Genome, transcriptome and proteome features of malignant cells

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Genome, transcriptome and proteome features
of malignant cells as a source of combinatorial
biomarkers for clinical translation
Ancha Baranova
George Mason University,
Fairfax, VA
Key word to understanding of
cancer phenomenon
PROGRESSION
From bad
to worse
then to full catastrophe
LUNG CARCINOMA PROGRESSION
e.g. carcinogen
from the smoke
e.g. Smoke
How long it usually takes:
DECADES
It takes ≈17 years for a large benign tumor
to evolve into an advanced cancer
but <2 years for cells within that cancer to
acquire the ability to metastasize
Sequencing studies show
that virtually all of the
mutations necessary
for metastasis are
already present in all of
the cells of the
antecedent carcinoma.
10.1073/pnas.0712345105; Jones et al., 2008
17 years
TRUTH: Majority of human tumors sit in
our bodies undiagnosed for decades
Major implication for translational research:
1) need for early biomarkers;
2) need for evaluation of how far away the tumor
was from sprouting metastasis  basis for postsurgical treatment and care
Problem: in biomarker research all
low-hanging fruits already collected
PSA, CEA, AFP….
Single biomarkers have problems with
differentiating “grey area” diseases, i.e.
inflammatory conditions
Solution:
Biomarker panels
P
S
A
L
e
v
e
L
Controls Prostate BPH Other
Benign
cancer
cancers genitourinary
Barak et al., 1989
diseases
Now: from where these biomarker for
biomarker panels are usually coming ?
A fishing
expedition:
Differences
often reflect
Inflammation,
fibrosis
and other
common properties
Image courtesy of Purdue University, Dr. W. Andy Tao
Two-pronged approach proposed:
TUMOR vs. a MIX of
various normal cells
Perform transcriptome (in
silico) and proteome
(using antigen screening)
subtractions
Most TARGETED
approach:
DISTANCE ANALYSIS:
Use entire pattern of gene
expression to evaluate of
how far away the excised
tumor was from sprouting
metastasis
Most GENERAL
approach:
Based on previous works of collaborative consortium:
Two-pronged approach proposed:
TUMOR vs. a MIX of
various normal cells
Perform transcriptome (in
silico) and proteome
(using antigen screening)
subtractions
Most TARGETED
approach:
Will uncover tumor
biomarkers
that cannot be masked
by antigen production
in normal tissue
Most Targeted Approach:
Consortium
Blokhin Russian Oncological Scientific Center, Moscow
(sample collection and processing)
Caerus Discovery LLC, Manassas, VA
(capture of protein biomarker as differentially expressed
antigens)
Most TARGETED
approach:
Institute of Chemical Biology and Fundamental Medicine
SB RAS, Novosibirsk
(development of tumor protein biomarkers as targets for
antibody-guided drug delivery)
Biomedical Center, StPeterburg
(differential display of tumor RNAs)
Research Center for Medical Genetics RAMS
(non-coding Tumor RNAs)
George Mason University, Fairfax, USA
(biomarker validation, bioinformatics support and
general coordination)
Two-pronged approach proposed:
DISTANCE ANALYSIS:
Use entire pattern of gene
expression to evaluate of
how far away the excised
tumor was from sprouting
metastasis
Most GENERAL
approach:
Simple words explanation forusing
entire transcriptome as biomarker
• Who is that? -- Instant answer (same person, Darwin)
Biomarker approach:
X: Distance from the end of nose
to the upper lip
Y: Diameter of the eye orbit
Z: Number of hairs in the beard
Two-pronged approach proposed:
Blokhin Russian Oncological Scientific Center, Moscow
(sample collection and processing)
Institute of Chemical Biology and Fundamental Medicine
SB RAS, Novosibirsk
(next gene sequencing and microarray)
DISTANCE ANALYSIS:
Use entire pattern of gene
expression to evaluate of
how far away the excised
tumor was from sprouting
metastasis
Vavilov Institute of General Genetics
(next gene sequencing and microarray)
Research Center for Medical Genetics RAMS
(distance analysis of samples based on summed
evaluation of non-coding RNAs)
Most GENERAL
approach:
University of Arkansas for Medical Sciences (Little Rock,
AK)
(distance analysis of whole genome patterns)
George Mason University, Fairfax, USA
(development of attractor descriptors, bioinformatics
support and general coordination)
VISION for the FUTURE
New generation of tumor markers specific to
the malignancy but not to the any normal cell
type will allow:
1) True early diagnostics of dormant tumors
2) More specific antibody-guided delivery of
therapeutic agents to the tumors
VISION for the FUTURE
Comparison of prognoses for
This tumor and That tumor
Same strategy can be realized
using NextGen Seq
Very possible;
low sequence coverage of transcripts will be enough;
cost-efficient cut-off needs to be determined
VISION for the FUTURE
REFERENCE LAB
Profiles 100s normal samples for prostate;
Establishes its own, equipment-specific
NORMAL SPACE
For every single tumor sample,
the distance from normal tissue space is measured
How bad is my tumor?
Answer:
exact distance
from “Ideal” norm
Your tumor
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