BLOOD-BASED MARKERS

Blood is an attractive surrogate specimen source because of its
availability and the presumed pooling of metabolic processes in
the circulation, as reflected, it is postulated, in that compartment.
DNA-Based Markers in Blood The quantity of DNA
leaching into the blood itself has been proposed as a marker, 24
albeit controversially. 25,26 Attempts to detect DNA-based somatic
markers in the blood have been myriad, 27 including
oncogene mutations, somatic mutations, and other modifications,
with mixed results. For the most proximate steps in
tobacco carcinogenesis, the measurement of DNA adducts
of known tobacco carcinogens in blood cells, several large
European studies using 32 P postlabeling of adducts did not
show consistent relation to smoking, nor risk. 28,29 A more recent
large, pooled data analysis also suggests a weak association
of bulky DNA adducts and lung cancer, perhaps apparent in
current and recent smokers only. 30
Aberrant DNA methylation in blood has been detected
for the last decade, albeit its origin remains unclear , but these
have been as disappointing as diagnostic tools. 31–33
For risk assessment, blood-based genome-wide association
and family linkage studies for germline variants associated
with lung cancer have emerged, although in somewhat sparse
number. A susceptibility locus on chromosome 6q23–25 was
reported from a multi-institutional consortium examining
high-risk family pedigrees, led by National Institute of Health
(NIH) investigators 34 (see Chapter 4). The individual candidate
genes in the region have not yet been confirmed with regard
to association of their variants with lung cancer risk.
Individual variants in component enzymes in specific
pathways have been explored in some detail in cross-sectional,
case-control population-based studies, with particular attention
paid to carcinogen metabolism, 35 DNA repair, 36–38 and
inflammation. 39 In general, these data for individual variants
have been inconsistent across populations but may have some
incremental information when integrated into comprehensive
risk assessment models that include demographic data. These
are reviewed in greater detail in the cited references.
RNA-Based Markers in Blood There have been a small
number of well-executed and suggestive studies of RNA expression
in recovered circulating tumor cells 40–42 and/or peripheral
blood lymphocytes. 43 Free circulating RNA studies are inherently
challenging for quality template recovery, RNA-specific
amplification, and detection of signal above background.
Proteomic-Based Markers in Blood A variety of
proteomic-based approaches to obtaining patterns that distinguish
cancer from noncancer tissue, premalignancy from
normal tissue, and the corresponding signals reflected in the
blood, have been approached 44 in a validation population, for
example, a signature yielded a sensitivity of 58% and a specificity
of 85.7%. 45 A more recent study combining proteomicdetected
protein markers and proteins involved in known
lung cancer pathways has suggested that a four-protein panel
in blood may have significant diagnostic value. 46 None of the
protein studies to date entail a temporal component.
Candidate Proteins in Blood Several academic and
commercial ventures have proceded from proteomics studies
generating candidates to protein identification and construction
of panels that distinguish lung cancer cases from appropriate
controls with independent validation in separate populations. 45
Candidate proteins such as circulating serum carcinoembryonic
antigen (CEA) and cytokeratin 19-fragment (CYFRA 21-1)
values and lymphocyte antigen 6 complex locus K (LY6K) have
demonstrated some signal in distinguishing lung cancer cases
from controls, particularly in combination, although classification
is not adequate for disease diagnosis, even in combination
(sensitivity 65% to 70%). 47
Autoantibodies with lung tumor–specific epitopes have
been reported as showing some signal in lung cancer. 48 A
recent report suggested that a panel of p53, c-myc, HER-2,
NY-ESO-1, CAGE, MUC-1, and GBU4-5 autoantibodies
detected by enzyme-linked immunosorbent assay (ELISA) in
blood conferred a sensitivity of 76%, specificity of 92%. 49 Onchip
synthesis of protein libraries that are used for detecting
antitumor antibodies appear promising.
Metabolomics in Blood To our knowledge, the promise
of metabolomics, using high-throughput generation of spectroscopic
signatures representative of the metabolic states of a
cell, 50–52 have not been applied to early detection of lung cancer.
For candidate metabolites in blood, levels of S-adenosylmethionine
have been reported as higher in lung cancer cases than in
smoking controls. 53 Overall, there is a general paucity of investigations
of lung cancer–related metabolites in blood.
Molecular Phenotypes in Blood Mutagen sensitivity
and DNA repair capacity have been evaluated extensively
in blood, particularly by several groups working at the MD
Anderson Cancer Center in Houston, Texas. The identification
of the phenotypes, measuring cytogenetic or more precisely ascertained
DNA damage, presumably integrate a large number of
genes and pathways into a cancer-relevant trait with impressive
capacity to distinguish lung cancer cases versus controls in crosssectional
studies. 54,55,37 Performance in prospective studies in
“integrative epidemiologic” investigations are pending.