Investigate DNA and RNA to identify relevant biomarkers
DNA and RNA molecules are the basis of the constitution of each cell, each organ and therefore each organism.
Isolating these molecules and deciphering their mechanisms makes it possible to identify certain biomarkers (or biological markers) that will be associated with pathologies or to the response to external agents such as drugs, pollution, etc.
DNA and RNA: Definition and function
DNA and RNA (deoxyribonucleic acid and ribonucleic acid, respectively) are molecules with differences in their structure and function in the cell.
DNA represents the matrix of all the cells of an organism and contains the encryption of genes. These genes are expressed in the form of RNA: RNA coding for a protein (~2% of the human genome) and non-coding RNA (~20% of the human genome). These genes allow the synthesis of the elementary building blocks of life, promote certain enzymatic reactions and allow an extremely complex regulation of all these elements.
Unlike DNA, which is constituted at birth and changes little over the course of Life, RNA is constantly evolving, reflecting the general state of health of the cell, organ and organism to which it belongs.
“Knowing our genes, or relevant ones, helps us to take charge of our health. If DNA is our blueprint, RNA are the daily messengers that help implement the plan. RNA are more changeable than DNA and not as stable”, explain Dr. Sharad Paul, a New Zealand cancer surgeon and author of « The Genetics of Health », a study on the role genes play in life.
Investigate DNA and RNA to identify relevant biomarkers
In the course of researches, the purpose of DNA analysis is to identify genomic mutations, from single DNA building block (base pair) to a large segment of a chromosome that includes multiple genes. Two main types of alteration, so called mutations, are observed:
- Constitutional genetic alterations, inherited from a parent, which are also called germline mutations because they are present in the parent’s egg or sperm cells, which are also called germ cells. If this DNA contains a mutation, the child that grows from the fertilized egg will have the mutation in each of his or her cells. These alterations may be part of the "positive" evolution of a species over time.
- Somatic (or acquired) genetic alterations, which occur at some time during life and are present only in certain cells, not in every cell in the body. These changes can be caused by environmental factors such as ultraviolet radiation from the sun, or can occur if an error is made as DNA copies itself during cell division. Acquired mutations can lead to the development of a pathology (genetic diseases, cancers, etc.).
The DNA was considered as the tractable class of disease-causing mutations. These modifications are highly explored, especially since the advent of DNA sequencing.
The most studied mutations are the single-nucleotide polymorphisms (SNPs) and Insertion/Deletions (InDels) sequences, which represent unique mutation or sequence that can be modified, inserted or deleted randomly or targeted into the genome of an individual, or a group of individuals with common characteristics (healthy or sick, drug treated or placebo, same ethnicity, etc.). These processes also represent mechanisms that can lead to the occurrence of a biological phenomenon or disease such as resistance or susceptibility to some infections.
DNA can also undergo “chemical” changes such as the methylation (or demethylation) of a deoxyribonucleic acid. These epigenetic modifications, natural phenomenon, are normally controlled by the cell itself but sometimes undergone by an external agent (pollution, etc.), and lead to a change in the expression of genes and therefore the induced proteins.
Remark: During the last decade, in the field of oncology research, specific DNA molecules are strongly investigated in the case of solid tumor identification. If cell-free DNA (cfDNA) is detected naturally and normally in liquid biopsies (blood, saliva or urine), researchers look for detecting circulating tumor DNA (ctDNA). These ctDNA are originate from the tumor or from circulating tumor cells (CTC), intact tumor cells that shed from primary tumors.
From DNA to RNA
In the process of gene expression (transcription), the genes encoded into the DNA are copied and transcribed into RNA molecules. The RNA family is very large and can be divided into two families:
- The protein-coding RNAs (mRNA or coding RNA). The most studied is the messenger RNA (mRNA) and represents less than 3-5% of RNA molecules in the cell. They are involved in the production of proteins, hormones, enzymes, etc.
- and non-coding RNAs, i.e. RNAs lacking a protein-coding potential. Non-coding RNAs are then divided into different classes according to their localization or mechanism of action able to physically interfere with another RNA, DNA or a protein in order to modify their activities. For instance, long noncoding RNA as ribosomal or transfer RNA (more than 90% of total RNA molecules in a cell) are involved in translation processes, small nuclear RNA in RNA modification, or small interfering RNA, microRNA and piwi-interacting RNA in RNA silencing.
In the course of researches, the analysis of certain RNAs aims to identify molecular processes that are naturally controlled by the cell, but which are disrupted in some cases:
- Alternative splicing: process allowing one gene to produce different RNA molecules and to introduce diversity (according to an environmental or biological need, a cell alteration, a pathology, a drug response, etc.). Thus, each RNA can be translated (process to synthetize a protein from a RNA molecule) in multiple proteins, and thus different cellular functions, with positive or negative effects;
- Post-transcriptional modifications of RNAs (RNA editing): process allowing to introduce structural modifications of the RNA (polymorphism, methylation...) at the time of its maturation and, consequently, to modify the produced protein;
- RNA degradation (degradome): process allowing to control the lifespan, and therefore the activity of an RNA molecule, which can be from a few seconds to several days.
DNA and RNA biomarkers in medical practice and clinical trials
DNA and RNA are today used as biomarkers for the diagnosis and prognosis of various diseases. Detectable in tissues or fluids (liquid biopsies: saliva, urine, serum or blood), these nucleic acids are thus considered as routine biomarkers for cancer diagnosis, monitoring of tumor progression and prediction of therapeutic response such as response or resistance to a molecule.
Over the past few decades, clinical trials using biomarker or biomarkers able to the stratification of patients have proven successful in the development of new drugs. Since the end of 2018, more than 30 drugs have been developed in combination with diagnostic tests to identify the patients most likely to benefit from these new treatments. This approach is followed today for scientists & industrials involved in precision medicine.
RNA Biomarkers: a therapeutic approach in real time
More specifically, RNA analysis (or gene expression analysis) is a particularly relevant approach in diagnosis and predictive diagnosis with very good experimental results obtained in different diseases, especially in oncology. RNA analysis presents the advantage that it can be performed on a liquid biopsy, especially a blood sample, a non-invasive approach adapted for routine clinical use: ease to use, safe to use, high throughput and low cost.
Compared to analyses carried out on the tumor (random sampling not representative of the diversity of the clonal population) or on cerebrospinal fluid in neurodegenerative pathologies (risks for the patient, high cost, low throughput…) or by medical imaging (low throughput, high cost…), the analysis of gene expression using (total) blood fully meets the needs identified of many scientists and medical teams.
RNA biomarkers allow:
- a very early analysis of the appearance or evolution of the disease,
- a differential analysis of gene expression,
- an informative and accurate analysis,
- a specific analysis of the response to drug.
In recent years, numerous studies have demonstrated the relevance of using RNA analysis technologies for the identification of relevant diagnostic biomarkers. These RNA detection technologies are today used by several in vitro diagnostic tests (IVD) and allow detection, stratification or therapeutic orientation for patients suffered from breast or colon cancer.
Consequently, DNA and RNA changes, evolutions or modifications can be classified as gain-of-function or loss-of-function, or also as alterations, and must be considered as high potential actionable targets or biomarkers, as well in drug treatment development as in innovative diagnostic ones.
Acobiom expertise implemented an innovative approach to improve personalized cancer management in the decision-making process, by using RNA biomarkers to help in the patient stratification.
Based on its know-how and technological platform, the company offers also a range of omics services for the analysis, identification and validation of DNA or RNA biomarkers.
