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The Age of Personalized Medicine - Daniel A. Notterman, M.A., M.D.
1. The Age of Personalized Medicine
Daniel A. Notterman, MA, MD
Professor of Pediatrics, Biochemistry and Molecular Biology
Vice-Dean for Research and Graduate Studies, College of Medicine
Associate Vice-President for Health Science Research, Penn State
University
9. DNA: Wonder Molecule
• The 3 billion base pairs
in each cell fit into a
space just 6 microns
across (head of a pin =
2000 microns across).
• If you stretched the
DNA in one cell all the
way out, it would be
about 2 meters (6 feet)
long.
• All the DNA in all your
cells put together
would be about twice
the diameter of the
Solar System.
10. Human Diversity Factoids
Any two humans are more
than 99 percent the same at
the DNA level.
This still implies more than 50
millions chances for us to
differ.
These differences explain gtctagagcc accgtccagg gagcaggtag ctgctgggct ccggggacac tttgcgttcg
61 ggctgggagc gtgctttcca cgacggtgac acgcttccct ggattggcag
ccagactgcc
individual susceptibility to 121 ttccgggtca ctgccatgga ggagccgcag tcagatccta gcgtcgagcc
ccctctgagt
disease, response to drugs or 181 caggaaacat tttcagacct atggaaacta cttcctgaaa acaacgttct gtcccccttg
241 ccgtcccaag caatggatga tttgatgctg tccccggacg atattgaaca atggttcact
reaction to the environment. 301 gaagacccag gtccagatga agctcccaga atgccagagg ctgctccccc
cgtggcccct
We can now determine the 361 gcaccagcag ctcctacacc ggcggcccct gcaccagccc cctcctggcc
cctgtcatct
most important 2-4 million 421 tctgtccctt cccagaaaac ctaccagggc agctacggtt tccgtctggg cttcttgcat
481 tctgggacag ccaagtctgt gacttgcacg tactcccctg ccctcaacaa gatgttttgc
differences in a day, for $500. 541 caactggcca agacctgccc tgtgcagctg tgggttgatt ccacaccccc
gcccggcacc
In a couple of years we’ll be 601 cgcgtccgcg ccatggccat ctacaagcag tcacagcaca tgacggaggt
tgtgaggcgc
able to measure all—for 661 tgcccccacc atgagcgctg ctcagatagc gatggtctgg cccctcctca gcatcttatc
721 cgagtggaag gaaatttgcg tgtggagtat ttggatgaca gaaacacttt tcgacatag
under $1,000. 781 gtggtggtgc cctatgagcc gcctgaggtt ggctctgact gtaccaccat ccactacaa
841 tacatgtgta acagttcctg catgggcggc atgaaccgga ggcccatcct
caccatcatc
901 acactggaag actccagtgg taatctactg ggacggaaca gctttgaggt gcgtgtttg
961 gcctgtcctg ggagagaccg gcgcacagag gaagagaatc tccgcaagaa
aggggagcct
1021 caccacgagc tgcccccagg gagcactaag cgagcactgc ccaacaacac
cagctcctct
1081 ccccagccaa agaagaaacc actggatgga gaatatttca cccttcagat
ccgtgggcgt
1141 gagcgcttcg agatgttccg agagctgaat gaggccttgg aactcaagga
tgcccaggct
1201 gggaaggagc caggggggag cagggctcac tccagccacc tgaagtccaa
aaagggtcag
1261 tctacctccc gccataaaaa actcatgttc aagacagaag ggcctgactc agactga
12. The Human Genome Project
A revolution in genetics
Conception
Competition Completion
The Human Genome Project
Started in 1990 and completed in 2003
The goal was to define and annotate about 25,000 genes
The estimated cost was of $ 2.3B
The project led the way to a new horizon in genetic testing
13. What Is Personalized Medicine?
The systematic use of biologic and environmental information about an
Individual patient to:
1. define disease risk
2. select or optimize treatment and lifestyle
Since every person is genetically unique, ultimately each patient will receive a
unique prescription—based on the intersection of their biologic and
environmental profile.
14. Genetics is not everything!
Same Genome: Different Environment
15. What Is Needed To Apply
Personalized Medicine?
Biological Data
Genomics (all of our DNA
information)
Metabolomics (all of our
chemical information)
Environment
External, social, cultural, b
ehavioral
Phenotype
Normal physiology and
systems biology (how the
body works)
Disease and health
characteristics
Automated personal
phenotype unit (human black
box)
16. Personalized Medicine: Why Now?
Large biologic data sets (GENOTYPE)Large Clinical Data Sets (PHENOTYPE) Computer performance
17. Personalized Medicine
Why does it matter ?
In treating all people with a certain lung cancer without having a genetic test,
10% of people might respond.
In treating people who have a genetic test and are found to have a tumor mutation,
85% of people treated for that mutation might respond.
The best drug for a specific disease
in a particular person.
19. … And Results In Better And
Less Expensive Care.
Risk of hospitalization among patients
who underwent VKORC1 and CYP2C9
genotyping, as compared with a
historical control group, 6 months after
the initiation of warfarin therapy.
NEJM, 3/24/2011
21. A Personalized Approach To
Leukemia In Children
Pui C and Evans W. N Engl J Med 1998;339:605-615
22. Personalized Care: Breast Cancer
The Problem:
On clinical grounds alone, it may not be known whether a
specific woman should have chemotherapy in addition to
tamoxifen.
A Case:
A 42 year-old woman is found to have a 1.5 cm mass in
her
right breast. Excisional biopsy establishes that it is
malignant.
A single lymph node in the axilla is positive for a “micro
metastasis.” The cancer is ER+. To make a better
prediction
of the risk of recurrence, she receives an OncotypeDx
Breast
Cancer Assay Assay®
24. OncotypeDx
• Recommended since 2007 for evaluation of woman
with node-negative ER + breast cancer.
• About a third of the patients have received a change
in treatment recommendation based on this test.
25. Personalized Approach To Cancer:
Malignant Melanoma
A 26 year-old graduate student went to a dermatologist
because of a mole on the nape of his neck. His girlfriend
had noticed a recent change in color.
26. Malignant Melanoma
An excisional biopsy was performed. Unfortunately, the lesion was deep.
He was offered and received standard chemotherapy.
5 mm
27. Malignant Melanoma 2007
The patient did well for 6 months. At that time he developed a cough. A
chest X ray was positive and a PET/CT revealed widespread metastasis.
He died within 3 months.
28. Melanoma 2013:
Targeting Treatment To A Specific Variant In The Melanoma Gene
• Zelboraf® is an inhibitor of a cancer
driver called B-Raf, which is frequently
implicated in malignant melanoma.
• It works only in the 60% of patients
whose melanomas have a specific B-Raf
It is essential to personalize therapy by mutation. In these patients, tumour
determining the genetic composition of an regression is observed in a significant
proportion. In patients without this
individual’s cancer. mutation, Zelboraf® can stimulate
cancer growth.
30. Risk To Brain Health: ApoE
• ApoE is known to be an important risk for Alzheimer’s
Disease.
• From 10 to 50% of people have 1 high risk allele (form of
the gene) called ApoE4
• Recent studies also implicate this allele (ApoE4) in the
outcome of traumatic brain injury (TBI)—head trauma.
ApoE Risk
Genotype • ApoE4 increases the risk of Dementia
2,2 Hyperlipidemia Pugilistica (chronic TBI). Does this apply to
(Type II) other forms of athletics where concussion
2,3 Risk of AD occurs?
3,3 Normal • Should athletes be screened for ApoE4?
3,4 Risk of AD • ApoE4 is also associated with a worse outcome
4,4 Risk of AD following acute TBI—as in an auto accident.
(20X by 75)
31. Age-related macular degeneration
• Most common cause of
irreversible vision loss in Western
world for people over 60 (1 in
2000)
• Genetics: 45% to 70%
• Environment: 30% to 55%
• Smoking, diet poor in antioxidants or
zinc, high fat, possible sunlight exposure
34. Making The Diagnosis: Sequencing in a
Child with Intractable IBD
• 5 year old child with extensive
history of GI issues – presumed to
be Crohn’s disease (IBD).
• Over 100 operations in 3 years in
addition to immunosuppression.
• DNA samples were collected and
prepared for sequencing.
• Identified a point mutation in XIAP which
causes immunodeficiency and colitis.
• Bone marrow transplant: CURED!
• Demonstration of the clinical utility of
sequencing and its implications for
disease gene discovery and clinical
diagnosis.
Worthey E, et al. (2011) Genet Med Mar;13(3):255-62.
35. Whole Genome Sequencing in the NICU
• Newborns with genetic diseases
are often desperately ill.
• Standard genetic diagnosis can
take days to weeks, so the infant
may have died before diagnosis is
known.
• Many times, the physicians don’t
think of the correct genetic test to
order.
• 3700 genetic disease genes
remain to be identified.
36. 2 Day Whole Genome
Analysis for Sick
Newborns
• To check capabilities, 2 babies were
retrospectively diagnosed.
• Then Illumina 2500 was used to diagnose 3
babies and a whole family.
• 50 hours.
• $7666, potentially a cost saving.
• Correct diagnosis was made in each case.
Science Tran Medicine, 2012.
37. Prenatal Testing for Trisomy and other Genetic Disorders
Male fetus’s Y Chromosome in mother’s blood
38. Where are we headed with
Personalized Medicine?
• Monogenetic treatment
stratification—now
• Genome on an iPhone for
medical care—now to 2 years
• Rapid diagnosis of ~10,000
genetic disorders—now
• Comprehensive treatment and risk
stratification—10 years
• Automated precise
prescription dispenser based
on genotype and
phenotype—20 to 30 years
Notes de l'éditeur
Obvious that genetics plays a role in physical characteristics. What of behavioral? Just as height is product of genes and nutrition, it is likely that behavioral, emotional and cognitive differences are also predicated on this interplay.
