BMB

reports
Mini Review

Biomarkers for the lung cancer diagnosis and their advances in

proteomics
Hye-Jin Sung & Je-Yoel Cho*
Department of Biochemistry, School of Dentistry, Brain Korea 21, Kyungpook National University, ProtAnBio, Daegu, Korea

Over a last decade, intense interest has been focused on bio- ing, response to therapy, therefore, guidance on therapy, and
marker discovery and their clinical uses. This interest is accel- clinical end points or surrogate end points. Cancer biomarkers
erated by the completion of human genome project and the contribute to the advances in understanding the cancer staging.
progress of techniques in proteomics. Especially, cancer bio- Currently, established convention of cancer staging is the ana-
marker discovery is eminent in this field due to its anticipated tomically based TNM (tumor, node, metastases) system, devel-
critical role in early diagnosis, therapy guidance, and prognosis oped in France in the 1940s by Pierre Denoix. Cancer bio-
monitoring of cancers. Among cancers, lung cancer, one of the markers will provide more knowledge in many areas of biol-
top three major cancers, is the one showing the highest mortal- ogy, which the TNM system cannot.
ity because of failure in early diagnosis. Numerous potential The clinical information given by cancer biomarkers is sig-
DNA biomarkers such as hypermethylations of the promoters nificant in selection of appropriate treatment leading to person-
and mutations in K-ras, p53, and protein biomarkers; carci- alized cancer therapy. Currently, a number of cancer therapies
noembryonic antigen (CEA), CYFRA21-1, plasma kallikrein B1 are carried out based on specific cancer biomarkers. Chronic
(KLKB1), Neuron-specific enolase, etc. have been discovered myelogenous leukemia (CML) treatment with ‘imatinib mesy-
as lung cancer biomarkers. Despite extensive studies thus far, late’ in BCR-ABL translocation patients (3), ‘rituximab’ for CD20
few are turned out to be useful in clinic. Even those used in positive lymphoma patients (4), and ‘trastuzumab’ for HER2/neu
clinic do not show enough sensitivity, specificity and reprodu- positive breast cancer patients are the examples of biomarkers of
cibility for general use. This review describes what the cancer drug targets (5), which are therefore therapy directing. These in-
biomarkers are for, various types of lung cancer biomarkers dis- dicate the anticipated benefits of biomarkers also as the guid-
covered at present and predicted future advance in lung cancer ance on therapy and identification of new targets in cancer
biomarker discovery with proteomics technology. [BMB reports treatment.
2008; 41(9): 615-625]
Types of cancer biomarkers
There are several distinct types of cancer biomarkers based on
Cancer biomarkers different areas: genetics, epigenetics, proteomics, metabolomics,
imaging technology, and general physical techniques. Genetics-
Biomarkers are referred to every means of tools for quantifiable based cancer biomarkers utilize DNA arrays, polymerase chain
measurements of biological homeostasis, which distinguish reaction (PCR), reverse transcriptase polymerase chain reaction
what is abnormal from what is normal (1). Thus, the simplest (RT-PCR), DNA sequencing, fluorescent in situ hybridization
definition of a biomarker in more applicable means is a mole- (FISH) etc. to detect the genetic alterations occurring in the can-
cule that indicates an alteration in physiology from normal. A cerous state. On the other hand, recent development of epi-
more practical definition of a biomarker would require clinical genetic modification analysis also provides tools as cancer bio-
utility of this molecule (2). Cancer biomarkers give good guid- markers. Epigenetic modification usually occurs in CpG island
ance on many areas of cancer biology. They are not only useful of the gene regulatory regions, which results in the down-regu-
in early diagnosis of cancers but also provide important in- lation of the gene expression. These alterations can evade the
formation in cancer therapy such as, verification of cancer stag- cells from their normal cell cycle control, and thus result in can-
cer cells formation (6, 7). Proteomics techniques include mass
spectrometry (MS), ELISA, and immunohistochemistry etc., and
*Corresponding author. Tel: 82-53-420-4997; Fax: 82-53-421-1417; utilize these tools to discover novel cancer biomarkers and vali-
E-mail: [email protected] date them in clinical trials. Other than using macromolecules
such as proteins and DNAs, metabolomics is concerned with the
Received 1 September 2008
study of low molecular weight molecules or metabolites such as
Keywords: Biomarkers, Diagnosis, Lung cancer, Proteomics, Serum/ amino acids, peptides, lipids, and carbohydrates. The metab-
plasma olome is believed to represent only about 2,500 small mole-

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 Biomarkers for the lung cancer
Hye-Jin Sung and Je-Yoel Cho

cules and may provide an insight to cancer biomarkers. Broadly lung cancer. As early detection as IA stage of lung cancer can
used imaging techniques such as Positron Emission Tomography raise the 5-year survival to 80%, comparing to 15% of overall
(PET), Computed Tomographic (CT) scans and Magnetic Reso- non-small cell lung cancer (NSCLC) (12). Therefore, discovery
nance Imaging (MRI) are still major means of cancer diagnosis of novel lung cancer specific biomarker is emerging as an im-
and have distinct ability to localize the cancer that molecular portant platform toward early detection and targeted therapy.
based biomarkers cannot.
DNA-based lung cancer biomarkers
Application of cancer biomarkers in cancer diagnosis and Cancers are thought to arise by genetic alteration, environ-
therapy mental factors and combined both. Although fewer than 10%
Unlike uniformity of long-established TNM system, cancer bio- of cancers are considered to be linked to Mendelian in-
markers are considered to be more suitable to the heteroge- heritance of genetic traits (13), genetics are closely related to
neous nature of cancer. In the case of lung cancer, although the nature of the cancer. Following the development in ge-
categorized in small cell lung cancer (SCLC) or non-small cell nomics, fundamental advances in DNA- or RNA-based cancer
lung cancer (NSCLC) by histological character, there can be biomarkers have been brought into clinical uses.
many other criteria dividing subtypes of lung cancers for exam- Similar to other cancers, lung carcinogenesis is also mul-
ple, EGFR mutation-induced lung cancers. These sub-catego- ti-step process resulting from the accumulation of altered mol-
ries cannot be determined without invasive biopsied tissue test ecules generated from genetic and epigenetic abnormalities of
and therefore cancer type specific biomarkers will be useful in genes which are involved in cell cycle, senescence, apoptosis,
more accurate cancer diagnosis. Thus, possibility of accurate repair, differentiation, and cell migration controls (14-16).
diagnosis of cancers by biomarkers is expected to bring some Uncontrolled cell growth is derived from either oncogene acti-
benefits in molecular based cancer patient care. First, with po- vation or tumor suppressor gene (TSG) inactivation, thus, ge-
tential to predict possibility to progress into cancerous status, netics-based cancer biomarkers are closelely related to these
biomarkers can prevent cancer in person who has high risk (1). genes (14, 17). Considering that the close connection exists
Cancer biomarkers are expected to not only predict the predis- between genetic changes and malignant transformation of lung
posed factors but also diagnose cancer patients at early of their cancer, it is obvious that genomics would also provide poten-
stage. This will greatly increase the chances to treat cancer and tial lung cancer biomarkers.
reduce the mortality. Second biomarkers will be guidance to
cancer therapy. Some biomarkers change in expression levels A. Chromosomal changes
responding to treatment. This change will indicate the response Inactivation of tumor suppressor genes during the cell division
to therapy and will tell the important clinical endpoint or surro- is one of the key factors that drive clonal cells of cancer into
gate endpoint. In other aspects of biomarker contribution to the uncontrolled growth, migration and metastasis (18). In many
cancer therapy is the drug target discovery. In other words, tis- cases the inactivation is induced by loss of DNA or chromoso-
sue derived biomarkers can be used for potential drug targets mal rearrangement accidentally happening during cellular
as well as imaging diagnostic biomarkers. Aminopeptidase-p division. Most well-known frequently occurring abnormality is
and Annexin A1 discovered in lung endothelial surfaces of deletion of the short arm of chromosome 3 (3p) where several
mouse lung cancer model (8) and coatomer protein complex, TSG are present (Table 1) (19-22). Loss of chromosomal mate-
subunit gamma (COPG), thymopoietin (TMPO) and peroxir- rial has also been reported to be detected in metaplastic epi-
edoxin 4 (PRDA 4) found by our group from endothelial cells thelium tissues of smoker or exsmokers. The loss of one allele
in human lung cancer tissues are good examples of biomarkers or loss of herterozygosity (LOH) indicates predisposing poten-
role in drug targets (9). Finally, in case of molecular based can- tials to lung cancers, too (23, 24).
cer biomarkers, they will help to find new drug target mole-
cules for personalized cancer therapy. B. Gene hypermethylation
Altered hypermethylation, methylation of the cytosine phos-
Lung cancer and its biomarkers at present phate guanosine rich regions (CpG islands) of various pro-
moter regions, is a representative epigenetic change in the cell
Lung cancer is one of the most prevalently occurring and the and may cause gene silencing. As an alternative mechanism
most life-threatening neoplasia in most part of the world. It has for inactivating TSGs, hypermethylation is generally discovered
an incidence of 1.2 million people in worldwide, and ac- in most tumors, including lung cancer (15, 25-31). Thus, cer-
counted for about 25% of all cancer deaths (10, 11). In Korea, tain methylation status in the genes can be biomakers in lung
the incidence and the mortality associated with lung cancer cancers especially in TSGs. For example, the hypermethylation
are predicted to steadily increase. This is largely attributed to of inactivation of p16, p15, glutathione transferase 1, O(6)-me-
the diagnosis at late stage. Some ongoing diagnostic tools at thylguanine-DNA methyltransferse (O6-MGMT), tissue inhibitor
clinics include CT scans, bronchoscopy and sputum analysis, of metalloprotease (TIMP)-3 and death associated protein
none of which turns out to be effective in early diagnosis of (DAP)-kinase following the hypermethylation of their promoter

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 Biomarkers for the lung cancer
Hye-Jin Sung and Je-Yoel Cho

Table 1. Gene-based biomarkers in detection of lung cancer: potential

Groups Types of genes

Chromosomal changes Deletion of the short arm of chromosome 3 (3p) (21) 27-88% in circulating DNA of lung cancer patients

Hypermethylation Serine protease family member-trypsinogen IV (PRSS3) (22) -

Tissue inhibitor of metalloproteinase (TIMP)-3 (37) -
Death associated protein (DAP)-kinase (38) -
P16, FHIT (39) Associated with an increased risk of lung cancer recurrence
after therapy

Genetic changes K-ras (40) 20-30% in circulating DNA of lung cancer patients
P53 (40) 27% in circulating DNA of lung cancer patients

regions are well-known in lung cancers (Table 1) (7). can be found. In blood, however, more potential biomarkers ex-
ist and this include the biomarkers found in biopsied cancer tis-
C. Genetic change of oncogenes sue and many circulating protein fragments generated in the dis-
In an opposite action to previous gene silencing, activation of eased tissue microenvironment or by circulating proteins and
genes involved the growth factors, their receptors, their mes- cells derived from the diseased tissue. Because the ultimate goal
sengers or cell cycle activators by mutations also play key of biomarker is specific, early and non-invasive diagnosis and
roles in carcinogenesis and cancerization. Mutation of ras, a post-therapy monitoring of cancer, blood has been thought as an
second messenger delivering proliferation signal to nucleus, is appropriate biological material. Thus, many biomarker discov-
discovered to be also involved in lung cancer. Most ras muta- eries are carried out with blood-based strategies (44, 45) and
tion discovered in lung cancer patients appears on codon 12 most of lung cancer biomarkers listed below and already studied
of K-ras and is known to be related to precancerous state of are mostly serum biomarkers.
lung cancers (32, 33). p53-retinoblastoma gene (Rb) pathway
can result in genotoxic stress once activated. p53 mutation los- A. Lung cancer protein biomarkers: currently available
es its control of Rb phosphorylation and G1 arrest leading to Some of lung cancer biomarkers are clinically available although
uncontrolled growth of tumor cells (34-36). Thus, mutations or the use of those is not recommended in clinical diagnosis (Table
alterations of protooncogene, which cause hyperactivation of 2). An oncofetal protein, carcinoembryonic antigen (CEA) con-
cell cycle, can be good biomarkers in lung cancers (Table 1). centration is elevated in lung cancer patients especially in ad-
enocarcinoma and large cell lung cancer (LCLC) (46-48). CEA
Protein biomarkers alone has limit to diagnosis and is preferably used in combina-
Despite the significant advances in genomics- and genetics- tion with CYFRA. As a therapy response monitoring indicator,
based biomarker discovery, there is still no novel cancer specif- CEA is used for advanced NSCLC and adenocarcinoma (49, 50).
ic biomarker in clinical uses. DNA-based biomarkers, described However, CEA and CYFRA have been also found to be associated
previously, are known to have potential as a lung cancer bio- with other types of cancers such as colorectal cancers (51, 52).
marker but no biomarkers have adequate sensitivity, specificity Thus they are not thought to be lung cancer-specific biomarkers,
and reproducibility. This is due to the fact that mRNA levels are but more general cancer biomarkers.
not always linked directly to levels of proteins, the molecules CYFRA 21-1 proteins are indicator of increased level of cyto-
that actually biologically do functions (41). Currently, human keratin 19 fragements that implies the presence of lung cancer
genome is known to contain 20,488 genes (42). Proteins, how- (46, 47, 53, 54) and has in potential monitoring treatment re-
ever, give much more varieties due to alternative splice var- sponse of advanced NSCLC patients. Unlike CYFRA21-1, tissue
iants, protease cleavages, and post- translational modifications polypeptide antigen (TPA) measures cytokeratin 8, 18 and 19
such as glycosylation, phosphorylation, ubiquitination, methyl- detecting NSCLC (55). Progastrin-releasing peptide (ProGRP),
ation, acetylation and so on. This means protein biomarkers can quite stable protein, is produced by the nueroendocrine tissues
be more specific to cancer type and status. of the gastrointestinal and respiratory tracts and is also an avail-
Protein lung cancer biomarkers can be classified by the source able lung cancer biomarker for SCLC (47, 54, 56). Neuron-spe-
of the proteins into three categories: serum biomarkers, tissue bi- cific enolase (NSE) is a glycolytic enzyme produced in central
omarkers, and sputum biomarkers (Fig. 1) (43). In sputum, cancer and peripheral neurons (57). However, NSE is also increased in
cells apart from cancer sites are major protein sources. In biop- SCLC and its elevated level shows great potential to be a mon-
sied lung tissue, not only cancer cells but also other molecules in- itoring tool for post-therapy. Again, these protein biomarkers
volved in self-defense of human body such as, immune cells, cy- usually lack their lung-cancer specificity in terms of their usag-
tokines and derivatives from immune or inflammatory response es as biomarkers.

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 Biomarkers for the lung cancer
Hye-Jin Sung and Je-Yoel Cho

Fig. 1. Schematic workflow of lung can-

cer biomarker discovery. Biomaterials
from three for protein biomarker discov-
ery, lung tissues, sputum, and body flu-
ids, are usually used. In sputum, cancer
cells apart from cancer sites are sup-
posed to be detected. In biopsied lung
tissues, not only cancer cells but also
other molecules involved in self-defense
mechanism of human body such as, im-
mune cells, cytokines and derivatives
from immune or inflammation responses
can be found. In body fluids, although
pleural fluids, ascite, urine etc can be
used, blood is most commonly used in
biomarker studies for its advantages of
easy access and routine blood chemistry
measurements in the patients. In blood,
however, more potential biomarkers ex-
ist and this includes many biomarkers
found in biopsied cancer tissues and
many circulating protein fragments gen-
erated in the diseased tissue microenvi-
ronment or by circulating proteins de-
rived from the diseased tissues. After
proper preparation each protein can be
analyzed by similar procedures of the
identification, verification, and validation.
For protein identification, prepared sam-
ples are analyzed by mass spectrometry.
LC-ESI-MS/MS and MALDI-TOF/MS are
most commonly used platforms. Potential
biomarkers, elevated or decreased in
their expression levels, are confirmed by
Western blot, ELISA or by recent devel-
opment of multiple reaction monitoring.

Epidermal growth factor receptor (EGFR) mutation is novel pha2 (96), and a fragment of apolipoprotein A-1 (97) for lung
biomarker for the diagnosis of EGFR mutation induced NSCLC cancer biomarker is mentioned in some studies and need more
that is, strong predictive biomarker for EGFR-targeted protein clinical validation to be available in clinics. In the process of se-
tyrosine kinase inhibitors (58). As consequent of this bio- rum glycoprotein analysis in lung cancer patients, our group has
marker discovery, molecules that target this pathway (e.g., er- identified plasma kallikrein B1 (KLKB1) fragment as potentially
lotinib, gefitinib, cetuximab, panitumumab) are currently used useful biomarker in diagnosis of lung adenocarcinoma (98).
for specific cancer therapy purpose (59). KLKB1 has homology to proteins of the serine protease-trypsin
family and is related to surface-dependent procoagulation, fi-
B. Lung cancer protein biomarkers: potential brinolysis, kinin generation, and inflammation. It has also ho-
There are also many potential lung cancer biomarker molecules, mology to KLK3, of which protein product is known as prostate
although not yet available in clinical usage as those listed above specific antigen (PSA). About 18 kDa fragment of KLKB1, possi-
(Table 3). The potency of serum amyloid A (95), haptoglobin-al- bly containing H4 domain of it, showed especially high de-

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 Biomarkers for the lung cancer
Hye-Jin Sung and Je-Yoel Cho

Table 2. Protein-based biomarkers in detection of lung cancer: currently available

Therapy Prognosis
Diagnosis Ontology Details References
monitoring monitoring

AdenoCA, Cellular component Use in combination with

AdenoCA, LCLC AdenoCA,
CEA Advanced Cell membrane: lipid anchor CYFRA. (46-50, 60-71)
(>10 ug/L) NSCLC
NSCLC Immunoglobulin superfamily Often elevated in smokers.

NSCLC, SCC Structural constitutent of Often elevated in patients with

Advanced NSCLC, (46-50, 53-55,
CYFRA21-1 (Sensitivity for NSCLC varies cytoskeleton benign lung diseases.
NSCLC SCC 60-62, 72-83)
between 23 and 70%)

TPA NSCLC, SCC - NSCLC - (46, 53, 55)

SCLC Neuropeptide hormone Increased in renal failure and

(＞200 ng/L=Highly activity some benign lung diseases.
(48, 54, 56,
ProGRP suspicious) SCLC - Use in combination with NSE
84-90)
(Sensitivities for SCLC range
47-86%)

Phosphoglycerate dehydro- Use in combination with

SCLC
genase activity ProGRP
(＞100 ug/L=High (60, 66, 72, 74,
Subcellular location May correlates with short
NSE probability) SCLC SCLC 77, 78, 83, 86,
(cytoplasm) survival
(Sensitivities for SCLC as high 91-94)
Increased in inflammatory
as 74%)
diseases

Tumor M2- AdenoCA Pyruvate kinase activity Increased in multiple

pyruvate (Sensitivities for SCLC range - AdenoCA Glycolysis malignant diseases and some (85)
kinase 50-71%) Cytoplasm inflammatory diseases

CEA=carcinoembryonic antigen, CYFRA 21-1=cytokeratin 19 fragment, TPA= tissue polypeptide antigen, ProGRP=progastrin-releasing peptide, NSE=neu-
ron-specific enolase, AdenoCA=adenocarcinoma, SCC=squamous cell carcinoma, SCLC=small cell lung cancer, NSCLC=non-small cell lung cancer

Table 3. Protein-based biomarkers for the detection of lung cancer: potential

Diagnosis Ontology Details Reference

Lipid transporter activity Elevated to

Acute phase response 62.4 μg/ml
Serum amyloid A Lung cancer (95, 101)
Immune cell chemotaxis (2 μg/ml in healthy control)
Extracellular region

Serine-type endopeptidase activity

Defense response
Haptoglobin-α 2 AdenoCA - (96)
Proteolysis
Extracellular region

Lipid transporter activity Apolipoprotein A-1 fragment:

Lipase inhibitor activity downregulated in cancer
APOA1 AdenoCA Cholesterol efflux, homeostasis, metabolic pateients (96)
process, transport
Extracellular region

Peptidase activity 17-18 kDa fragment of plasma

KLKB1 AdenoCA (98)
Proteolysis kallikrein B1

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 Biomarkers for the lung cancer
Hye-Jin Sung and Je-Yoel Cho

multiple capture antibodies are efficient method to detect the

presence of numerous proteins rapidly, and electrophoresis is
particularly useful in separating proteins by molecular weight
and/or pKa. The major techniques that fundamentally sup-
ported the discovery of cancer biomarkers was mass spectrom-
etry which can determine precise mass and charge of protein,
thus identity of the actual precursor proteins.
In the sense of limitation of current proteomics technology,
mainly mass spectrometry-based, it is generally accepted that
subproteome analysis is important to look for proteomes deep-
er and more specific low abundant proteins. This is mainly
11
due to the high dynamic range, more than 10 order magni-
tude, of proteins present in the serum; highest proteins of albu-
min about 40 mg/ml to Interleukin-6, one of lowest proteins,
about 10 pg/ml (107). Thus, before searching biomarker pro-
teins in the body fluids, proteomes in the body fluids need to
Fig. 2. A diagram showing the generation of plasma kallikrein (KLKB1) be separated by its characteristics; such as by glycoproteome
fragment. A KLKB1 has homology to proteins of serine protease-trypsin or phosphoproteome enrichments, ion charges, hydro-
family and by the action of Factor XIIa, KLKB1 are cleaved into two
main chains: a heavy chain containing four domains with procoagulant phobicity or hydrophilicity by SCX/SAX, reverse phase or nor-
activity and a light chain, active catalytic domain, with trypsin-like mal phase chromatography, or by their molecular weights etc.
activity. A fragment including H4 domain of KLKB1 is produced in Glycoproteome analysis in the body fluids has great advan-
the sera of lung cancer patients, which can be a potential biomarker,
whereas it is not or minimally produced in normal population. tages in the area of cancer biomarker discovery. About half of
the serum proteins are known to be glycosylated and the gly-
cosylation status on glycoproteins, their degrees and forms, is
tection in the lung adenocarcinoma (Fig. 2). The finding of also altered by certain disease conditions including cancers.
KLKB1 fragment supports the recent ideas of serum peptidomes Also, various known biomarkers are found to be glycoproteins;
as great diagnostic potential biomarkers in cancer diagnosis (99), such as breast cancer biomarkers CA-125 and ErbB.
and this low molecular weight protein fragment also implies that
that there will be much more potent lung cancer biomarkers de- Proteomic technology ahead and biomarkers in the future
rived from cancer-type-specific enzymatic breakdowns (100). Since cancer biomarker discovery has started extensively with
the progress of proteomic technology, many protein molecules
Proteomics and lung cancer biomarkers in advance have been indicated as potential cancer biomarkers. There are
several hurdles that have been acted as major causes of cancer
Proteomic technology at present biomarker unsuccessfulness. First, lack of analytic reagent, es-
Following the completion of human genome project, proteo- pecially antibodies for validation of mass-spectrometry data or
mics has emerged as a new area of study. Proteomics means for clinical tests had great hindrance. Lack of commercially
large-scale characterization of proteins including more compli- available specific antibodies makes it much slower to validate
cated features; isoforms, modifications, interactions, functional the cancer biomarker candidates through immunoblot analysis
structures, etc. (102). Dramatic progress of proteomic tech- or enzyme-linked immunaborbent assays (ELISAs). Second,
nologies such as, protein separation, quantification, and identi- most of the previously published studies had technical limi-
fication makes it possible to search proteins more intensive tations; insufficient sensitivity, inability to detect low abundant
and to understand their functions deeper (103, 104). Therefore proteins etc.
systemic overview of whole expressed proteins became possi- Proteomic techniques are gradually improving in sample
ble and this is linked to improvement of cancer therapy in di- preparation steps and also analysis steps. Improvement in sam-
agnosis, treatment and prognosis monitoring. ple preparation tools will reduce the intrinsic limitations in bio-
Proteomics has approached in cancer biomarker field in two logical samples, such as variation among individuals, differ-
aspects; one is profiling the whole protein expressions and the ences in genetic make-up, and nonspecific changes (108) and
other is identification of specific individual protein which is po- progress in analytic techniques will increase sensitivity to detect
tent as a biomarker. Former enables systemic overview of neo- low abundance or low molecular weight protein molecules.
plasia and ultimately the improvement in cancer diagnosis and Recently, remarkable new orthogonal MS-based clinical assay
therapy and the latter brings discovery of new cancer specific (multiple-reaction-monitoring, MRM-MS (109, 110) is expected
biomarker and early diagnosis (57, 105). Proteomics employs to accelerate the discovery of cancer biomarkers, the ver-
mass spectrometry, protein microarrays, and electrophoresis as ification of the biomarkers, and also their clinical translations.
analytical tools to identify proteins (106). Microarrays using Modification of this tool using isotope-coded antibody capture

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 Biomarkers for the lung cancer
Hye-Jin Sung and Je-Yoel Cho

technology (111) or by multi-dimensional fractionation (112), 7. Belinsky, S.A. (2004) Gene-promoter hypermethylation as
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Kwon, T.H., Lee, E.B., Ryoo, H.M. and Cho, J.Y. (2008)
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Acknowledgements panying non-small-cell lung cancers. J. Natl. Cancer Inst.
This work was supported by the grant No. FPR08A2-120 of the 87, 1224-1229.
21C Frontier Functional Proteomics Project from the Korean 17. Wood, L.D., Parsons, D.W., Jones, S., Lin, J., Sjoblom, T.,
Leary, R.J., Shen, D., Boca, S.M., Barber, T., Ptak J.,
Ministry of Education, Science and Technology (MEST) and al-
Silliman, N., Szabo, S., Dezso, Z., Ustyanksky, V.,
so in part by the grant No. RT104-01-01 from the Regional Nikolskaya, T., Nikolsky, Y., Karchin, R., Wilson, P.A.,
Technology Innovation Program of the Ministry of Knowledge Kaminker, J.S., Zhang, Z., Croshaw, R., Willis, J.,
Economy (MKE). Due to the space constraints, we apologize Dawson, D., Shipitsin, M., Willson, J.K., Sukumar, S.,
for the inability to cite all relevant references. Polyak, K., Park, B.H., Pethiyagoda, C.L., Pant, P.V.,
Ballinger, D.G., Sparks, A.B., Hartigan, J., Smith, D.R.,
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