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Next Generation Sequencing in Precision Medicine and Personalized Medicine

The terms precision medicine and personalized medicine are sometimes used synonym together with the terms stratified medicine and P4 medicine. The definition of these terms is not always biunique.


Precision Medicine

Despite very high homology between human genomes, every human genome has its own characteristic sequence. Thousands of single nucleotide variations (polymorphisms), insertions, deletions or reversions can influence gene functions and can lead to different phenotypes or diseases. Often genetic differences does not display phenotypic differences between individuals. Some diseases that can be associated with specific genetic variations are for example diabetes, Alzheimer, Epilepsy, types of heart diseases or some types of mental illnesses. In precision medicine, genetic variations are considered in order to find the best treatments for the individual patient. Besides genetic variations, precision medicine also considers environment factors as well as lifestyle and behavior for individual patient treatment. Some of these factors are for example, fitness, obesity, and nutrition. Precision medicine is leaving the concept of the intermediate patient with one universal treatment for each individual patient.


Personalized Medicine

Briefly, personalized medicine means the individual and tailored treatment of patients corresponding to their disease or symptoms. Personalized medicine includes precision medicine, but also comprises additional factors. Personalized medicine takes into account all biomarkers related to certain diseases including the microbiome. The microbiome of an organism can include multiple different bacteria or viruses. All of these viruses and bacteria have its own characteristic genome that can lead to different virulence types or resistances against treatments. It is not biunique if precision medicine considers only genetic variations of the individual patient or if precision medicine also considers genetic variations in the microbiome or disease related pathogens.


Precision Medicine Initiative (PMI) Cohort Program

In 2015 US president Obama launched the precision medicine initiative in the USA in order to revolutionize and improve the health care system. This initiative includes a budget of $215 million for the year 2016. This program will extend precision medicine to all diseases and aims to build a national research cohort. This program will support research in the fields of human biology, behavior, genetics, environment, data science and computation in order to develop new ways for disease treatments. For more information visit the website of the National Institutes of Health


Hereditary Diseases and Precision Medicine

To understand the genetic factors leading to individual phenotypes and diseases genetic data of thousands of individual patients are needed. Different projects including the 100.000 Genomes Project and the NIH Human Microbiome Project are undertake in order to generate these sequence data. Next generation sequencing is the technology of choice to provide these sequence data.
If the genetic factors and biomarkers are known NGS can be used for diagnosis of hereditary diseases and for cancer prognosis and diagnosis. Currently, a large number of variations in numerous genes are known to be associated with certain hereditary diseases. A number of commercial provider and diagnostic laboratories developed specific NGS gene panels for the detection of genetic variations related or leading to certain hereditary diseases. Including different panels for diagnosis of genetic variation related to epilepsy, heart diseases, neuro genetics, metabolic disorders, muscle and mitochondrial genetics, hematologic diseases, respiratory diseases, and many more rare genetic disorders. Additionally, the NGS Hub provides a database of diagnostic laboratories that offer NGS or genetic testing service for precision medicine.
Sometimes, genetic factors alone are not sufficient for disease manifestation and development of clinical signs. Other factors including epigenetic, lifestyle, or environmental factors will be critical for and contribute to phenotype displaying and disease outbreak.


Cancer Genetics and Precision Medicine

For cancer genetics applies almost the same as for hereditary diseases. Different genetic markers are known to be associated with higher risk or occurrence of certain cancer types. Next generation sequencing is applied in cancer prognosis for the detection of known genetic variants. Additionally, cancer cells can rapidly mutate and develop individual genotypes. Sequencing of these cells can support to find the best available and most effective treatment methods.
As the development of certain cancer types is very complex and partially poorly understood the current available methods and solutions for cancer prognosis and diagnosis based on genetics can only assist existing diagnostics methods and sometimes do not enable conclusive diagnosis.


The Human Microbiome and Personalized Medicine

The human microbiome is the entirety of all microorganism of the human body. The human microbiome can be divided into different microbiomes such as the microbiome of the gut, the lung, or the skin. Within these microbiomes there are numerous bacteria that are associated with digestion or other functions. Certain bacteria (H. pylori, Fusobacterium) or viruses (HPV, HBV, HCV) are associated with the development of certain cancers such as colorectal, lung, or cervical cancer. For more information we recommend the webinar of K. Greathouse from the National Cancer Institute.

Different sequencing methods such as meta-genome analysis and bacterial 16S RNA analysis are used in order to obtain more information about the microbiome composition. As different microorganisms are associated with certain diseases and occurrence of certain cancer types, the microbiome composition can be used for disease prognosis, diagnosis and classification of disease status.

For different viruses such as HIV and HCV a number of different viral inhibitors exist and are used for treatment of infections. These RNA viruses display high mutation rates and a number of genetic variants are known that lead to drug resistant phenotypes. Therefore, the knowledge about the phenotype are important to choose the most effective treatment.

Antibiotic resistance is one of the greatest problem within the human healthcare system. The number of resistant and multi resistant pathogens is rising and the number of effective and protective antibiotics is decreasing. Therefore, the characterization of the bacterial pathogen and the knowledge about potential bacterial resistance genes is important in order to choose the best treatment.


FDA Drafts Guidelines for NGS Based Tests for Precision Medicine

The market of NGS based genetic testing is constantly growing with numerous new tests for different diseases and syndromes. Likewise, the number of service and consultancy provider increases. As these tests are used for disease prognosis, diagnosis and screening it is of outmost importance that test results are accurate, useful and reliable.

The U.S. Food and Drug Administration (FDA) released two draft guidances related to next generation sequencing based tests for the detection of medically important genetic markers. These guidances are released in order to support the Precision Medicine Initiative announced by President Obama in 2015. This guideline is in place to ensure that patients and doctors can rely on the test results. The document will include different recommendations for test validation in order to ensure accuracy, reliability, repeatability, sensitivity and specificity of the test results.

The guidance “Use of Standards in FDA Regulatory Oversight of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Used for Diagnosing Germline Diseases” is in place to inform and provide recommendations for the design, development and validation of genetic tests based on NGS. This guideline includes the complete workflow starting from DNA sample and extraction, library preparation, sequencing, data analysis and result interpretation. This includes not only the validation of the methods and protocols but also validation of used NGS technologies, software and consumables.

The second guidance draft “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Next Generation Sequencing (NGS)-Based In Vitro Diagnostics” is in place in order to inform about public genome databases that will support during test development and validation and help clinicians during interpretation of the test results.

Current regulations apply for conventional diagnostic methods. New technologies including next generation sequencing will open new opportunities for personalized medicine and genetic testing. This approach to regulate NGS based test development will help to create regulatory processes for genetic test development and application.

More information are provided on the website of the U.S: Food and Drug Administration


Summary and Outlook for Precision Medicine

Currently, the research focus on better understanding and applying of modern molecular genetic methods in precision medicine. Main topic is the identification and detection of genetic variations related to certain cancer types and hereditary diseases. This information will be used for the development of new diagnostic tools and for targeted drug development. Additionally, genetic variations of pathogens (viruses and bacteria) are investigated in order to select and develop the best treatments for infectious diseases.

Many molecular genetic methods and its applications are still not approved for diagnostics. Health care systems often do not bear the costs for genetic analysis. The health insurances consider this as an additional burden. Long-term, the application of genetic testing in precision medicine can help patients to obtain the most effective treatment. Suboptimal or wrong treatments for HIV, HCV, Cancer or resistant pathogens can have dramatic impacts on the patient and causes very high costs for the health care systems.

Decreasing costs for genetic analysis, reliable and consistent reference data sets, standardized testing protocols, and better understand will lead to higher acceptance of molecular genetic methods like NGS and its application in diagnostics in the health care system.


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