Biology Reference
In-Depth Information
NON
STANDARD ABBREVIATI
ONS
biostatistics algorithms. The Human Proteome
Project was launched in September 2010 with
a goal to identify and characterize at least one
protein product for each of the 20,300 protein-
coding genes.
1
Disease-driven initiatives of the
Human Proteome Project lay the foundation for
clinical and diagnostic applications of proteins,
such as development of disease biomarkers.
Da
Daltons
ELISA
enzyme-linked immunosorbent assay
ESI
electrospray ionization
FDA
the U.S. Food and Drug Administration
FWHM
full width at half maximum
LC
liquid chromatography
m/z
mass-to-charge-ratio
MALDI
matrix-assisted laser desorption/
ionization
MS
PROTEIN BIOMARKER DISCOVERY
AN
D DEVELOPMENT PIPELI
NE
mass spectrometry/spectrometer
MS1
mass spectrum collected for all precursor
ions in sample prior to fragmentation
MS/MS
Development of protein biomarkers is
a multiple phase procedure, analogous to the
drug development process. The biomarker devel-
opment pipeline includes the formulation of
a speci
tandem mass spectrometry, or mass
spectrum collected for fragment ions
PTM
post-translational modi
cation
cation of
proteins, selection of biomarker candidates, verifi-
c clinical question,
identi
SILAC
stable isotope labeling by amino acids
in cell culture
SRM
-
cation of candidates in an independent cohort of
samples, rigorous validation of candidates, devel-
opment and validation of a clinical assay, and
selected reaction monitoring
TOF
time-of-
ight mass spectrometry
XIC
extracted ion chromatogram
finally assay approval by regulatory health
agencies, such as the U.S. Food and Drug
Administration (FDA) or the EuropeanMedicines
Agency (
Figure 1
). The cost of a biomarker devel-
opment study is estimated in the range of one-
tenth of a drug development study; the
discovery-to-clinical assay timeline may exceed
many years. For example, the latest cancer
biomarker cleared by the FDA, the HE4 protein,
was discovered in 2000,
2
but its clinical assay
was only approved in 2008.
3
Prior to the launch of a biomarker discovery
study, one should
INTRODUCTION
ned as a large-scale study of
protein expression, structure, and function in
time and space. Relative to genome, transcrip-
tome, or metabolome analysis,
Proteomics is de
large diversity
of protein sequences
and multiple post-
translational modi
cations make proteome anal-
ysis an even more challenging undertaking.
Unlike the genome, the proteome is dynamic;
a static set of genes may result in different
proteomic phenotypes depending on the devel-
opmental stage of an organism and environ-
mental factors. The dynamic nature of the
proteome results in a wide range of protein refer-
ence values in healthy individuals, thus compli-
cating the clinical applications of proteomics.
The last two decades have seen an impressive
progress in proteomics, mainly due to signi
first consider unmet clinical
needs, decide whether a diagnostic molecule has
a potential to answer a speci
c clinical question
with a certain con
dence, and predict whether
the answer would aid in physicians
decision
making. It should always be acknowledged that
the clinical decision will be made based on
a biomarker performance in combination with
noninvasive medical imaging techniques, such as
magnetic resonance imaging (MRI) and ultra-
sound. Performance of a marker with high area
'
cant
advances in mass spectrometry, high-throughput
antibody production, and bioinformatics and
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