TP53 gene
2.Mutations within the promoter of the TERT gene
3.Mutations within the promoter of the BRCA1 gene
4.Mutations within the promoter of the Rb gene

A

Mutations within the promoter of the TERT gene

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3
Q

Enhancer hijacking can occur through which of the following mechanism :
1. Insulator deletion
2. Interchomosomal translocation
3. Intrachromosomal inversion
4.Intrachromosomal deletion
5. all of the above

A

All of the above

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4
Q

Which of the following statements is false regarding CpG islands?

a. 25% of CpG islands are found in the main gene body
b. Are notably associated with regions of the genome that are devoid of protein-coding genes
c. Approximately 50% of CpG islands are found in the vicinity of known transcriptional start
sites
d. CGIs associated with transcriptional start sites remain unmethylated even when the gene is not
being transcribed.
e. CpG islands are important because they are areas of the gnome that have been protected from
mutating properties of methylation through evolutionary time

A

b. Are notably associated with regions of the genome that are devoid of protein-coding genes

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5
Q

True or false: 25% of CpG islands are found in the main gene body

A

True

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6
Q

True or false: Approximately 50% of CpG islands are found in the vicinity of known transcriptional start
sites

A

True

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7
Q

True or false: CGIs associated with transcriptional start sites remain unmethylated even when the gene is not
being transcribed.

A

True

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8
Q

True or false: CpG islands are important because they are areas of the gnome that have been protected from
mutating properties of methylation through evolutionary time

A

True

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9
Q

Whats the epigenetic control of gene expression?

A

involves modifications to DNA or associated proteins that regulate which genes are turned on or off without altering the underlying DNA sequence.

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10
Q

How somatic cancer driver genes are identified using genomics

A

CRISPR/Cas9, Whole genome sequencing

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11
Q

what are key features of cancer

A

Aberrant gene function and altered proteins

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12
Q

True or false: the disruption of epigenetic regulatory mechanisms is prevalent in cancer

A

True

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13
Q

True or false: both genetic and epigenetic alterations ultimately lead to abnormal gene expression

A

true

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14
Q

What are the 4 subgroups of medullablastoma

A

1- Wnt
2- Sonic hedgehog
3 - group 3
4 - group 4

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15
Q

What is epigenetic?

A

how environmental factors can change gene activity without altering the DNA sequence

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16
Q

True or false: different cell types are programmed to express different sets of genes but they have the same DNA/set of chromosome

A

True

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17
Q

How do we get different types of cells in the first place?

A

The estabilishment of different cell lineages and cell differentiation involves different gene expression programmes during development, which do not depend on the DNA sequence itself, but on epigenetic factors

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18
Q

What are the 2 types of epigenetic gene regulation?

A

1- Histone modification
2- DNA methylation or modifying the DNA itself

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19
Q

The expression state of a gene is determined by the … or … of its DNA regulatory regions, promoters or enhancers, in … and by the presence of … and …

A

packaging or accessibility
in chromatin
Transcription factors
Chromatin modifying enzymes

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20
Q

Accessibility of chromatin to transcriptional regulation is controlled by …

A

modification to the DNA itself or by modification/rearrangement of nucleosomes

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21
Q

Features of the nucleosomes:
X turns of DNA wrapped around…and two subunits, and N-terminal tails of histone protrude out of …

A

2 turns of DNA wrapped around a histone octamer
the nucleosome

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22
Q

True or false: 4 histone proteins that make up the nucleosomes but its actually an octamer

A

True

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23
Q

True or false: Tails can be pos-translationally modified..by additions of acetyl groups or methyl groups to those histones

A

True

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24
Q

What are the different groups of the epigenetic code?

A

Writers, erasers, readers, movers

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25
Q

Writers will..

A

add modifications

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26
Q

Erasers will

A

remove post-translational modification

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27
Q

Reader are…

A

proteins that read histone modification, such as acetylated or methylated residues

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28
Q

Movers are..

A

chromatin-remodeling proteins that move nucleosomes and allow gene transcription

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29
Q

What is the variant of H3 histone and what does it do

A

H3.3 and its important in transcriptional activation

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30
Q

True or false: epigenetic modifications allowed us to annotate non-coding regions of the genome

A

True

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31
Q

H3K4me1 is an
H3K27ac marks…

A

enhancer
active elements or strong enhancers and promoters

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32
Q

To map the epigenome, we use…
It’s a way to…

A

Chipseq (way to enrich DNA)

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33
Q

In chip-Seq of histone modification, they use an…to pull down those histones post-translational modification and sequence the DNA attached to those histones
-then they pile those reads up in the genome
- Get … in the locatioin where that particular histone is marked

A

-antibody to pull down those histones post-translational modification and sequence the DNA attached to those histones
-then they pile those reads up in the genome
- Get peaks in the locatioin where that particular histone is marked

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34
Q

True or false: Epigenetic annotations reveal the cell type-specificity of Non-coding elements

A

True

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35
Q

H3K4me1 (monomethylation) is an…

A

active enhancer

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36
Q

H3K4me3 (trimethylation) is an…

A

active promoter

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37
Q

H3K27ac is an…but if its trimethylated its an

A

active promoter
inactive promoter

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38
Q

True or false: Instead of profiling the histone marks, we can also profile open region, where the transcriptional machinery is present and theres multiple assets

A

TrueT

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39
Q

True or false: ATAC-sec is an assay for transposase-accessible chromatin using sequencing

A

True

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40
Q

Can we use ATAC-seq for mapping the open chromatin regions? if yes, how?

A

ATAC-seq usise a transposease which will insert into regions where there are no nucleosomes essentially and we can sequence those regions.

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41
Q

Whats the common trait and difference between Chip-seq and ATAC-seq

A
  1. they both study chromatin
    2.ChIP-seq pinpoints where specific proteins bind to DNA, showing their interactions and regulatory roles, while ATAC-seq maps open chromatin regions, revealing accessible areas of the genome involved in gene regulation.
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42
Q

True or false: Chromatin accessibility profiles reveal distinct molecular subtypes of cancers

A

True

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43
Q

Whats DNA methylation?

A

Addition of methyl group at CpGs

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44
Q

True or false: Epigenetic mechanisms act to change the accessibility of chromatin to transcriptional regulation via modification to DNA or by modification/rearrangement of nucleosomes (histones)

A

true

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45
Q

Does DNA methylation vary between different cells types and different stages in development

A

Yes

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46
Q

Whats the general roles of DNA methylation (4)

A

1-gene expression silencing
2- Genomic imprinting
3- X-chromosome inactivation
4- Suppression of retrotransposon elements

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47
Q

True or false; DNA methylation has writers and erasers

A

true

48
Q

True or false: DNA methylation is limited to cytosines and occurs with the context of the dinucleotide CG

A

True

49
Q

Name the two de novo methyltransferases that methylate CG dinucleotides

A

DNMT3A and DNMT3B (theyre writers)

50
Q

Whats the name of the enzyme that maintains existing DNA methylation patterns

A

DNMT1

51
Q

Whats TET

A

Ten eleven translocation - an enzyme that are methylcytosine transferase and initiate demethylation

52
Q

True or false: DNA methylation is a source of mutations

A

True

53
Q

true or false: C–>T mutations are common in human DNA : demaination of cytosine is a common reaction inc ells and normall produces uracil

A

True

54
Q

True or false: Uracil is in DNA not RNA

A

False, its in RNA

55
Q

What are some features of CpG islands (CGI) (3 features)

A

1- have a G+C-rich base composition
2- high density of the dinucleotide CpG
3- 1kb or less in lenght and are associated with genes

56
Q

Which region is more prone to deamination?

A

CpGs=
Unmethylated regions

56
Q

True or false: Approximately 50% of CpG islands are located in the vicinity of known transcriptional start sites

A

True

56
Q

True or false: CGIs is association with transcriptional start sites and remain unmethylated even when the gene is not being transcribed

A

True

57
Q

Whats deamination? removal of?

A

it refers to the removal of an amino group from a cytosine base, leading to the conversion of cytosine to uracil, which can cause changes in the DNA

57
Q

True or false: CpG islands are important because they represent areas of the genome that have been protected from the mutation properties of methylation through evolutionary time (deamination)

A

True

57
Q

What does deamination of cytosine cause?

A

produces uracil, and its normally found in RNA, so leads to alterations in DNA and changes the functions

58
Q

True or false: In normal cell we see CpG islands that are hypomethylated, and in cancer, we see an hypermethylation

A

True

59
Q

What are the Role of DNA methylation in cancer (3)

A

Gene silencing
Gene instability
Tumor heterogeneity

60
Q

True or false: Change in the chromatin structure are not depend of changes in DNA. methylation, histone modification and the positionning of nucleosomes

A

False, changes in the chromatin structure is dependent of changes in DNA methylation, histone modification and positioning of nucleosomes

61
Q

True of false: oncogenes are activated by gain-of-function mutations

A

True

62
Q

True or false: Tumor suppressors are recessively acting cancer genes in which the inactivation of both alleles promotes cell proliferation or inhibits apoptosis

A

True

63
Q

What the single nucleotide variants (SNV)

A

are alterations in the DNA sequence where a single nucleotide (A, T, C, or G) is substituted by another at a specific position in the genome.

64
Q

True or false : Mutations in cancer driver genes are under negative selection and confer a proliferative advantage to cancer cells

A

False, theyre under a positive selection

65
Q

What kind of mutations make you predisposed to cancers

A

germline cancers

66
Q

How do we detect driver mutations (somatic)

A

By sequencing normal VS tumor sample and look at variant in tumor genome that arent present in normal gene

67
Q

In sequences of normal vs tumor samples.. half the reads are mutations, not all of them.. why?

A

Because we have two chromosomes, and these mutations tend to be heterozygous (one parents gives the mutation)

68
Q

How do we detect cancer driver genes?

A

Sequence a bunch of tumor samples, map them to genes, and calculate some background mutation rate

69
Q

By sequencing tumor sample vs control sample, what does the sequencing say about the function of the driver genes

A

Nothing, it doesn’t say anything interesting about the function, or if its an oncogene or tumor suppressor

70
Q

True or false: Oncogenes differ from tumor suppressor genes in the distribution of cancer-associated mutations

A

True

71
Q

Whats a truncation?

A

Loss of function due to shortening or premature stop in protein, so tumor suppressor

72
Q

Hotspot mutations = oncogene or tumor suppressor?

A

Oncogene

73
Q

What are IDH1/IDH2 cancer-associated mutations : Theyre specific missense mutations producing mutant enzymes that convert … to… and that can inhibit … and lead to this hypermethylation in tumors.

A

Theyre specific missense mutations producing mutant enzymes that convert 2-oxoglutarate to 2-hydroxyglutarate and that can inhibit TET enzymes and lead to this hypermethylation in tumors.

74
Q

CNVs- copy number variants : are alterations in the DNA that involve …being duplicated or deleted, resulting in an abnormal number of copies of certain sections of DNA

A

Are alteration in the dNA that involves segments of the genome being duplicated or delete, resulting in an abnormal number of copies of certains sections of DNA

75
Q

How can you detect CNVs?

A

Next generation sequencing (analyzing read-depth), FISH (fluorescent probes to visualize and identify CNVs)

76
Q

True or false: In detection of DNA copy number variation, coverage is not necessarily equal across the genome

A

True

77
Q

True or false: Many low-level amplifications occur on circular extrachromosomal DNA (ecDNA)

A

False, high-level amplification

78
Q

True or false: When we look at copy numbers variance to find drivers… were interested in recurrance, so we want to see multiple patients with a similar gained region because we hypothesize in those regions ; the genes within those regions are potential oncogenes because these gains would lead to an increase in expression

A

True

79
Q

True or false: For recurrent copy number loss (deletions) we’re looking for recurrence across patients that show some type of selective advantage for that gene being either gain or loss

A

True

80
Q

What are you calculating when analyzing tumors

A

background mutations rate, or amplification rate, or copy number rate

81
Q

What are the 4 subgroups for detection of cancer driver genes and actionable genomic alterations

A
  1. Wnt
  2. SHH
  3. Group 3
  4. Group 4
82
Q

True or false: a major, unanticipated outcome of cancer genome sequencing projets is that roughly 50% of human cancers harbour mutations/alterations in chromatin-related proteins

A

True

83
Q

True or false: mutations in pediatric glastoma where they see recurrent mutations in K27 or H3Lysine27 and G35R

A

True, G34R is likely resulting and inhibiting the lysine36 position which is nearby, but its also recurrent, showing that the histone tails are important to these cancers

84
Q

Complete: Mutations in histone H3.3 (encoded by H3F3A or H3F3B) commonly occur at three residue: ….

A

K27, K36, G34

85
Q

Complete: H3.3K27M and H3.3-K36M mutations are … and reduce the genome wide … of H3K27 and H3K36

A

dominant negative and reduce the genome wide mthylation

86
Q

True or false: For H3K36, we see mutations to SETD2, and NSD1, NSD2

A

True

87
Q

EZH2 is part of which complex?

A

Part of PRC2 complex, and its mutated, amplified and deleted in cancer

88
Q

Whats the SWI/SNF complex?

A

SWI/SNF chromatin remodeling complex is a group of proteins that alter the structure of chromatin, allowing access to DNA and influencing gene expression by modifying how tightly DNA is packed around histone proteins.

89
Q

True or false: 20% of all cancers harbour mutations in SWI/SNF-encoding genes

A

True

90
Q

True or false: Nine different genes encoding subunits of the SWI/SNF family of chromatin-remodelling complexes are recurrently mutated in cancer

A

True

91
Q

Whats the most mutated complex accross all cancers

A

SWI/SNF

92
Q

True or false: SWI/SNF is involved in moving the nucleosomes so either sliding them, evicting them or opening them. Theyre chromatin remodelers, and allow access for transcription factors or the transcriptional machinery to bind to the chromatin DNA

A

True

93
Q

Is there a competition between SWI/SNF and PRC complex?

A

yes, theres antogonism between them so you cant have all components mutated in the same tumor. Theres some synthetic lethal relationship between SWI/SNF and PRC which may be exploited for cancer

94
Q

True or false: You can mutate ARID1A and EZH2 loss.

A

you cant see mutations with these two, they would kill the cell

95
Q

Whats the Cis-effect

A

the cis-effect describes how genetic elements or changes affect nearby genes on the same DNA strand

96
Q

True or false; The majority of the genome is non-coding regions

A

True

97
Q

True or false: about 2% of the genome actually codes for protein coding genes and the rest is non-coding

A

True

98
Q

True or false: the majority of the mutations are outside of the coding regions, majority are passenger and regions that are not active within the tumor

A

True

99
Q

True or false : The majority of the genome is non-coding

A

True

100
Q

Non-coding regulatory elements harbor a larger…

A

fraction of somatic mutations

101
Q

True or false: non-coding enhancers outside of oncogenes (MYC, MYCN, AE, KLF5, EGFR) are selectively amplified with or without their respective oncogenes

A

True

102
Q

Enhancers are selectively amplified with or without their respective oncogenes

A

WITH

103
Q

Do all CNVs (copy number variants) target the genes within them

A

Not all CNVs affect genes directly; some impact non-gene regions of the DNA, influencing how genes function without changing the genes themselves.

104
Q

How do we assign enhancers to their target genes?

A

3D chromatin structure analysis = Even if we look at the genome as a linear thing, in reality, inthe nucleus, its organized in 3D, and theres a method to indicate which regions are in close physical contact with each other, and theyre all based of this chromatin confirmation capture approach

105
Q

What are TAD domains

A

Topologically associated domains ; neighborhoods in the genome that keep certain genes and their controls together, separate from others, helping regulate gene activity.

106
Q

True or false: TADs are regions in the genome that tend to interact with themselves but they dont interact with each other (boundaries)

A

True

107
Q

True or false: Enhancer hijacking event can explain aberrant gene expression patterns

A

true

108
Q

Is MYCN is amplified in many different tumors

A

Yes

109
Q

Whats GFI1B, and its link to TAD boundaries

A

GF1B is important for the development of blood cells (patelet)
If also marks boundaries in TADS

110
Q

True or false: SNCAIP duplication is highly recurrent in Group4 medulloblastoma

A

True, there’s focal amplification or duplication of SNCAIP

111
Q

True or false: If you duplicate TAD boundary, you create new TADs that include enhancers from neighbour TAD within that regions allowing them to activate those potential cancer genes /

A

True

112
Q

ecDNA enables distal DNA interactions ….what are ecDNA

A

circular DNA structures separate from the main chromosomal DNA, often found in cancer cells.

113
Q

Whats th interplay between the genome and the epigenome drives aberrant gene expression in cancer

A

Changes in the epigenome (chemical modifications to DNA and proteins) alongside genetic alterations can disrupt normal gene control, leading to abnormal gene behavior in cancer.

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