Genomics: Increasing Throughput Drives Innovation - University of ...

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Feb 22, 2013 (4 years and 3 months ago)

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Genomics and Personalized
Medicine

Claire M. Fraser
-
Liggett, PhD

University of Maryland School of Medicine

Professor, Departments of Medicine and Microbiology and
Immunology

Director, Institute for Genome Sciences



University of Maryland School of Medicine

Mini
-
Med School

September 16, 2009

DNA: the hereditary material in all organisms

Human DNA consists of ~ 3 billion letters (chemical bases)

and the order of these provides the instructions (genes) for

building and maintaining an organism

DNA variation among individuals


DNA sequence variation among individuals is
responsible for our biological and physical
differences


GENOMICS

The study of an organism’s genome (it’s complete
genetic blueprint), how the genes interact with
each other, and with the environment

Institute for Genome Sciences

University of Maryland School of Medicine



The


Human




Genome




Project

1990

2001

The Human Genome Project’s goal was to provide researchers with powerful tools to understand the genetic factors in
human disease, paving the way for new strategies for their diagnosis, treatment and prevention.





The Human Genome Project required the development of new high
throughput technologies for sequencing (reading) DNA





1990

2000

$1.00

$0.10

$0.01

Cost per finished base

$3 billion

<$20,000

an


ea ger



man




ran





t o





the




sto r e






for







b e er

Analysis of DNA Sequence: 1990

Institute for Genome Sciences

University of Maryland School of Medicine


completedin2003thehumangenomeproject(HGP)wasa13yearproj
ectcoordinatedbytheU.S.departmentofenergyandthenationalinstit
utesofhealthduringtheearlyyearsoftheHGPthewellcometrust(U.K.
)becameamajorpartneradditionalcontributionscamefromJapanFr
anceGermanyChinaandothersseeour
history
pageformoreinformat
ionproject
goals
wereto
identify
alltheapproximately20,0025,000ge
nesinhumanDNA
determine
thesequencesofthe3billionchemicalba
sepairsthatmakeuphumanDNA
store
thisinformationindatabases,
i
mprove
toolsfordataanalysis
transfer
relatedtechnologiestothepriva
tesectorand
address
theethicallegalandsocialissues(ELSI)thatmay
arisefromtheprojectthoughtheHGPisfinishedanalysesofthedatawil
lcontinueformanyyearsfollowthisongoingresearchonourM
ilestone
s
pageanimportantfeatureoftheHGPprojectwasthefederalgovernm
ent‘slongstandingdedicationtothe
transferoftechnologytotheprivat
esector
bylicensingtechnologiestoprivatecompaniesandawarding
grantsforinnovativeresearchtheprojectcatalyzedthemultibilliondoll
arU.S.biotechnologyindustryandfosteredthedevelopmentofnewm
edicalapplications

Analysis of DNA Sequence: 2001

C
ompleted in 2003, the Hum
an

Genome Project (HGP) was a 13
-
y
ea
r project coordinated
by the U.S. Department of Ener
g
y and the National Institutes of Health. During the early
years of the HGP, the Wellcome Trust (U.K.) became a major partn
er
; additional
contributions came from Japan, France, Ger
man
y, China, and others. See our
history

page for mo
r
e information. Project
goals

were to




identify

all the approximately 20,000
-
25,000 genes in hum
an

DNA,



determine

the sequences of the 3 billion chemical base pairs that make up

human DNA,



s
to
re

this information in databases,



improve

tools for data analysis,



transfer

related technologies to the private sector, and



address

the e
th
ical, legal, and social issues (ELSI) that may aris
e

from the

project.


Though the HGP is finished, analy
s
es of the da
t
a will continue f
or
many y
e
ars. Follow this
ongoing research on our
Milestones

page. An important
f
eature
o
f the HGP p
r
oject was
the federal government's long
-
standing dedication to the
transfer of technology to the
private sector
. By licensing technologies to private companies and awarding grants for
innovative research, the project catalyzed the multi
b
illion
-
dollar U.S. biot
e
chnology
industry and fost
er
ed the development of new medical applications.

Analysis of DNA Sequence: the future

Institute for Genome Sciences

University of Maryland School of Medicine


100 million species

Each individual

has different DNA

Within individual, some

cells have different DNA

(i.e. cancer)

DNA Sequencing
Applications

Impact of DNA Sequence Variation


Out of the more than 3 billion letters (bases) of DNA present in the
human genome, less than 1% (30 million) of them differ among
individuals



Many differences in DNA sequence have no effect



In some cases, the effect of a single base (letter) change can be
severe (sickle cell disease, hemophilia, cystic fibrosis, Tay Sachs
disease)



In other cases, the effect is less severe, having minimal effect on
human health unless found in combination with other specific DNA
variants or environmental factors (coronary heart disease, diabetes,
asthma, hypertension)

Institute for Genome Sciences

University of Maryland School of Medicine


Single gene defect

Multiple genes

From Manolio et al. (2008) JCI 118: 1590
-
1605

Institute for Genome Sciences

University of Maryland School of Medicine


What is Personalized Medicine?


The concept that managing a person’s health
should be based on an individual patient’s
specific characteristics



This contrasts with much of medical practice
today that assumes everybody should get the
same care, determined by averaging responses
across large groups of subjects in clinical trials

Institute for Genome Sciences

University of Maryland School of Medicine


How Does Genomics Facilitate
Personalized Medicine?


Use of genetic variation to evaluate disease risk



Use of genetic variation to determine the response to
medications


increase the efficacy and safety of drug
therapy



Stratification of a disease based on information about the
underlying molecular basis for a particular disease



Initiation of appropriate and individualized preventive
measures when possible


Institute for Genome Sciences

University of Maryland School of Medicine


BRCA2

Chromosome 13

Mutations in the tumor suppressor genes, BRCA1 and BRCA2, are associated

with a significant increase in the risk of breast, as well as other, cancers


Studies have identified hundreds of mutations in each of these genes that

increase the risk of cancer


Mutation screening has had a enormous impact on managing cancer risk in

affected individuals


-

surveillance (mammograms vs. MRI)


-

prophylactic surgery


-

risk avoidance


-

chemoprevention



BRCA1 and BRCA2: an early success story

March 29, 2009

More than a dozen genes are now linked to an

increased risk for breast cancer

Identification of Genes Linked to Disease


Create a catalog of common genetic variants in
humans to guide genetic studies of health and
disease



-

what the variants are



-

where they occur in DNA



-

how they are distributed among populations



Use the information to link genetic variants to
the risk for specific illnesses individual responses



Genome
-
Wide Association Studies

Multiple genes are likely involved in common diseases,

each with a relatively small effect

Nature

447
, 661
-
678 (7 June 2007)

Genome
-
wide association study of 14,000 cases of seven common diseases and 3,000 shared
controls

The Wellcome Trust Case Control Consortium


~100 regions for 40

common diseases/traits


Eye diseases

Diabetes

Cancer

GI disorders

Cardiovascular

Lipid metabolism

Neuropsychiatric

Autoimmune

Infectious disease

Genes involved in lipid metabolism

Genomic Biomarkers in the Context of Approved Drug Labels


Pharmacogenomic information is contained in about ten percent of labels for drugs
approved by the FDA.

A significant increase of labels containing such information has
been observed over the last decade.


Genomic biomarkers can play an important role in identifying responders and non
-
responders, avoiding toxicity and adjusting the dosage of drugs to optimize their
efficacy and safety.

In the context of drug labels, these genomic biomarkers can be
classified on the basis of their specific use, for example:


Clinical response and differentiation

Risk identification

Dose selection guidance

Susceptibility, resistance and differential disease diagnosis

Polymorphic drug targets


Institute for Genome Sciences

University of Maryland School of Medicine


From Rettie and Tai (2006)

Molecular Interventions 6:223
-
227

b
1
-
adrenergic Receptor Genetic Variants Predict Treatment

Response in Heart Failure

389

At 389 R is found in all

species except for man,

where it can be R or G

Human hearts, ex vivo contraction

Arg hearts are hyperactive

compared to Gly hearts

In heart failure, patients with

Arg respond to the beta
-
blocker

bucindolol, while those with Gly do not

Liggett SB et al., PNAS 2006

2005

Gene expression studies reveal differences between normal and
tumor cells that can be used to classify human cancers

Lu J et al. MicroRNA expression profiles classify human cancers. Nature 435: 834 (2005)

Gleevec (Novartis) is a unique treatment for certain forms of cancer

(chronic myeloid leukemia and GI stromal tumors). It specifically targets one protein

that allows these cancer cells to grow and multiply. As a result, this greatly reduces

adverse side effects associated with treatment.

How can this information be of value?

Better diagnostics and treatment regimens

Potential for Personalized Medicine:

A Case Study


Laura Doherty
-
Reynolds was diagnosed with
cancer in 1996 at the age of 29


No cancer in her immediate family


Abdominal swelling sent her to the doctor


After blood test, x
-
rays, and a CT scan she was
scheduled for surgery


At surgery, two tumors were discovered that
were diagnosed as metastatic undifferentiated
carcinoma at stage four

Institute for Genome Sciences

University of Maryland School of Medicine


Potential for Personalized Medicine:

A Case Study


Because the origin of the primary tumor could not
be determined by pathology, it was difficult to select
the best chemotherapy strategy


Chemotherapy involved a combination of drugs
that had been shown to work for different types
of tumors


No way to predict if the chemotherapy would
work for Laura

Institute for Genome Sciences

University of Maryland School of Medicine


Potential for Personalized Medicine:

A Future Case Study


Laura Doherty
-
Reynolds was diagnosed with early
-
stage cancer in 2016 at the age of 25


This finding was not entirely a surprise because her
genome information, obtained when she was 12,
identified two genes that increased her risk of
developing breast and ovarian cancer


Laura’s known increased risk for cancer justified
annual screening assays and identified her cancer
at an early stage through a blood test

Institute for Genome Sciences

University of Maryland School of Medicine


Potential for Personalized Medicine:

A Future Case Study


Surgery was carried out and it was less traumatic
because the tumor had not metastasized


The treatment strategy for Laura’s tumor was designed
based on knowing


The drug susceptibility profile of her tumor


The chances that her tumor type was likely to recur


Her ability to quickly metabolize the drugs that she
would receive

Institute for Genome Sciences

University of Maryland School of Medicine


Stakeholders in Personalized
Medicine


Patients


majority of the public supports genetic
testing if it can be used to improve health
outcomes


Doctors


PM will require a new approach to
patient care away from the “one drug fits all”
paradigm


Pharmaceutical industry


impact on the mass
-
market blockbuster drug model

Stakeholders in Personalized
Medicine


Diagnostics industry


PM opens new
opportunities for development of more specific
tests


Insurance industry


will PM ultimately reduce
costs


Regulators


current administration supports PM
initiatives

Genetic Information Nondiscrimination Act: May 21, 2008

GINA makes it illegal for health insurers and employers

to use genetic information in coverage or employment

decision making.