Aberrant gene expression in cancer biology Flashcards by Rozhin Agoush

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

H2A, H2B, H3, H4

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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

Mutations within the promoter of the TERT gene

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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

All of the above

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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

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

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

True

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

True

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

True

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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

True

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Whats the epigenetic control of gene expression?

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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How somatic cancer driver genes are identified using genomics

CRISPR/Cas9, Whole genome sequencing

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what are key features of cancer

Aberrant gene function and altered proteins

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

True

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

true

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What are the 4 subgroups of medullablastoma

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

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What is epigenetic?

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

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

True

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

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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What are the 2 types of epigenetic gene regulation?

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

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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 …

packaging or accessibility
in chromatin
Transcription factors
Chromatin modifying enzymes

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Accessibility of chromatin to transcriptional regulation is controlled by …

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

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

2 turns of DNA wrapped around a histone octamer
the nucleosome

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

True

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

True

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What are the different groups of the epigenetic code?

Writers, erasers, readers, movers

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Writers will..

add modifications

Erasers will

remove post-translational modification

Reader are...

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

Movers are..

chromatin-remodeling proteins that move nucleosomes and allow gene transcription

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

H3.3 and its important in transcriptional activation

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

True

H3K4me1 is an H3K27ac marks...

enhancer active elements or strong enhancers and promoters

To map the epigenome, we use... It's a way to...

Chipseq (way to enrich DNA)

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

-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

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

True

H3K4me1 (monomethylation) is an...

active enhancer

H3K4me3 (trimethylation) is an...

active promoter

H3K27ac is an...but if its trimethylated its an

active promoter inactive promoter

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

TrueT

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

True

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

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

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

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.

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

True

Whats DNA methylation?

Addition of methyl group at CpGs

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)

true

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

Yes

Whats the general roles of DNA methylation (4)

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

True or false; DNA methylation has writers and erasers

true

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

True

Name the two de novo methyltransferases that methylate CG dinucleotides

DNMT3A and DNMT3B (theyre writers)

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

DNMT1

Whats TET

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

True or false: DNA methylation is a source of mutations

True

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

True

True or false: Uracil is in DNA not RNA

False, its in RNA

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

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

Which region is more prone to deamination?

CpGs= Unmethylated regions

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

True

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

True

Whats deamination? removal of?

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

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)

True

What does deamination of cytosine cause?

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

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

True

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

Gene silencing Gene instability Tumor heterogeneity

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

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

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

True

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

True

What the single nucleotide variants (SNV)

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.

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

False, theyre under a positive selection

What kind of mutations make you predisposed to cancers

germline cancers

How do we detect driver mutations (somatic)

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

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

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

How do we detect cancer driver genes?

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

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

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

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

True

Whats a truncation?

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

Hotspot mutations = oncogene or tumor suppressor?

Oncogene

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.

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.

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

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

How can you detect CNVs?

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

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

True

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

False, high-level amplification

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

True

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

True

What are you calculating when analyzing tumors

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

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

1. Wnt 2. SHH 3. Group 3 4. Group 4

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

True

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

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

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

K27, K36, G34

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

dominant negative and reduce the genome wide mthylation

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

True

EZH2 is part of which complex?

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

Whats the SWI/SNF complex?

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.

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

True

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

True

Whats the most mutated complex accross all cancers

SWI/SNF

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

True

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

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

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

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

Whats the Cis-effect

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

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

True

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

True

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

True

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

True

Non-coding regulatory elements harbor a larger...

fraction of somatic mutations

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

True

Enhancers are selectively amplified with or without their respective oncogenes

WITH

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

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

How do we assign enhancers to their target genes?

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

What are TAD domains

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

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

True

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

true

Is MYCN is amplified in many different tumors

Yes

Whats GFI1B, and its link to TAD boundaries

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

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

True, there's focal amplification or duplication of SNCAIP

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 /

True

ecDNA enables distal DNA interactions ....what are ecDNA

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

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

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.

Aberrant gene expression in cancer biology Flashcards

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