van criekinge 2017_11_13_rodebiotech
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Lab for Bioinformatics and
computational genomics
25 “genome hackers”mostly engineers (statistics)
42 scientiststechnicians, geneticists, clinicians
>250 people Hardware/software engineers,
mathematicians, molecular biologists
Prof. Dr. ir Wim Van Criekinge
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Next Generation (Epi)genetic biomarkers
Chief Scientific Officer
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CLIA Lab US Service Lab EU
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Kanker Beter Opsporendoor
Kanker Beter te Begrijpen
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Kanker Beter Opsporendoor
Kanker Beter te Begrijpen
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Kanker is een ziekte van het genoom
Genetic code - DNA
The human genome comprises the information contained in
one set of human chromosomes which themselves contain
about 3 billion base pairs (bp) of DNA in 46 chromosomes (22
autosome pairs + 2 sex chromosomes). The total length of
DNA present in one adult human is calculated by the
multiplication of
(length of 1 bp)(number of bp per cell)(number of cells in the body)
(0.34× 10-9 m)(6× 109)(1013)
2.0× 1013 meters
That is the equivalent of nearly 70 trips from the earth to
the sun and back.
Genetic code - DNA
Genetic code - DNA
Time (years)
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Cancer is impairing key pathways/modules/networks
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Importance of Epigenetics (I)R & D
Allows to (re)use one genomes
for different purposes
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Importance of Epigenetics (II)R & D
• Allows to (re)use one genomes for different purposes
• Allows to integrate intrinsic with environmental signals
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Importance of Epigenetics (III)R & D
• Allows to (re)use one genomes for
different purposes
• Allows to integrate intrinsic with
environmental signals
• Epigenetics driving etiology of many
human diseases
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Kanker Beter Opsporendoor
Kanker Beter te Begrijpen
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PSA Screening
Impact on Mortality
Welch HG et al. N Engl J Med 2015;373:1685-1687.
Incidence of Metastatic Prostate Cancer at Initial Diagnosis: 1975–2012
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25% Will receive a false-negative result
15% Will suffer complications from biopsy (e.g. bleeding, infections, etc.)
~ 3% Will be hospitalized in 30 days following biopsy
Biopsies are
Gold Standard for Cancer Detection
Gershman et al.; Eur Uro 2016
Loeb et al.; Eur Uro 2013
Loeb et al.; J Urol. 2011.
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Sampling error, Needle Missed Mark
Negative Prostate Biopsy
Standard 12-core biopsy
TRUS Guided Prostate BiopsyElevated PSA, Abnormal DRE, Family History
Elevated Clinical Risk Factors
Patient Compliance, Infections,
Unnecessary Repeat Biopsy
43% have repeat biopsyWelch HG et al:. J Natl Caner Inst 2007;99: 1395 – 400. Pinsky PF et al:. BJU International 99, no. 4 (April 2007): 775–779.
Unnecessary Repeat BiopsiesFear of Undetected Prostate Cancer
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How ConfirmMDx WorksConfirmMDx detects an epigenetic field effect associated with the presence of cancer at the DNA level
Biopsy
Cancer
Field Effect
Henrique R, et al:,Mol Cancer Res 2006;4:1-8
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ConfirmMDx Clinical ValidationThe Journal of Urology 2013
Epigenetic Multiplex DNA
Methylation Test
•GSTP1 – DNA detoxification
•APC – apoptosis
•RASSF1 – cell cycle regulation
The most significant independent
predictor of cancer detection on
repeat biopsy
90% NPV
Stewart GD et al; Journal of Urology 2013
MATLOC Study
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ConfirmMDx Positive Results
Personalized risk assessment for likelihood of harboring
aggressive cancer
Men who benefit from MRI/biopsy and early detection
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ConfirmMDx Positive
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Methylation
Negative
Methylation
Positive
Low Risk
Active Follow Up
Negative
Prostate BiopsyConfirmMDx
High Risk
Repeat Biopsy
Routine
Screening
Risk Profile
Provides Personalized Risk AssessmentPatient Profile: Men being considered for repeat prostate biopsy
96% NPV for Clinically Significant Cancer
90% NPV for All Cancers
Van Neste et al; The Prostate 2016
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SelectMDx for Prostate CancerClinical Validation of a Risk Profile for the Detection of High Grade Cancer
SelectMDx Risk Profile: Strongest predictor of high-grade disease
98% NPV for GS ≥7 cancer
AUC of 0.89 (95% CI 0.85-0.95)
European Urology 2016
Van Neste et al., European Urology 2016
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Collect First Void Urine in
Transport Medium
RNA Isolation
KLK3 RT-qPCRHOXC6 RT-qPCR
HOXC6/KLK3
DLX1 RT-qPCR
DLX1/KLK3
Cq-Values:
Ratios:
Score:
SelectMDx qPCR
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Elevated PSA Urologist DRE Urine
Urine test for the prediction of histopathological outcome of prostate biopsy
SelectMDx for Prostate CancerNon-invasive, Liquid Biopsy to Identify Patients for Prostate Biopsy
Follow-upDiscuss with
patient
MRi or Biopsy
routine PSA
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Patient ReportSample
Improves the Identification of Men
for Prostate Biopsy:
High Risk
• Personalized risk profile
• Increased risk for aggressive cancer
• Men who may benefit from biopsy
Very Low Risk
• 98% NPV for GS ≥7 Disease
• May avoid biopsy
• Return to routine screening
Identification of a Candidate Gene Panel for the Early Diagnosis of Prostate Cancer. Leyten et al. Clin Cancer Res, 2015
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Provides Patient’s Personalized Risk Profile
SelectMDx for Prostate Cancer
A patient at increased risk will receive a report which indicates his likelihood for
prostate cancer on biopsy and probability for aggressive disease
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Routine ScreeningElevated PSA,
Abnormal DRE
Very Low Risk
for GS ≥ 7 PCa
Consider
Biopsy or MRI
Increased Risk
for GS ≥ 7 PCa
99.6% NPV for GS ≥8
98% NPV for GS ≥7
Very Low Risk
Avoid Biopsy
For patients being considered for initial prostate biopsy
Identify men at high risk for aggressive cancer
Assay performed on non-invasive, urine sample
Improved Risk Stratification for
Clinically Significant Cancer
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AssureMDx for Bladder CancerNon-invasive, Liquid Biopsy to Identify Patients with Bladder Cancer
Patient
Blood in urine
Test
Runs on any open
PCR/Sequence instrument
Follow-up
Yes/No
CT scan or Cystoscopy
Result
Likely hood risk
score
Routine monitoring
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32Biomarkers Before Biopsies complements the ProstateMDx.org website
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Epigenetic Editing
Genome Hacking/(re)progamming