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BioInformatics
Analysis of Cancer Pathways
Using Spotfire
Michael Moorhouse, PhD.
with material supplied by:
Peter van der Spek, PhD.
Erasmus Medical Center, Rotterdam,
Department of Bioinformatics
Making Decisions in a Clinical Environment
Genome Research & Epidemiology
Forensics
Diagnostic Classification
& Clinical Trials
Erasmus Medical Center
Rotterdam, The Netherlands
Disease Management - the future
•Classifying biological
subgroups
•Identifying novel targets
for therapy
New opportunities
for disease
management
•Companion diagnostics
for directed therapy
•Assessing and
managing risk
Morphological Differences are
Characterized by Different
Gene Signatures
Dataset: Pomeroy et al. Nature 415, 436-442 (2002)
Brain Tumour Classification
MD
MGlio
AT/RT CNS
AT/RT Renal/Extrarenal
Ncer
PNET
Dataset: Pomeroy et al. Nature 415, 436-442 (2002)
MD
Mglio
-3
-2
Rhab
-1
0
Ncer PNET
+1
standard deviation from mean
+2
+3
M93119
M30448
S82240
D80004
D76435
X83543
X62534
M96739
U26726
HG311-HT311
X86693
M93426
U48705
X86809
U45955
U53204
X13916
D87258
Z31560
M32886
J04164
M12125
D29958
D17400
D83174
D83735
D84454
L38969
U12465
D80005
D87463
U90902
D26070
X63578
Z15108
L35592
L10338
L33243
L77864
J04469
M80397
X14830
U97018
HG4178-HT4448
K02882
X52228
U22314
D29675
S82471
M54951
INSM1 Insulinoma-associated 1
Casein kinase II beta subunit
RhoE
KIAA0182 gene
Zic protein
APXL Apical protein
HMG2 High-mobility group
NSCL-1
11 beta-hydroxysteroid dehydrogenase type II
Ribosomal Protein L30
High endothelial venule
PTPRZ Protein tyrosine phosphatase
DDR gene
Major astrocytic phosphoprotein PEA-15
Neuronal membrane glycoprotein M6b
Plectin (PLEC1)
LDL-receptor related protein
Serin protease with IGF-binding motif
SOX2 SRY (sex determining region Y)-box 2
SRI Sorcin
RPS3 Ribosomal protein S3
Skeletal beta-tropomyosin
KIAA0116 gene
PTS 6-pyruvoyltetrahydropterin synthase
CBP1 Collagen-binding protein 1
Adult heart mRNA for neutral calponin
UDP-galactose translocator
Thrombospondin 3 (THBS3)
RPS11 Ribosomal protein S11
KIAA0183 gene
KIAA0273 gene
Clone 23612 mRNA sequence
Type 1 inositol 1,4,5-trisphosphate receptor
Parvalbumin
PRKCZ Protein kinase C, zeta
Germline mRNA sequence
SCN1B Sodium channel
PKD1 Polycystic kidney disease protein 1
Stat-like protein (Fe65)
Mitochondrial creatine kinase (CKMT)
POLD1 Polymerase (DNA directed), delta 1
CHRNB1 Cholinergic receptor, nicotinic, beta polypeptide 1
Echinoderm microtubule-associated protein homolog HuEMAP
Af-17
IGHD gene
MUC1 Mucin 1, transmembrane
Neural-restrictive silencer factor
Inducible nitric oxide synthase gene
SSX3
Human atrial natriuretic factor gene
Classic
-3
-2
-1
Desmoplastic
0
standard deviation from mean
+1
+2
+3
HG1980-HT2023
U63842
X67951
X64330
J03241
U44839
Z27113
X12447
U73328
U59913
Z75190
X15183
U61263
L07515
M34677
U40391
D16611
L37127
U33839
X81817
X51804
Y09305
X14885
X57398
X02152
X64364
U04806
U52191
M35296
D50840
S69189
L03785
M82919
U65092
S49592
D79994
X95586
U79299
X71973
U31342
U48437
D86957
HG2279-HT2375
Z19585
M16405
U32315
U11701
Y11251
U68018
M81181
U58334
L38490
Tubulin, Beta 2
NeuroD3 gene
PAGA Proliferation-associated gene A
ATP-citrate lyase
TGFB3 Transforming growth factor, beta 3
Putative ubiquitin C-terminal hydrolase (UHX1)
H.Sapiens gene for RNA polymerase II subunit
ALDOA Aldolase A
DLX7 Distal-less homeobox 7
SMAD5
Apolipoprotein E receptor 2
Human mRNA for 90-kDa heat-shock protein
Acetolactate synthase homolog
Human heterochromatin protein homologue (HP1)
Human nested gene protein gene (coag. factorVIII)
Serotonin N-acetyltransferase gene
CPO Coproporphyrinogen oxidase
RNA polymerase II
No description available
BAP31
Human PMI gene for a putative receptor protein
Protein kinase, Dyrk4
Transforming growth factor-beta 3 (TGF-beta 3)
NME1 Non-metastatic cells 1 (NM23A)
LDHA Lactate dehydrogenase A
BSG Basigin
FLT3/FLK2 ligand mRNA
SMCY (H-Y) mRNA
Tyrosine kinase arg gene
Ceramide glucosyltransferase
Peroxisomal acyl-coenzyme A oxidase
MYL5 Myosin, light polypeptide 5
GABRB3 Gamma-aminobutyric acid (GABA) A receptor, beta 3
Melanocyte-specific gene 1 (msg1)
Transcription factor E2F like protein
KIAA0172 gene
PSMB5 Proteasome subunit, beta type, 5
Human neuronal olfactomedin-related ER localized protein
GPX4 Phospholipid hydroperoxide glutathione peroxidase
Human nucleobindin gene
Amyloid precursor-like protein 1
KIAA0202 gene
Triosephosphate Isomerase
THBS4 Thrombospondin 4
Human m4 muscarinic acetylcholine receptor gene
Syntaxin 3
LIM-homeobox domain protein (hLH-2)
Novel member of serine-arginine domain protein, SRrp129
Mad protein homolog (hMAD-2)
ATP1B2 ATPase, Na+/K+ transporting, beta 2 polypeptide
Bcl2, p53 binding protein Bbp/53BP2
ARF4L ADP-ribosylation factor 4-like
HG3543-HT3739
X53331
X65724
D14530
Y00757
U25789
L27560
X83543
X52966
L06797
M14745
HG3431-HT3616
D79205
D82345
D38549
U14972
X59841
J03242
HG3214-HT3391
X06617
J02611
X16064
Z74616
L40386
X04741
M55210
M96739
U73304
M65292
HG311-HT311
M83233
U07919
X57959
J04080
X76029
U14973
U24576
L41066
X60489
M62843
HG662-HT662
HG613-HT613
L42379
M13241
U12404
M55998
S82240
U78027
X06700
D13413
M74719
M93119
M92287
HG33-HT33
Insulin-Like Growth Factor 2
MGP Matrix protein gla
NDP Norrie disease protein
40S Ribosomal protein S23
SGNE1 Secretory granule, neuroendocrine protein 1
Ribosomal protein L21
Insulin-like growth factor binding protein 5 (IGFBP5)
APXL Apical protein (Xenopus laevis-like)
RPL35A Ribosomal protein L35a
Human (clone L5) orphan G protein-coupled receptor
BCL2 B
Decorin
Ribosomal protein L39
NB thymosin beta
KIAA0068 gene
Ribosomal protein S10
PBX3
IGF2 Insulin-like growth factor 2 (somatomedin A)
Metallopanstimulin 1
RPS11 Ribosomal protein S11
APOD Apolipoprotein D
Human mRNA for translationally controlled tumor protein
COL1A2 Collagen, type I, alpha-2
DP2 (Humdp2)
Human mRNA for protein gene product (PGP)
LAMC1 Laminin, gamma 1
NSCL-1
CB1 cannabinoid receptor (CNR1) gene
HFL1 H factor (complement)-like 1
Ribosomal Protein L30
TCF12 Transcription factor 12
ALDH6 Aldehyde dehydrogenase 6
RPL17 Ribosomal protein L7
C1S Complement component 1, s subcomponent
Neuromedin U
40S ribosomal protein S29
Breast tumor autoantigen
NF-AT3
Elongation factor-1-beta
Paraneoplastic encephalomyelitis antigen HUD
Epstein-Barr Virus Small Rna-Associated Protein
Ribosomal Protein S12
Quiescin (Q6) mRNA
N-MYC
HSPB1 Heat shock 27kD protein 1
Alpha-1 collagen type I gene
RhoE
L44L gene
COL3A1 Alpha-1 type 3 collagen
Tumor-associated 120 kDa nuclear protein p120
SEF2-1A protein (SEF2-1A)
INSM1 Insulinoma-associated 1
CCND3 Cyclin D3
Ribosomal Protein S4
Pathway Mapping
Requires
GO Classification
Classic
IGF2
N-MYC
PTCH
GLI
Desmoplastic
GO-Viewer in
Decisionsite portal
GO Classification I
• Molecular function is what something does. It is a capability that a
•
•
physical gene product (or gene product group) carries as a potential. It
describes only what it can do without specifying where or when this usage
actually occurs. Examples of broad functional terms are "enzyme,"
"transporter," or "ligand." Examples of narrower functional terms are
"adenylate cyclase," or "Toll receptor ligand."
[There is a potential for semantic confusion between a gene product and its
molecular function, because very often these are described in exactly the same
words. For example, "alcohol dehydrogenase" can describe what you can put
in an Eppendorf tube (gene product) or it can describe the function of this
stuff. There is, however, a formal difference -- a "product" has a (potentially)
many-to-many relationship with a "molecular function."
An example: there are many gene products that have the function "alcohol
dehydrogenase" (some of these may indeed be encoded by a gene with the
name alcohol dehydrogenase, but many will not be); a particular gene product
may have both (or more) the functions "alcohol dehydrogenase" and
"acetaldehyde dismutase."]
e.g. GPCR, Kinase
GO Classification II
• Biological process is a biological objective. A biological process is
•
•
accomplished via one or more ordered assemblies of molecular functions.
Usually there is some temporal aspect to it, although a process event may be
essentially instantaneous. It often involves transformation, in the sense that
something goes into a process and something different comes out of it.
Examples of broad biological process terms are "cell growth and
maintenance," or "signal transduction." Examples of more specific terms are
"pyrimidine metabolism" or "cAMP biosynthesis."
A biological process is not equivalent to a pathway. We are specifically not
capturing or trying to represent any of the dynamics or dependencies that
would be required to describe a pathway.
[The semantic distinction between a biological process and a molecular
function can, at times, be hard to draw, and GO takes a pragmatic, rather than
dogmatic, approach: As a general rule a process must have >1 distinct steps.]
e.g. Apoptosis
GO Classification III
• A cellular component is just that, a component of a cell but with
the proviso that the component is part of some larger object, which
may be an anatomical structure, e.g. "rough endoplasmic reticulum" or
"nucleus" or a gene product group, e.g. "ribosome," "proteasome" or a
heterodimeric protein.
• Molecular function, biological process and cellular component are
attributes of gene products. In principle these may all be assigned
independently or may be inherited; in practice they are assigned
independently, that is to say the three graphs, of function, process and
cellular component, are independent.
• The relationships between gene product to molecular function,
biological process and cellular component are all many to many.
e.g. Nucleus, Cytoplasm
Affymetrix uses GO terms since April 2003
NetAffx Gene Ontology Mining Tool
Select your own Array
GO viewer
GO-Tool Configuration
Select Records of Interest
Gene Ontology Procedure
2 Filter
1 Connect
3 Unfold & Explore…..
Show & Hide Empty Nodes
Mark Selected Genes
Acknowledgements
•
•
•
•
•
Johan Helmstad
Tobias Fandriks
Niklas Lindgren
Christopher Ahlberg
Information Sources:
– GO Consortium
– Dataset: Pomeroy et al. Nature 415, 436-442 (2002)
• OpenOffice.org