The Network is a Biomarker in Cancer Signatures

4th Conference in Quantitative Biology QUB, September 2013 Sol Efroni

The Network is a Biomarker in Cancer

Signatures

Sol EfroniThe Mina & Everard Goodman

Faculty of Life SciencesBar Ilan University


My Lab

Rep-Seq

Benichou et al,Immunology 2012

• Vainas et al,Autoimmunity 2011

• Mascanfroni et al,Nature Immunology 2013

Cancer Genomics

Systems Immunology



Introduction • Biomarkers • Regulation • Implementation

Complex Biomarkers

Clinically motivated multi gene markers


The problem with Multi-gene mRNA markers

Robustness






TCGA

“...a comprehensive and coordinated effort to accelerate our understanding of the molecular basis of cancer through the application of genome analysis technologies, including large-scale genome sequencing”




Phenotype comparison

Tumor Normal



Tumor Normal


Phenotype comparison



? ?? ?

? ?

?A single number to represent thePathway within thissample


Example

Regulation as metric


Gene 1

Gene 2

Gene 1is a perfectbiomarker

Gene 2is a perfectbiomarker

1

2

The pathway is enriched with the interesting genes Gene 1 and Gene 2 and and is therefore important

Gene 1

Gene 2

1

2

?1

-1

Network

Gene 1is a poorbiomarker

Gene 2is a poorbiomarker

The two gene network is a perfectbiomarker

Perfect corr

Perfect anti corr






Efroni et al IET Systems Biology 2013

Greenblum et al. BMC Bioinformatics 2011

Efroni et al PLoS ONE 2009



Pathways as biomarkersand

pathways as targets inGBM

and in Ovarian cancer


Rotem Ben-Hamo Dr. Helit Cohen

Introduction • Biomarkers • Regulation • Implementation ovarian


Methodology

Gene Expression

Clinical Data

Copy Number Variation

Methylation

microRNA

Whole Genome/Exome

Sequencing

Ovarian Cancer – 511 patients, 348 whole exomes


Data Collection


Ovarian cancer gene signature



Ben-Hamo R, Efroni S. BMC Systems Biology (2012)

Survival Analysis: Gene based



A pathway view highlights a single pathway



Duke1 Dataset 119 patients Duke2 Dataset 42 patientsTCGA 511 patients

Ovarian Cancer: PDGF Signaling Pathwayprovides a robust signature



Again, a collection of sources for clinical and molecular data

GBM

Introduction • Biomarkers • Regulation • Implementation GBM


• Pathway 1• Pathway 2• Pathway 3• Pathway 4• Pathway 5• Pathway 6• …

• Pathway 579



The p38 pathway is most significant

“p38 signaling mediated by mapkap kinases”



Preliminary Results

Ben-Hamo R, Efroni S. Genome Medicine (2011)Ben-Hamo R, Efroni S. Systems Biomedicine (2013)

The p38 pathway is robust across multiple datasets



Another type of regulation has been suggested:microRNA Control over Pathways

Inui M et al. Nature Reviews Molecular Cell Biology (2010)





hsa-miR-9 hsa-miR-9

R2 = -0.21R2 = -0.67

P38 s

ign

alin

g p

ath

way

P38 s

ign

alin

g p

ath

way

P38/MAPKP Pathway AND hsa-miR-9



Preliminary Results - Computational

hsa-miR-9 hsa-miR-9

R2 = -0.21R2 = -0.67

P38 s

ign

alin

g p

ath

way

P38 s

ign

alin

g p

ath

way

P38/MAPKP Pathway AND hsa-miR-9



Preliminary Results - Experimental

Expression levels of P38 pathway genes in HeLa Vs. HMEC cell lines

• HeLa: cervical cancer cell line.• HMEC: (Human mammary epithelial cell) primary cell line.

microRNAs regulation of pathways - GBM



Expression levels of P38 pathway genes in HeLa cell lines after miR-9 transfection

microRNAs regulation of pathways - GBM



miR-9 down regulation of the p38 network improves prognosis

?

Can we see the same effect with drug response?



Drug response• Patients are treated using a wide spectrum of 69

different drugs• Drugs are classified into two groups:• drugs that target genes in the p38 pathwayAnd• drugs that do not target genes in the pathway



Out of the 69 drugs given to the patients 6 drugs target genes that are part of the p38 network

Drug Name Target Pathway

Accutane RARA map kinase inactivation of smrt co-repressor

CCNU STMN4 Signaling mediated by p38-gamma and p38-delta pathway

Celebrex COX2 Signaling mediated by p38-alpha and p38-beta pathway

Cis Retinoic Acid RARA map kinase inactivation of smrt co-repressor

Sorafenib RAF1 p38 signaling mediated by MAPKAP kinases

Tamoxifen ESR1 Signaling mediated by p38-alpha and p38-beta pathway



Group1

• Low survival

• 169 patients

• Average overall survival time – 433 days

• Median survival time – 310 days

• All patients did not received p38 targeted

drugs

Group2

• High survival

• 63 patients

• Average overall survival – 896 days

• Median survival time – 691 days

• All patients received p38 targeted drugs

Ben-Hamo R, Efroni S. Genome Medicine (2011)Ben-Hamo R, Efroni S. Systems Biomedicine (2013) (CAMDA first prize)







Summary

Measurethe

Network

Targetthe

Network


Summary

Core biology hides in functional wiring of the network

By selecting for robust signatures we achieve significant markers for prognosis

By following the outline of these signatures we discover biology that may lead to treatment

Acknowledgements

Helit CohenRotem Ben Hamo

Alona Zilberberg

Jennifer BenichouRivka CashmanMoriah CohenMiri GordinDror HibshIdo SlomaHagit PhilipRenana Kozol

SYSTEMS BIOMEDICINE JOURNAL

Mechanisms

Documents

The Network is a Biomarker in Cancer Signatures