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Pharmacogenetics > Epigenetic testing for stratified medicine > Flashcards

Epigenetic testing for stratified medicine Flashcards

1
Q

What is Stratified medicine based upon?

A

On identifying subgroups of patients with distinct mechanisms of disease, or particular responses to treatments. This allows us to identify and develop treatments that are effective for particular groups of patients.

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2
Q

What is Waddington’s epigenetic landscape?

A

A metaphor for how gene regulation modulates development.

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3
Q

What are the key roles of epigenetics in normal development and over the life course?

A 
‣ Gene expression regulation
‣ Reprogramming: cell lineage & tissue differentiation
‣ Genomic stability
‣ Genomic Imprinting
‣ X-chromosome inactivation
‣ Human Disease
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4
Q

What is a biomarker according to the WHO?

A

“any substance, structure, or process that can be measured in the body or its products and influence or predict the incidence of outcome or disease”

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5
Q

What is the NIH definition of a biomarker?

A

“a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”

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6
Q

What is the working definition of a biomarker?

A

A biological marker that can be accurately and reproducibly measured.
ideally it is present in easily accessible samples, such as blood or saliva, prior to diagnosis.

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7
Q

What is the aim of a biomarker?

A

To improve disease diagnosis and therapy.

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8
Q

What are causes of epigenetic variation in human populations?

A

Genes- Germline, Somatic

Time- Stochastic, Directional

Environment- Internal environment, External environment, Sex, Complex phenotypes, Hormone

Gene expression

Complex phenotypes

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9
Q

What can be either a cause or a consequence of epigenetic variation in human populations?

A

Gene expression

Complex phenotypes

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10
Q

What is the aim of Epigenome-wide association studies (EWAS)?

A

assay epigenetic changes across the genome and associate these with phenotypes or environmental exposures to identify differentially methylated regions
(DMRs) in complex traits or environmental factors.

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11
Q

What are EWAS Methods and considerations?

A

EWAS study design: tailor to research question

Power

Tissue & cell-specificity: disease relevance/cell heterogeneity

Methylation assay: coverage vs sensitivity

Statistical analysis: data quality control & association tests

Multiple testing correction

Validation of DMR using independent assay

Replication of DMR in an independent sample

DMR cause/consequence of trait?

Longitudinal&MR follow up DMR functional follow up to establish functional relevance

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12
Q

Compared to GWAS, there are more potential what in EWAS?

A

Confounding factors making study design, cell-heterogeneity correction, and cause/consequence explorations crucial in an EWAS

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13
Q

For the past few decades DNA methylation has not changed in specific genes

True or false

A

False

For the past few decades DNA methylation changes in specific genes have been linked to Imprinting disorders, X-chromosome abnormalities, and multiple cancers

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14
Q

What allow for DNA methylation assays throughout genome, and identify epigenetic changes in a wide range of traits in epigenome-wide association studies (EWAS)?

A

Recent technologies

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15
Q

EWAS have uncovered what?

A

Striking methylation changes related to ageing and environmental exposures such as smoking. Modest-moderate effects have been observed in a number of human diseases (T1D, T2D, RA, etc) and other exposures

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16
Q

What are epigenetic biomarkers of disease used for?

What are some examples?

A

Risk stratification to diagnosis, to disease sub-type identification, to disease progression

Examples include cancers, neurological disorders, and others

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17
Q

What are epigenetic biomarkers of environmental exposures used for?

A

Risk stratification, risk-tailored interventions

18
Q

What are epigenetic biomarkers of medication used for?

A

Stratified patient groups in treatment, and ultimately personalised treatment

19
Q

What are the most common epigenetic biomarkers?

A

DNA methylation vs histone modification biomarkers

20
Q

Epigenetic biomarkers of disease have been found in…

A

Cancer
Obesity and metabolic disease - risk for obesity, obesity, progression to metabolic disease, Type 2 diabetes
Immune-system disorders (e.g. T1D, RA) Neurological diseases (e.g. AD, PD, MS) Many others

21
Q

What are the characteristics of epigenetic biomarkers of disease?

A

Apart from cancer, typically (very) small effects

Epigenetic biomarkers specific to the disease can be revealed earlier than clinical, histopathological or radiological markers.

Biomarkers in blood usually, in some cases age-specific

Ensure no confounding effects in discovery study, e.g. cell heterogeneity

22
Q

What is Cancer defined by?

A

Uncontrolled division of abnormal cells

23
Q

Progressive epigenetic changes in cancer occur when?

A

Initiation and progression

24
Q

More recently, what do genome-wide scans confirm?

A

gross epigenetic abnormalities in cancer tissue

25
Q

DNA methylation changes in cancer fall into which two categories?

A
  1. Genome-wide hypomethylation and 2. CpG-specific changes at:
  2. Repetitive sequences- Loss of methylation is one of the characteristic features of a cancer cell. This leads to genome instability as allows repetitive sequences to trigger genome rearrangements, chromosome translocations that lead to gross genomic instability
  3. CpG Island promoters
  4. CpG Island Shore
  5. Gene Body

2, 3 and 4 present series of specific changes that alter function of specific genes such as gain or loss of methylation in a cancer cell which has functional consequences for nearby genes

26
Q

The reversibility of epigenetic changes makes them excellent drug targets. Currently what classes of epigenetic drugs are in use?

A

Broad target enzymes:

  • Methyltransferase (DNMT) inhibitors
  • Histone deacetylase (HDAC) inhibitors

Sirtuin family of enzymes - HDAC activity

Histone methyltransferases - specific target sites (e.g. EZH2, DOT1L)

Successful use in multiple cancers, and in trial stage for specific other diseases, e.g. neurological disorders

27
Q

What are potential future targeted applications of epigenetic?

A

Combination approaches

Epigenetic editing at specific CpG-sites in the genome

28
Q

What are examples of epigenetic therapies in cancer?

A

i) DNA methylation
- DNMT3A (de novo methyltransferase) mutations in acute myeloid leukemia (AML) with impact on prognosis, and also in myelo-dysplastic syndromes (MDS), and MPDs.
- DNMT inhibitors (azacitidine and decitabine) reactivate expression of aberrantly silenced genes, with impacts on MDS [FDA approved in clinic].
(ii) DNA hydroxymethylation

  • TET enzymes convert 5mC to 5hmC, in first step of de-methylation.
  • TET-2 mutations reported in numerous malignancies; lead to chronic myelomonocytic leukemia (CMML) in TET-2 deficient mice; linked to high 5mC levels in malignant blood cells; associated with poor prognosis.

(ii) Histone changes
Acetylation/Deacetylation/Methylation/Demethylation/Phosphorylation/ Readers

29
Q

What are examples of epigenetic therapies in Multiple Sclerosis?

A

Genetic biomarkers for response to standard glucocorticoids therapy

Epigenetic biomarkers are being developed for response to therapy (glucocorticoids, and others)

Trials for epigenetic drugs in MS: HDAC and DNMT inhibitors

30
Q

What are examples of epigenetic therapies in Alzheimers disease?

A

Genetic biomarkers for AD (APP, PSENs, APOe4, LOX)

Epigenetic changes in post-mortem brain tissue, lead to pre-clinical studies for potential epigenetic drug in AD: HDAC inhibitors.

31
Q

What is Alzheimers disease?

A

Most common neurodegenerative disorder characterised by deposition of plaques, hyper-phosphorylation of NF tangles, and cytokine

32
Q

What is Multiple Sclerosis?

A

Chronic inflammatory disease, where autoreactive T-cells attack myelin-based protein damaging the sheaths of nerve cells in brain and spinal cord

33
Q

What is the rationale for combined genetic and epigenetic testing in stratified medicine?

A

Rationale: most common complex human diseases are due to a combination of genetic with environmental risk factors of small to moderate effects

Genetic mutations are already used as biomarkers in stratified medicine, but in most cases genetic changes explain only a proportion of the risk of developing disease

Combining genetic and environmental risk factors improves disease risk prediction (e.g. in breast cancer)

Epigenetic changes have been identified as valuable biomarkers of environmental exposures

Thereby combined genetic and epigenetic testing should provide a measure of the joint genetic and environmental risk.

34
Q

Environmental Epigenetics in Humans focuses upon Genome-wide studies and Candidate-gene studies and asks what?

A

What exposures?

How much epigenetic change?

Where are the changes?

Systemic effects?

Epigenetic +/- Expression?

35
Q

There are many completed and on-going efforts to identify DNA methylation markers of environmental exposures

Majority of effects are direct external environmental exposures. What are some examples?

A

Cigarette smoking, alcohol consumption, diet, pollution, sunlight, etc

36
Q

There is a very strong and replicated DNA methylation signals for what environmental exposure?

A

Tobacco smoking: effect also present for in utero exposure to cigarette smoke

Signals also identified for other exposures, but effects are of smaller magnitude and can be specific: environment risk difficult to measures

37
Q

DNA methylation is a potential biomarker of environmental risk factors

True or false

A

True

38
Q

There are hundreds of smoking differentially methylated signals with 50+ replicated. Which of these are the top hits?

A

AHRR, F2RL3, GFI1, 2q37

39
Q

What is the strongest and most replicated smoking methylation change?

Explain its mechanism of action

A

AHRR

AHRR encodes a transcription factor that inhibits the aryl hydrocarbon receptor pathway (AHR pathway)

AHR pathway enhances the expression of detoxification enzymes of environmental pollutants, such as polycyclic aromatic hydrocarbons contained in cigarette smoke.

Cigarette smoking-induced decreases in AHRR DNA methylation and related increases in AHRR expression may compromise the body’s capacity to metabolize and thus remove harmful environmental chemicals.

A potential mechanism of increased risk of carcinogenesis in smokers?

40
Q

At some methylation signals, the effects revert upon smoking cessation.

True or false

What does this mean

A

True

DNA methylation is a predictor not only of smoking status, but also of how long ago one quit

41
Q

The strongest evidence for early life exposures linked to epigenetic changes is found in what?

A

Maternal smoking:

Maternal smoking induces major epigenetic changes that persist over time, and are also seen in studies of direct exposure to tobacco smoking in adults

Maternal nutrition:

Dutch Hunger Winter Study: food restriction in utero has adverse effects on metabolism and cardiovascular health, and age-associated decline of cognitive functions2. Epigenetic analyses show persistent epigenetic changes associated with prenatal exposure to famine 3.

42
Q

What are examples of combining genetic and epigenetic biomarker profiling for risk stratification and treatment in cancer?

A
  1. Non-small-cell lung carcinoma (NSCLC)

Risk and treatment stratification: different risk profile and treatment options in patients with ALK and BRAF gene mutations, potentially targeting their gene function in molecular treatment.

  1. Breast cancer
    Risk stratification: BRCA1 and BRCA2 mutation carriers: 3-6X (or 9-36) increased risk compared to general population

Risk stratification: 3-gene methylation panel (ITIH5, DKK3 and RASSF1A) may serve as early detection biomarker in blood

  1. Colon cancer
    Personalised therapy: KRAS gene function determines if drug therapy alone, or in combination with chemotherapy, is applied.

Pharmacogenetics (16 decks)

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