Sie sind auf Seite 1von 30

The Age of

Precision Medicine :
From Next Generation Sequencing
to Clinical Implications
Raditya Wratsangka
DNA Sequencing 2

 DNA sequencing is the process of determining the

precise order of nucleotides within a DNA
 It includes any method or technology that is used
to determine the order of the four bases—
adenine, guanine, cytosine, and thymine—in a
strand of DNA.
 The advent of rapid DNA sequencing methods has
greatly accelerated biological and medical
research and discovery.
Sanger Sequencing

 Frederick Sanger, a pioneer of sequencing.

 The foundation for sequencing proteins was first laid by the work of
Frederick Sanger who by 1955 had completed the sequence of all
the amino acids in insulin

 Sanger is one of the few scientists who was awarded two Nobel
prizes, one for the sequencing of proteins, and the other for the
sequencing of DNA
Human Genome Project (HGP)
 Human Genome Project (HGP) technological advances in the
speed and scale of sequencing analysis have maintained an
accelerating pace.
 Sequencing is used in molecular biology to study genomes
and the proteins they encode.
 Information obtained using sequencing allows researchers to
identify :
 changes in genes,
 associations with diseases and phenotypes,
 and potential drug targets.
High-throughput sequencing
(HTS) methods

 Several new methods for DNA sequencing were developed in the mid
to late 1990s and were implemented in commercial DNA sequencers
by the year 2000.
 These were called the "next-generation" or "second-generation"
sequencing methods.
 The large quantities of data produced by DNA sequencing have also
required development of new methods and programs for sequence

 The high demand for low-cost

sequencing has driven the
development of high-throughput
sequencing technologies that
parallelize the sequencing process,
producing thousands or millions of
sequences concurrently.
 In ultra-high-throughput sequencing
as many as 500,000 sequencing-by-
synthesis operations may be run in
What is Precision Medicine?
 Precision Medicine or Personalized medicine is the tailoring of
medical treatment to the individual characteristics of each patient.
 The approach relies on scientific breakthroughs in our
understanding of how a person’s unique molecular and genetic
profile makes them susceptible to certain diseases.
 This same research is increasing our ability to predict which medical
treatments will be safe and effective for each patient, and which
ones will not be.

Equipped with tools that are more precise, physicians can select a therapy or treatment
protocol based on a patient’s molecular profile that may not only minimize harmful side
effects and ensure a more successful outcome, but can also help contain costs compared
with a “trial-and-error”approach to disease treatment.
Precision Treatment 10
Breast Cancer

 One of the earliest and most common examples of precision

medicine came in trastuzumab.
 About 30% of patients with breast cancer have a form that over-
expresses a protein called HER2, which is not responsive to standard
 Trastuzumab was approved for patients with HER2 positive tumors
in 1998 and further research in 2005 showed that it reduced
recurrence by 52% in combination with chemotherapy.

 BRAF is the human gene responsible for the production of a protein

called B-Raf, which is involved in sending signals inside cells to direct
cell growth, and shown to be mutated in cancers
 In 2011, a drug called vemurafenib, a B-Raf protein inhibitor, and the
companion BRAF V600E Mutation Test were approved for the
treatment of late stage melanoma
 Vemurafenib only works in the treatment of patients whose cancer
tests positive for the V600E BRAF mutation
 Around 60% of patients with melanoma have a BRAF mutation, and
approximately 90% of those are the BRAF V600E mutation
Cardiovascular Disease

 The primary method for managing heart transplant rejection was the
invasive technique of endomyocardial biopsy – a heart biopsy
 Today, a genetic diagnostic test such as a gene expression profiling test
is performed on a blood sample, providing a non-invasive test to help
manage the care of patients post-transplant
 New research suggests that ongoing testing may be useful in longer-
term patient management by predicting risk of rejection and guiding
more tailored immunosuppressive drug regimes.
Pharmacogenomics 14

Esplin, Oei, Snyder. Pharmacogenomics (2014) 15(14)


a multi-faceted approach to
patient care
Precision *) that not only improves
Medicine our ability to diagnose and
treat disease,
*) but offers the potential
to detect disease at an
earlier stage, when it is
easier to treat effectively

Risk Assessment:
Genetic testing to reveal predisposition to disease

Behavior/Lifestyle/Treatment intervention to prevent

Early detection of disease at the molecular level

Diagnosis :
Accurate disease diagnosis enabling individualized
treatment strategy

Treatment :
Improved outcomes through targeted treatments
and reduced side effects

Management :
Active monitoring of treatment response and
disease progression

Esplin, Oei, Snyder. Pharmacogenomics (2014) 15(14)


Esplin, Oei, Snyder. Pharmacogenomics (2014) 15(14)


Esplin, Oei, Snyder. Pharmacogenomics (2014) 15(14)


Esplin, Oei, Snyder. Pharmacogenomics (2014) 15(14)

Who is Precision Medicine?
The people and groups engaged in precision medicine and
helping to drive it forward

 The realization of precision medicine relies on the input

and contributions of a broad community of stakeholders,
 all working together toward a shared goal of harnessing
breakthroughs in science and technology to improve
patient care.
Academic Researchers
Patients and Consumers Conducting basic and clinical research to
Participating in genetic testing and clinical uncover new insights into human genetics
trials and working with health care and the molecular basis of disease,
providers to proactively manage disease enabling greater precision in diagnosis
risk and/or treatment strategies and more targeted drug development

Health Care Providers IT/Informatics Companies

Employing an understanding of the Creating electronic tools and resources to
patient’s genetic profile and utilizing new collect and store patient health
technologies to individualize the approach information, making it available to inform
to disease prevention, detection, clinical decisions and improve safety while
diagnosis, treatment, and management protecting patient privacy
Biopharmaceutical Companies Advocacy Groups
Developing targeted therapies and Advancing personalized medicine in
conducting innovative research based patient care by educating consumers and
upon an understanding of genetic providers, accelerating research, and
variation and its effects on the safety and supporting necessary changes in policy
effectiveness of the candidate drug and regulation

Diagnostic Companies
Exploring new business models to
Developing tools and tests to analyze and
incentivize the practice of personalized
interpret genetic information, improving
medicine through appropriate
the understanding of disease at the
reimbursement of molecular diagnostics,
molecular level and a patient’s likelihood
targeted therapies, and other
to respond to drug therapy
personalized treatment protocols
Ethical Issues in Precision Medicine 25

 The growth in the use of DNA sequencing has introduced a

number of ethical issues
 One key issue is the ownership of an individual's DNA and the
data produced when that DNA is sequenced
 The leading legal case on this topic, Moore v. Regents of the
University of California (1990) ruled that individuals have no
property rights to discarded cells or any profits made using
these cells, included the information derived from their DNA
 Individuals have a right to informed consent regarding removal
and use of cells.
Ethical Issues in Precision Medicine 26

 As DNA sequencing becomes more widespread, the storage, security and

sharing of genomic data has also become more important.
 For instance, one concern is that insurers may use an individual's genomic
data to modify their quote, depending on the perceived future health of
the individual based on their DNA
 In May 2008, the Genetic Information Nondiscrimination Act (GINA) was
signed in the United States, prohibiting discrimination on the basis of
genetic information with respect to health insurance and employment.
 In 2012, the US Presidential Commission for the Study of Bioethical Issues
reported that existing privacy legislation for DNA sequencing data were
insufficient, noting that whole-genome sequencing data was particularly
sensitive, as it could be used to identify not only the individual from which
the data was created, but also their relatives.
Ethical Issues in Precision Medicine 27

 It has been asserted that screening for genetic variations can

be harmful, increasing anxiety in individuals who have been
found to have an increased risk of disease
 For example, in one case, doctors screening an ill baby for
genetic variants chose not to inform the parents of an
unrelated variant linked to dementia due to the harm it would
cause to the parents.
 One study in The New England Journal of Medicine (2011) has
shown that individuals undergoing disease risk profiling did
not show increased levels of anxiety.
Accelerating the Adoption of
Precision Medicine
 As the ecosystem of stakeholders works to advance precision
medicine, collaboration with government regulators and policy
makers is necessary to encourage widespread use of these new
tools and technologies.
 The regulatory process must evolve in response
 to advances that are targeted to smaller patient populations based
on genetic profiles,
 and policies and legislation must be enacted that provide incentives
for innovative research and adoption of new technologies.
Accelerating the Adoption of 29

Precision Medicine To improve the

quality of
Precision Medicine patient care
Precision Medicine
Precision Medicine

Clinical Care
To help contain
health care cost

 Progress in the research, clinical care, and policy enabling precision medicine
together has great potential to improve the quality of patient care and to help
contain health care costs.