An integrated transcriptomic and computational analysis for biomarker identification in gastric cancer
Juan Cui
2
Yunbo Chen
1
Wen-Chi Chou
2
Liankun Sun
1
Li Chen
1
Jian Suo
1
Zhaohui Ni
1
Ming Zhang
1
Xiaoxia Kong
1
Lisabeth L. Hoffman
0
Jinsong Kang
1
Yingying Su
1
Victor Olman
2
Darryl Johnson
5
Daniel W. Tench
4
I. Jonathan Amster
0
Ron Orlando
5
David Puett
2
Fan Li
1
Ying Xu
2
3
0
Department of Chemistry, University of Georgia
1
Jilin University-University of Georgia Joint Research Center for Systems Biology, College of Medicine, Jilin University
, Changchun, Jilin 130021,
China
2
Department of Biochemistry and Molecular Biology and Institute of Bioinformatics, University of Georgia
,
Athens, GA 30602, USA
3
College of Computer Science and Technology, Jilin University
, Changchun, Jilin 130021,
China
4
Department of Pathology, Athens Regional Medical Center
,
Athens, GA 30606, USA
5
Department of Biochemistry and Molecular Biology and the Complex Carbohydrate Research Center
,
Athens, GA 30602
This report describes an integrated study on identification of potential markers for gastric cancer in patients' cancer tissues and sera based on: (i) genome-scale transcriptomic analyses of 80 paired gastric cancer/reference tissues and (ii) computational prediction of blood-secretory proteins supported by experimental validation. Our findings show that: (i) 715 and 150 genes exhibit significantly differential expressions in all cancers and early-stage cancers versus reference tissues, respectively; and a substantial percentage of the alteration is found to be influenced by age and/or by gender; (ii) 21 co-expressed gene clusters have been identified, some of which are specific to certain subtypes or stages of the cancer; (iii) the top-ranked gene signatures give better than 94% classification accuracy between cancer and the reference tissues, some of which are gender-specific; and (iv) 136 of the differentially expressed genes were predicted to have their proteins secreted into blood, 81 of which were detected experimentally in the sera of 13 validation samples and 29 found to have differential abundances in the sera of cancer patients versus controls. Overall, the novel information obtained in this study has led to identification of promising diagnostic markers for gastric cancer and can benefit further analyses of the key (early) abnormalities during its development.
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Gastric cancer represents the second leading cause of
cancer death worldwide, next only to lung cancer (1).
In 2002, 934 000 new cases were reported worldwide.
In the USA, 21 500 new cases of gastric cancer were
diagnosed in 2008, with 10 800 deaths from the disease
(2). The current 5-year survival rate of individuals
diagnosed with gastric cancer is 24% (1), reflecting
the reality that most cases are already in an advanced
stage when diagnosed. As with other cancers, the
challenge in early detection lies in the reality that the early
symptoms tend to be relatively non-specific, and detection
requires that invasive physical procedures, such as
gastrointestinal endoscopy, be carried out on a regular basis,
which may not be practical for general screening. The
most ideal solution for early detection is to find reliable
markers that can detect the cancer through simple blood
tests.
Recent comparative transcriptomic studies have
identified a number of gene markers of different types for
gastric cancer, such as diagnostic markers [NF2 (3), NEK6
and INHBA (4)], prognostic markers [CDH17 (5), PDCD6
(6)], and gastric-cancer-associated genes [TSPAN1, Ki67
and CD34 (7)]. While exhibiting some predictive
power, these gene markers were found highly
inconsistent as identified by different studies (Supplementary
Table S1), and none of them has reached the clinical
trial stage. A few serum markers such as a-fetoprotein
antigen (AFP), carcinoembryonic antigen (CEA), and
CA19-9, identified through large-scale blood screening
(8), have been used for gastric cancer detection. The
detection sensitivities of these markers are, however, rather low,
no more than 25% at the 90% specificity level (8), and
hence they have not been widely used clinically for
diagnostic purposes. Using immunoassay and proteomic
techniques, a few new serum markers were recently
proposed. including MUC1 and MUC5AC (8), pepsinogen
C and pepsin A activation peptide (9), and Reprimo (10),
although their true diagnostic power for gastric cancer,
especially at an early stage, is yet to be thoroughly
evaluated. More rigorous studies are in order on these
proposed markers.
The lack of reliable serum markers for gastric cancer
reflects the challenging nature of the problem, but also
suggests the possibility that all the information derivable
using the powerful omic techniques, in conjunction
with computational approaches, may not have been
fully utilized. For example, there have been only a few
published large-scale studies attempting to link the
information derivable from gene-expression profiles of
cancer tissues to proteomic biomarker identification
in patients sera. The general issue with (...truncated)