Results grade1 grade2 grade3 (1) Can we identify metabolites or metabolic pathways that are...
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![Page 1: Results grade1 grade2 grade3 (1) Can we identify metabolites or metabolic pathways that are associated with breast cancer clinical parameters? Alex-CIS-GCTOF.](https://reader030.fdocuments.in/reader030/viewer/2022032803/56649e265503460f94b15624/html5/thumbnails/1.jpg)
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
![Page 2: Results grade1 grade2 grade3 (1) Can we identify metabolites or metabolic pathways that are associated with breast cancer clinical parameters? Alex-CIS-GCTOF.](https://reader030.fdocuments.in/reader030/viewer/2022032803/56649e265503460f94b15624/html5/thumbnails/2.jpg)
0
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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
![Page 3: Results grade1 grade2 grade3 (1) Can we identify metabolites or metabolic pathways that are associated with breast cancer clinical parameters? Alex-CIS-GCTOF.](https://reader030.fdocuments.in/reader030/viewer/2022032803/56649e265503460f94b15624/html5/thumbnails/3.jpg)
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?
![Page 4: Results grade1 grade2 grade3 (1) Can we identify metabolites or metabolic pathways that are associated with breast cancer clinical parameters? Alex-CIS-GCTOF.](https://reader030.fdocuments.in/reader030/viewer/2022032803/56649e265503460f94b15624/html5/thumbnails/4.jpg)
Resu
lts
Can we validate biomarkers in a fully independent study?Cohort 2 (113 patients)
![Page 5: Results grade1 grade2 grade3 (1) Can we identify metabolites or metabolic pathways that are associated with breast cancer clinical parameters? Alex-CIS-GCTOF.](https://reader030.fdocuments.in/reader030/viewer/2022032803/56649e265503460f94b15624/html5/thumbnails/5.jpg)
Resu
lts
Can we validate lipidomic biomarkers in a fully independent study?
Cohort 2 (113 patients)
Matej Orešič et al. (subm.)
![Page 6: Results grade1 grade2 grade3 (1) Can we identify metabolites or metabolic pathways that are associated with breast cancer clinical parameters? Alex-CIS-GCTOF.](https://reader030.fdocuments.in/reader030/viewer/2022032803/56649e265503460f94b15624/html5/thumbnails/6.jpg)
Resu
lts
Can we validate lipidomic biomarkers in a fully independent study? Immunohistochemistry on tissue slides.
Orešič et al. (subm)
![Page 7: Results grade1 grade2 grade3 (1) Can we identify metabolites or metabolic pathways that are associated with breast cancer clinical parameters? Alex-CIS-GCTOF.](https://reader030.fdocuments.in/reader030/viewer/2022032803/56649e265503460f94b15624/html5/thumbnails/7.jpg)
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.
![Page 8: Results grade1 grade2 grade3 (1) Can we identify metabolites or metabolic pathways that are associated with breast cancer clinical parameters? Alex-CIS-GCTOF.](https://reader030.fdocuments.in/reader030/viewer/2022032803/56649e265503460f94b15624/html5/thumbnails/8.jpg)
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.
![Page 9: Results grade1 grade2 grade3 (1) Can we identify metabolites or metabolic pathways that are associated with breast cancer clinical parameters? Alex-CIS-GCTOF.](https://reader030.fdocuments.in/reader030/viewer/2022032803/56649e265503460f94b15624/html5/thumbnails/9.jpg)
Chemical and biochemical mapping of metabolomic resultsM
etho
ds
![Page 10: Results grade1 grade2 grade3 (1) Can we identify metabolites or metabolic pathways that are associated with breast cancer clinical parameters? Alex-CIS-GCTOF.](https://reader030.fdocuments.in/reader030/viewer/2022032803/56649e265503460f94b15624/html5/thumbnails/10.jpg)
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
![Page 11: Results grade1 grade2 grade3 (1) Can we identify metabolites or metabolic pathways that are associated with breast cancer clinical parameters? Alex-CIS-GCTOF.](https://reader030.fdocuments.in/reader030/viewer/2022032803/56649e265503460f94b15624/html5/thumbnails/11.jpg)
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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
![Page 12: Results grade1 grade2 grade3 (1) Can we identify metabolites or metabolic pathways that are associated with breast cancer clinical parameters? Alex-CIS-GCTOF.](https://reader030.fdocuments.in/reader030/viewer/2022032803/56649e265503460f94b15624/html5/thumbnails/12.jpg)
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
![Page 13: Results grade1 grade2 grade3 (1) Can we identify metabolites or metabolic pathways that are associated with breast cancer clinical parameters? Alex-CIS-GCTOF.](https://reader030.fdocuments.in/reader030/viewer/2022032803/56649e265503460f94b15624/html5/thumbnails/13.jpg)
0
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20
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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
![Page 14: Results grade1 grade2 grade3 (1) Can we identify metabolites or metabolic pathways that are associated with breast cancer clinical parameters? Alex-CIS-GCTOF.](https://reader030.fdocuments.in/reader030/viewer/2022032803/56649e265503460f94b15624/html5/thumbnails/14.jpg)
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.
![Page 15: Results grade1 grade2 grade3 (1) Can we identify metabolites or metabolic pathways that are associated with breast cancer clinical parameters? Alex-CIS-GCTOF.](https://reader030.fdocuments.in/reader030/viewer/2022032803/56649e265503460f94b15624/html5/thumbnails/15.jpg)
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