Van criekinge 2017_11_13_rodebiotech

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

©2016 All rights reserved

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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 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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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.


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


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


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


32Biomarkers Before Biopsies complements the ProstateMDx.org website


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Epigenetic Editing

Genome Hacking/(re)progamming

Van criekinge 2017_11_13_rodebiotech

Education

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