Transcript Presentation Title Here Presentation Subtitle Here

Practical Challenges in Clinomics: A
Mayo Perspective
Eric D. Wieben, Ph.D.
August 4, 2012
©2011 MFMER | slide-1
Disclosure Statement
of Financial Interest
• I, Eric Wieben,
DO NOT have a financial
interest/arrangement or affiliation with one
or more organizations that could be
perceived as a real or apparent conflict of
interest in the context of the subject of this
presentation.
From Wikipedia (so it must be real)
Clinomics is the study of -omics data
along with its associated clinical data.
Translational Program
Clinomics
Overall Objective
The objective of the Clinomics
Program is to create value from
genome sequence information
©2011 MFMER | slide-4
We can now sequence an entire set of
protein coding genes from individual
patients, or even entire genomes.
Should we?
What are the possible benefits?
What are the risks?
And it doesn’t come neatly labeled and interpreted
AGATAAGGAGTTCCAAACTGTGCTTTCTTATTTGTTATTTTAAAAAACAAGTTTTTATTT
GCTAATTCTCTATGGCCCTGCAAATCCTTTATTGGAAATAACCTTGGTCTCACTGCTGTC
TTTCTGTCCTTTGTACTGCGTAATGGGGCTTGAGGATTAGTGTGCTGATATTTGTGCAT
TAAATGCTTCTGTATATGCATGTGCCTTCTGAAAACTTTTTTAGGTTTGGAGCTGAATTT
TGGATTATTGATCATTCTCTTTTGCCTGGTCTTCCCTGTGACTGTTTTGCATGATGTTGG
GTAAAATAATAGTGTGGGTGAGCATGTCACAGTGCTTCTCAGTGTGTTAGAGAGGTGT
TGTGTACCTTATACCTGTTGTATTTTTTAAATCCTAACAAGAACCTAATGAGATGCAAGG
ATTACTACTATCCTGTATTCATAGCTGAGGAAACAGAGACAGATGTTAAACAACTGGATC
TTAAGGCAGCCAATAATGAAATTAGGTTTTAACCTCAGGTTTGTCTAGCTCAAAGTCCTG
AGTTCTATACACACACACACACACACACACACACACACACACACATCAGACAGCTCATT
TTGCAAGATTATATAGGCAAACAGTGTGATATTGAGGCTTCGCACGAAATGCTATCTGTG
ATCTTTAGGGTAGATAGCATTTTTAAAAATGTGTCTAATGTTGTAATGATGTCAACCATA
TCCATTATTTTTCCCGCCTTTGTATCCAAATAAACTACCCTTCCAATTTATGACAGATAT
CAATGTGACTAAATATGTCTTTCTCATATCTTTATTAGTTTTACTAAGAAAATACAGTAG
ATATTTTAAAAGTTGTGCTTTCATTCTGTTGTAAGTTGATAGTCTACATGGATGCCAATG
AAAACATGTTTTTATGTAGCTAATCAATTCAGAATTTGAGGTAACCAAGCCTGATGTATT
AATATGTAAAAAAATAAGGATCTCCTGTCTTTAAATATAAAAAAGTTTTGCAGTTCGTTG
TTAGATCTTTGAAACTTAATATTCAAGAACAATACCCTCAATTCTATCTGCATCACTAAA
ATAAGCAGTTTTGAAGGTTTGATATGTCTGTTACCAGACATGTGCTTAAAATGTTACATT
Molecular Anatomy
•Exons make up only about 1.5% of total
genome
Current estimate= 29,567 protein coding genes*
(up from 28,259 #)
29, 567 x 1500 coding/gene= 44 million
Just over 1% of the genome codes for protein—1 inch of 6 feet
http://www.ncbi.nlm.nih.gov/projects/CCDS/CcdsBrowse.cgi?REQUEST=SHOW_STATISTICS#Current_Homo_sapiens_36_3
Compared to the reference sequence, Venter has:
•3,213,401 single nucleotide
polymorphisms (SNPs)
•53,823 block substitutions (2–
206 bp)
•559,473 homozygous indels
(1–82,711 bp)
•62 CNVs
•292,102 heterozygous
insertion/deletion events
(indels)(1–571 bp)
•90 inversions
Levy et al., PLoS Biol. 2007 October; 5(10): e254
Korean
10162 nsSNPs
So what is the right
reference genome?
3511
3775
2373
5509
Chinese
African
9039 nsSNPs
11251 nsSNPs
Adapted from J-I Kim et al. Nature 000, 1-5 (2009) doi:10.1038/nature08211
Whole genome sequencing is leading to “cures”—
dopa responsive dystonia
Noah and Alexis Beery
http://www.youtube.com/watch?v=yUQFHecs8EQ
•M. N. Bainbridge, W. Wiszniewski, D. R. Murdock, J. Friedman, C.
Gonzaga-Jauregui, I. Newsham, J. G. Reid, J. K. Fink, M. B. Morgan,
M.-C. Gingras, D. M. Muzny, L. D. Hoang, S. Yousaf, J. R. Lupski, R.
A. Gibbs, Whole-Genome Sequencing for Optimized Patient Management.
Sci. Transl. Med. 3, 87re3 (2011).
Congenital Myasthenic Syndrome
Ellen was not diagnosed with CMS until 18 months old, there although
was obviously 'something wrong' from birth as she was unable to feed
and maintain her weight and suffered inexplicable weakness and
fatigue.
Diagnosed with Congenital
Myasthenic Syndrome at the Evelina
Children's Hospital at Guys and St
Thomas, Ellen is now on
pyridostigmine every three hours.
She attends mainstream school with
support. Her gene fault is currently
unknown.
From http://myasthenickids.org/
A few Mayo CMS
pedigrees
Selcen et al., Annals of Neurology 64: 71
The Concept
Patient inquiry
DNA Sequencing
Mutation Discovery
Improved Treatment
The Practicality--Individualized Medicine
Clinic
Stop
Stop
Stop
AZ Patient with Liver
Cancer
Fails Conventional
Therapy
Inquires about WGS
IM Clinic
Review Board
N
Potential to
Help?
Approve?
Y
Y
Business
Office
- Est. of Cost
- Deposit?
- What is
Billable?
*Ethics
*Genetics
N
Patient
Desire to
Proceed?
N
Y
Genome Savvy
MedOnc
Bioethicist
Medical Geneticist /
Genetics Counselor
Individualized
Medicine
Clinic
Y
Share Results
- MedOnc
- Medical
Geneticist
- Subspecialist?
Research
Consent(s)
Run Test(s)
N
Druggable
Target?
Y
N
Stop
Store Data and
Offer Copy to
Patient
Subscription?
Y
Ongoing
Interaction
Potential to
Help?
Stop
N
Research
Consent
Off Label Use
Monitor and
Track Results
The Issues
• Ethical challenges
• What are the risks?
• What are the potential benefits?
• Scientific challenges
• Data generation, accuracy,
interpretation and management
• Administrative/Legal challenges
• Clinical challenges
• Will it change treatment?
The pilot project—Driven by Ethics and
Medical Genetics Staff
• Sequence genomes exomes from ten members of
the Center for Individualized Medicine leadership
• Pick participants by lottery
• Engage in counseling
• Provide opportunity to opt out
• Determine what information each person wants
• Proceed with sequencing, etc
• Survey attitudes before and after
Ethical challenges
•
•
•
What are the risks?
• Most genetic “news” is bad
• Incidental findings
• VUS issue
• Effect of bad news extends beyond
the patient in the office
• Insurance risk?
What are the potential benefits?
• For THIS patient
What constitutes informed consent?
Scientific challenges
• Data generation, interpretation and
management
NGS
instruments
Data Storage
Interpretive Report
and Discrete Data
to EMR(s)
Interpretive Report
to LIS
Compute/Analysis
Consultant
Workbench
Scientific/Technical challenges
• Accuracy (85% perfect reads)
• Requires orthogonal validation
• Alignment
• What is the most appropriate
reference sequence?
• What about repetitive regions?
• Too much data
• 10,000 missense changes per
sample (80 nonsense)
• Storage?
Exome sequencing statistics for
newest 72Mb capture set
• Over 200 million reads per sample—
100 bp each (>250x coverage)
• 70,000 SNVs in coding region per
sample
• 70-80 Nonsense mutations
• 10,000 missense mutations
• 8000 indels in coding region*
Run 2 per lane
What’s the problem?
Note 62,000 rows!
©2011 MFMER | slide-22
What’s the problem?
What’s going
on outside
the exome?
There ARE
disease
causing
mutations
here!
HBB
©2011 MFMER | slide-23
What’s the problem?
Even in exons, coverage is not even.
So what are we missing?
HBZ
©2011 MFMER | slide-24
Mismapped repetitive sequences
Scientific/Technical Challenges
After all the other problems are “solved” and technical
conclusions are validated, there are still mysteries to be
considered
• VUS (Variants of Uncertain Significance)—generally
private mutations that may or may not constitute risk
alleles
• Do change the structure of important proteins
• Functional consequences?
• Reportable back to patient?
Challenges remain in the application of whole genome data to the practice
From Ashley et al. Clinical Assessment incorporating a personal genome, Lancet. 2010 May 1; 375(9725): 1525–1535
Administrative/Legal Challenges
• Cost—What is billable? Reimbursable?
• What goes into the EMR? How?
• What about proprietary genes and tests?
Clinical challenges
• Will it change treatment? For the better?
• Will it inform future discovery efforts that
could lead to better treatment?
• Will it inform genetic counseling?
A New Treatment’s Tantalizing Promise Brings
Heartbreaking Ups and Downs
By GINA KOLATA, New York Times, July 8, 2012
So why bother?
From http://myasthenickids.org/
Finding new mutations in a number of genetic diseases, including
CMS
These give insights into fundamental disease process, allow for
better counseling and (sometimes) suggest new therapies
“Individualized Medicine Clinic” to open September
30, 2012
• Advanced cancer patients
• “Diagnostic odyssey” patients
• Issues being considered
• Expectations, pre-counseling and informed
consent
• Unexpected results
• VUS interpretation?
• Implications for family
members
©2011 MFMER | slide-31
New Frontiers in Individualized Medicine
Environment, including microbiome
If the child looks like the father, it’s genetic
If the child looks like the neighbor, it’s environmental
MyGenome—Available NOW in the iTunes AppStore
©2011 MFMER | slide-34