What is Epigenetics?

Epigenetics is the study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself; “epigenetics has transformed the way we think about genomes”. We can’t change the hardwiring of our genetic code, but epigenetic factors such as lifestyle and diet can radically change what our genes do.

What is the significance of this?

Epigenetic change is a regular and natural occurrence but can also be influenced by several factors including age, the environment/lifestyle, and disease state; it can be viewed as not about your genes but how you communicate with your genes through your diet, lifestyle & the environment you bathe your genes in. Epigenetic modifications can manifest as commonly as the manner in which cells terminally differentiate to end up as skin cells, liver cells, brain cells, etc. Or, epigenetic change can have more unwanted and damaging effects that can result in diseases like cancer.

Stress, diet, behaviour, toxins and other factors activate chemical switches that turn genes on and off and regulate gene expression, in other words, you can change how your genes are expressed.

At least three systems including DNA methylation, histone modification and non-coding RNA (ncRNA)-associated gene silencing are currently considered to initiate and sustain epigenetic change [1].

What do you mean you can change how your Genes are Expressed?

Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product; the products, for the most part, produced by the genes are amino acids and proteins. Throughout the lifetime of a cell, new proteins must be produced to replenish older molecules that have been degraded, to facilitate morphological changes in response to environmental stimuli, and during the process of cell division to create new daughter cells. Thus, proteins are the build blocks for cell replenishment and are in constant demand.

For the most part you do not manifest disease merely by a defective gene, but by the regulation or expression of your genes, and the expression of your genes is much more dynamic and modifiable than had previously been realized.

I always thought there was nothing you can do about your Genes. Is this true?

There is a common misconception that we are stuck with the genes we inherited at conception but this is a myth; most genes are not set in stone or fixed, but rather modifiable and can be turned on or off.  In fact, you ARE changing your genetics daily and perhaps even hourly from the foods you eat, the air you breathe, and even by the thoughts you think.

What do you mean you can turn Genes On and Off?

The expression of genes in a body can be influenced by the environment, including the external world in which the body is located or develops, as well as the body’s internal world, which includes such factors as its hormones and metabolism. Thus bathing your genes in the right environment (good nutrients, regular exercise, nourishing stimulation), will turn the genes for health on and the “disease” genes off thereby influencing the way our body develops and functions.

You can “turn on” genes that prevent chronic diseases and “turn off” oncogenes that promote breast cancer and prostate cancer as well as turn off genes that cause inflammation and oxidative stress. Your genes are controlled by epigenetic coding that tells them to be expressed or not expressed — which is partly controlled by your environment and lifestyle.

Genetic and Epigenetic interplay towards cancer

Much effort has been invested in identifying genetic mutations (DNA alterations) in cancer and in inherited cancer syndromes this approach has proved successful.

Genes_EpigeneticsDiagram

Figure 1 – Epigenetic alterations in the genesis of cancer. How genetic and epigenetic alterations may cooperate in the genesis of cancer. 3 potential pathways are shown indicating how genetic change may precede epigenetic change, and vice versa, as the cause of cancer.

Epigenetic alterations are as important as genetic mutations in a cell’s transformation to cancer.[2] Cancer epigenetics is the study of epigenetic modifications to the genome of cancer cells that may not involve a change in the DNA sequence and can be induced by various factors [3]. There are three possible scenarios (figure 1):

  1. Epigenetic change ‘primes’ the cell for further DNA mutation leading to cancer initiation
  2. Epigenetic change leads directly to cellular transformation and cancer initiation
  3. DNA alteration leads directly to cellular transformation and cancer initiation

The mechanisms by which epigenetics functions is through the silencing of tumour suppressor genes and/or the activation of oncogenes. An oncogene is a gene that has the potential to cause cancer. The epigenetic silencing of tumour suppressor genes and the activation of oncogenes is usually done through the following mechanisms [4-9]:

  1. DNA methylation

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Figure 2 – DNA methylation is associated with Acute myeloid leukaemia (AML), Myelodysplastic syndromes (MDS), Myeloproliferative disorder (MPD) and Chronic myelomonocytic leukemia (CMML)

  1. Histone modification

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Figure 3 – Histone modification is associated with Acute myeloid leukaemia (AML), Acute lymphoblastic leukaemia (ALL), Diffuse large B-cell lymphoma (DLBCL), Non-Hodgkin lymphoma (B-cell) (B-NHL), Transitional cell carcinoma (TCC) and Myelodysplastic syndromes (MDS)

  1. Nucleosome (Chromatin) remodelling

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Figure 4 – Chromatin remodelling is associated with Acute myeloid leukaemia (AML), Acute lymphoblastic leukaemia (ALL), Transitional cell carcinoma (TCC), Diffuse large B-cell lymphoma (DLBCL), Myeloproliferative disorder (MPD) and Myelodysplastic syndromes (MDS)

  1. Noncoding RNA targeting

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Figure 5 – Noncoding RNA is associated with T-cell prolymphocytic leukemia (T-PLL), Acute myeloid leukaemia (AML), Acute lymphoblastic leukaemia (ALL), Myeloproliferative disorder (MPD), Chronic myeloid leukaemia (CML) and Non-Hodgkin lymphoma (NHL)

Epigenetic drugs in clinical use [10]

To date, five epigenetic drugs have been approved by the US Food and Drug Administration (FDA):

  • 2 DNA methyltransferase (DNMT) inhibitors.  (i) 5-azacytidine (5-aza-CR; manufactured by Celgene as Vidaza) was approved in 2004 specifically to inhibit DNA methylation. Two years later its variant 5-aza-2′-deoxycytidine was approved (5-aza-CdR; manufactured by Eisai as Dacogen). Both were approved for the treatment of higher-risk myelodysplastic syndrome (MDS). (ii) S110, which is a dinucleotide containing 5-aza-CdR and is suggested to have enhanced stability and efficiency, completes the list of DNMT inhibitors that are in use in the clinical setting.
  • 3 histone deacetylase (HDAC) inhibitors. (i) Vorinostat (Merck, known as Zolinza) — an FDA-approved HDAC inhibitor for the treatment of cutaneous T cell lymphoma (CTCL) — was also confirmed to induce complete response or haematological improvement in AML patients. (ii) Romidepsin (Celgene, known as Istodax)  revealed remarkable efficacies in the treatment of cutaneous T cell lymphoma (CTCL) patients. (iii) Panobinostat (Novartis, known as Farydak) was recently approved (February 2015) by the FDA for treatment of  Multiple Myeloma. An additional HDAC inhibitors —  CI-994 (Pfizer, known as Tacedinaline) — is currently being tested in clinical phase III trials for the treatment of non-small-cell lung cancer (NSCLC).

 

References:

1. Bishton M, et al. Epigenetic targets in hematological malignancies: combination therapies with HDACis and demethylating agents. Expert Rev Anticancer Ther. 2007;7(10):1439-49.
2. Dickinson M, et al. Histone deacetylase inhibitors: potential targets responsible for their anti-cancer effect. Invest New Drugs. 2010;28 Suppl 1:S3-20.
3. Feinberg AP. The epigenetics of cancer etiology. Seminars Cancer Biol. (2004) 14:427-432.
4. Johnstone R, editor Epigenetics & HDAC Inhibition as Therapeutic strategies in Oncology. EHA – MSD scientific symposium; 2010; Barcelona.
5. Kenealy M, editor Epigenetic studies guiding therapy. RCPA Pathology Update 2011; Melbourne.
6. Prince HM, editor Epigenetic therapies for lymphoma. Haematology of Australia and New Zealand (HSANZ); 2010; Auckland.
7. Spencer A, editor Pre-clinical evaluation and novel therapeutics. 13th International Myeloma Workshop; 2011; Paris, France.
8. Wei AH, editor Novel therapies for Acute Myeloid Leukemia. Haematology of Australia and New Zealand (HSANZ); 2010; Auckland.
9. Dawson MA, et al. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150(1):12-27.
10. Heyn H, et al. DNA methylation profiling in the clinic: applications and challenges. Nature. 2012;13:679-692.

 

(Information courtesy of ALLG)

What is a clinical trial?

A clinical trial is a scientific study, or an organised test of medicines and new treatment options involving patient and non-patient human volunteers. Clinical trials confirm whether medicines are safe and effective before they can be introduced as new treatments for a particular disease or condition.

Are all clinical trials the same?

No, there are four different types of clinical trials, each one associated with a different phase in the development of a new medicine or treatment:
Phase 1: Determines the safety of the medicine, how it works and how well it is tolerated in small groups of people
Phase 2: Determines the effectiveness of the medicine and further evaluate the safety in a larger group of people
Phase 3: Determines the effectiveness, monitors side-effects and compares it to commonly used treatments in large groups of people
Phase 4: Post marketing studies reflect additional information including the drugs risks, benefits and optimal use

Why participate in a clinical trial?

By participating in a clinical trial you can play a more active role in your own health care, gain access to new research treatments at no cost before they are widely available, receive extensive medical care associated with the trial and help others by contributing to medical research.

What happens in a clinical trial?

In a clinical trial a team including doctors, nurses and other health professionals  carefully follow the protocol or plan of the trial. They check the health of the participant at the start of the trial, give specific instructions for participating in the trial, monitor the participant through the trial and stay in touch after the trial is completed.

What is informed consent?

Informed consent is the process of learning the key facts about the clinical trial before deciding whether to participate. Doctors and nurses involved in the trial explain the details of the study and provide an informed consent document that outlines the study purpose, duration, required procedures, risks and benefits and key contacts. The patient then decides whether or not to sign the document. Informed consent is not a contract and the participant may withdraw from the trial at any time.

What are the benefits and risks of participating in a clinical trial?

Participants in clinical trials can play a more active role in their own health care, gain access to new research treatments at no cost before they are widely available, receive extensive medical care associated with the trial and help others by contributing to medical research.

There are risks to clinical trials; there may be unpleasant, serious or even life threatening side effects to experimental treatments. The treatment may not be effective for the participant. The protocol or plan may require more of their time and attention, including trips to the study site, more treatments, hospital stays or complex dosage requirements.