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Resu
lts S co re sca tte rp l o t (t1 vs. t2 )
S ta n d a rd d e via ti o n o f t1 : 4 .9 9 2
S ta n d a rd d e via ti o n o f t2 : 7 .0 8 9
+ /-3 .0 0 0 *S td .De v-1 2 .5 -1 0 .0 -7 .5 -5 .0 -2 .5 0 .0 2 .5 5 .0 7 .5 1 0 .0
t1
-2 0 .0
-1 7 .5
-1 5 .0
-1 2 .5
-1 0 .0
-7 .5
-5 .0
-2 .5
0 .0
2 .5
5 .0
7 .5
1 0 .0
1 2 .5
1 5 .0
t2
grade1grade2
grade3
(1) Can we identify metabolites or metabolic pathways that are associated with breast cancer clinical parameters?
Alex-CIS-GCTOF MS w/ BinBase: 470 detected compounds161 known metabolites, 309 without identified structure.
Partial Least Square (multivariate stats)
grade3
grade2
grade1
breast adipose
0
10
20
30
40
50
60
E+P+H- E+P+H+ E+P-H- E+P-H+ E-P+H- E-P+H+ E-P-H- E-P-H+
grade 1 grade 2 grade 3
Resu
ltsGrade n1 23 tumors show differential up-regulation in Pentose Phosphate Pathway, nucleotides, amino acids, arachidonic acid
(but not free fatty acids, gln)
production of NADPH, ribose units production of DNA, RNA
Resu
ltsGrade n1 23 tumors show differential up-regulation in Pentose Phosphate Pathway, nucleotides, amino acids, arachidonic acid
(but not free fatty acids, gln)
Amino acids
Amino acids
lactate
Ca te g . B o x & Wh iske r P lo t: g l u ta m ic a ci d
n o rm a l 1 2 3
g ra d e
0
1 E 5
2 E 5
3 E 5
4 E 5
5 E 5
6 E 5
glu
tam
ic a
cid
n o rm a l 1 2 3
g ra d e
0
2 0 0 0
4 0 0 0
6 0 0 0
8 0 0 0
1 0 0 0 0
1 2 0 0 0
1 4 0 0 0
be
ta-a
lan
ine
glu -ala
M e a n M e a n ±S E M e a n ±1 .9 6 *S E
n o rm a l 1 2 3
g ra d e
2 0 0 0
4 0 0 0
6 0 0 0
8 0 0 0
1 0 0 0 0
1 2 0 0 0
1 4 0 0 0
1 6 0 0 0
1 8 0 0 0
2 0 0 0 0
2 2 0 0 0
2 4 0 0 0
2 6 0 0 0
2 8 0 0 0
3 0 0 0 0
3 2 0 0 0
3 4 0 0 0
ma
late
malate
Ca te g . B o x & Wh iske r P lo t: c i tri c a ci d
n o rm a l 1 2 3
g ra d e
1 5 0 0 0
2 0 0 0 0
2 5 0 0 0
3 0 0 0 0
3 5 0 0 0
4 0 0 0 0
4 5 0 0 0
5 0 0 0 0
5 5 0 0 0
citr
ic a
cid
citrate
n 1 2 3 grade n 1 2 3 grade
n 1 2 3 grade n 1 2 3 gradeCa te g . B o x & Wh iske r P lo t: a ra ch id o n i c a ci d
M e a n M e a n ±S E M e a n ±1 .9 6 *S E
n o rm a l 1 2 3
g ra d e
2 0 0 0
4 0 0 0
6 0 0 0
8 0 0 0
1 0 0 0 0
1 2 0 0 0
1 4 0 0 0
1 6 0 0 0
1 8 0 0 0
arac
hido
nic
acid
C20:4 2HOglutarate
n 1 2 3 graden 1 2 3 gradeIDH1?
Resu
lts
Can we validate biomarkers in a fully independent study?Cohort 2 (113 patients)
Resu
lts
Can we validate lipidomic biomarkers in a fully independent study?
Cohort 2 (113 patients)
Matej Orešič et al. (subm.)
Resu
lts
Can we validate lipidomic biomarkers in a fully independent study? Immunohistochemistry on tissue slides.
Orešič et al. (subm)
Can we get biochemical maps of differential regulation for hormone receptor status?
Met
hods
(1) Up to 20% of the identified metabolites lack enzyme annotations.
(2) Metabolic endpoint metabolites accumulate more than intermediates. ‘Comprehensive maps’ do not work.
Can we get biochemical maps of differential regulation for hormone receptor status?
Met
hods
(1) Up to 20% of the identified metabolites lack enzyme annotations.
(2) Metabolic endpoint metabolites accumulate more than intermediates. ‘Comprehensive maps’ do not work.
Chemical and biochemical mapping of metabolomic resultsM
etho
ds
Resu
ltsGrade 1 tumors vs normal
Red nodes: up-regulated in tumors at p<0.05, size ~ x-foldBlue nodes: down-regulated in tumors at p<0.05, size~x-foldRed edges: enzyme substrate/product in KEGGRpair DBGreen edges: chemical similarity > 0.7
0
10
20
30
40
50
60
E+P+H- E+P+H+ E+P-H- E+P-H+ E-P+H- E-P+H+ E-P-H- E-P-H+
grade 1 grade 2 grade 3
Met
hods
% o
f pati
ents
Estrogen negativeEstrogen positive
triple neg.
ER+ PR+HER2-
ER- PR-HER2-
single neg.
Hormone receptor @ grade 3
Resu
lts
ER- PR- HER- (n=27) Vs ER+PR+ HER- (n=19) P<0.05
Breast Cancer: Grade 3Red : metabolite is enriched in triple negative Blue : metabolite is down regulated in triple negativeNode size= fold change. Largest fold change is 3.
Metabolic phenotype of triple negative tumorsPatients without Estrogen, Herceptin neu2, Progesteron receptor
0
10
20
30
40
50
60
E+P+H- E+P+H+ E+P-H- E+P-H+ E-P+H- E-P+H+ E-P-H- E-P-H+
grade 1 grade 2 grade 3
Met
hods
% o
f pati
ents
Estrogen negativeEstrogen positive
triple neg.
ER- PR-HER2+
ER- PR-HER2- double neg.
Hormone receptor @ grade 3
Resu
ltsEffect of HER2 status on metabolic phenotype
of triple negative tumors
ER- PR- HER- (n=27) Vs ER-PR- HER+ (n=11) P<0.05
Breast Cancer: Grade 3
Red : metabolite is enriched in triple negative Blue : metabolite is down regulated in triple negativeNode size= fold change. Largest fold change is 3.
0
10
20
30
40
50
60
E+P+H- E+P+H+ E+P-H- E+P-H+ E-P+H- E-P+H+ E-P-H- E-P-H+
grade 1 grade 2 grade 3
Met
hods
% o
f pati
ents
Estrogen negativeEstrogen positive
ER+ PR+HER2-
double pos.
ER+ PR+HER2+
triple pos.
Hormone receptor @ grade 2