Genome, transcriptome and proteome features of malignant cells as a source of combinatorial biomarkers for clinical translation Ancha Baranova George Mason University, Fairfax, VA
Dec 16, 2015
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
How long it usually takes: DECADES
17 years10.1073/pnas.0712345105; Jones et al., 2008
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.
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 post-
surgical treatment and care
TRUTH: Majority of human tumors sit in our bodies undiagnosed for decades
Single biomarkers have problems with differentiating “grey area” diseases, i.e.
inflammatory conditions
Barak et al., 1989
Controls Prostate cancer
BPH Other cancers
Benign genitourinary diseases
Solution: Biomarker panels
PSA LeveL
Now: from where these biomarker for biomarker panels are usually coming ?
Image courtesy of Purdue University, Dr. W. Andy Tao
A fishing expedition:
Differences often reflect Inflammation,
fibrosis and other
common properties
Two-pronged approach proposed:
Most GENERAL approach:
Most TARGETED approach:
DISTANCE ANALYSIS: Use entire pattern of gene expression to evaluate of how far away the excised tumor was from sprouting metastasis
TUMOR vs. a MIX of various normal cellsPerform transcriptome (in silico) and proteome (using antigen screening) subtractions
Two-pronged approach proposed:
TUMOR vs. a MIX of various normal cellsPerform 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
Based on previous works of collaborative consortium:
Most Targeted Approach: Consortium
Most TARGETED approach:
Blokhin Russian Oncological Scientific Center, Moscow (sample collection and processing)
Caerus Discovery LLC, Manassas, VA(capture of protein biomarker as differentially expressed antigens)
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:
Most GENERAL approach:
DISTANCE ANALYSIS: Use entire pattern of gene expression to evaluate of how far away the excised tumor was from sprouting metastasis
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:
Most GENERAL approach:
DISTANCE ANALYSIS: Use entire pattern of gene expression to evaluate of how far away the excised tumor was from sprouting metastasis
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)
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)
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
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 FUTUREREFERENCE LAB
Profiles 100s normal samples for prostate;
Establishes its own, equipment-specificNORMAL SPACE
For every single tumor sample, the distance from normal tissue space is measured