Biology of Lung Cancer

SECTION J
NEOPLASMS OF THE LUNG
51 BIOLOGY OF LUNG CANCER

PIERRE P. MASSION, MD • LECIA V. SEQUIST, MD, MPH • WILLIAM PAO, MD, PhD
INTRODUCTION Role of Inflammation in Lung STRATEGIES TO DEEPEN OUR

PREDISPOSITION TO LUNG CANCER Tumorigenesis UNDERSTANDING OF LUNG CANCER
Smoking Role of Viruses in Lung Tumorigenesis High-Throughput Profiling Techniques
Genetic Susceptibility and Familial Neuroendocrine Tumor Development, Molecular Networks—System Biology
Predisposition Genomics of SCLC TRANSLATING LUNG CANCER
EARLY EVENTS IN LUNG OTHER MOLECULAR ALTERATIONS BIOLOGY TO THE CLINIC
TUMORIGENESIS DRIVING THE TUMOR PHENOTYPE Biomarkers
Field Cancerization Effect Chromosomal Changes Personalized Medicine and Molecular
Genomic Instability Epigenetic Alterations of Gene Expression Therapeutics
Mucosal Response to Injury, the in Lung Cancer Mechanisms of Resistance
Emergence of Critical Mutations Proteomic Alterations
INTRODUCTION understanding of driver genes2 and the potential benefit of

therapeutic strategies using targeted therapies that inter-
Lung cancer is the number one cause of cancer-related fere with mechanisms of tumor growth and progression.3
death in the Western world. Lung cancer remains the The pathogenesis of lung cancer involves the accumula-
leading cause of cancer mortality for both men and women tion of multiple molecular abnormalities over a long period
in the United States.1 Its incidence is highly correlated with of time.4 Alterations in gene expression can result from
cigarette smoking, and lung cancer is eventually diagnosed abnormal microRNA expression or methylation, DNA
in about 10% of long-term smokers. Among the 10% to sequence changes, DNA segment amplification, deletion, or
15% of patients without a smoking history in whom lung whole chromosome gains or losses. These lesions allow cells
cancer develops, environmental or inherited causes of lung to escape the normal regulation of cell division, apoptosis,
cancer contribute to the risk. As large as the clinical chal- and invasion and/or alter its interaction with the host. The
lenges patients and physicians face in managing this disease, historical focus of much of this research has been to iden-
equally enormous are the challenges in detailing the tify and study the role of specific genetic abnormalities in
complex molecular pathogenesis of lung cancer. Major tumor cells related to chromosomal abnormalities, inacti-
progress has been made, however, and we are beginning to vation of specific tumor suppressor genes, the activation of
see this knowledge translated into the clinic. In this chapter, specific oncogenes, and the expression of hormone recep-
we summarize our understanding of how lung epithelial tors and growth factor production associated with the
cell injury leads to signaling pathway activation that trig- development of cancer. More recently, the contribution of
gers the uncontrolled proliferation, resistance to apoptosis, stromal interactions, the induction of angiogenesis, the
metastasis, and escape from immune surveillance seen in control of apoptosis, and epigenetic phenomena such as
lung cancer. Whereas all subtypes of lung cancer have his- posttranslational modification of critical genes have been
torically been divided between non–small cell lung cancer the subject of intense research. The completion of the first
(NSCLC) and small cell lung cancer (SCLC), the field is step- draft of the human genome sequence5,6 and the availability
ping away from purely histologic classification and moving of high-throughput technologies (e.g., microarrays) have
into molecular classification of tumors based on better also prompted investigators to propose studies to discover
912
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51 • Biology of Lung Cancer 913
molecular alterations of individual tumors with incredible Table 51-1 Characteristics of Lung Cancer Found in
sensitivity and unprecedented scope. Common molecular Never-Smokers
abnormalities in both precancerous and invasive lung
Peripheral disease in distal airways
cancers are being integrated and hold the promise for Adenocarcinoma
potential utility in prevention, early detection, and therapy. Female
Younger age
Environment tobacco smoke, human papillomavirus 16 and
18 infection
Familial and genetic risk
PREDISPOSITION TO Frequent EGFR and TP53 mutations
LUNG CANCER Rare KRAS mutations
SMOKING
GENETIC SUSCEPTIBILITY AND
Tobacco use continues to be a major cause of cancer in the FAMILIAL PREDISPOSITION
world. Worldwide, tobacco use causes more than 5 million
deaths per year, and current trends show that tobacco use In epidemiologic studies, smoking confers an approximately
will cause more than 8 million deaths annually by 2030.7 14-fold increased risk for lung cancer and, after controlling
Tobacco control efforts are leading to a decrease in cancer for tobacco use, a family history of lung cancer accounts
mortality in some areas of the world,8 but globally there are for an approximately 2.5-fold increased risk. Here, we
still more than 1 billion smokers.9 More than 85% of all address susceptibility as it relates to genetic susceptibility
lung cancers are attributable to cigarette smoking; however, and familial predisposition separately.
lung cancer develops in only a fraction of long-term ciga- Genetic susceptibility may be seen with rare autosomal
rette smokers, suggesting a role for variable inherited dominant genes that explain cases of early-onset lung
genetic susceptibility in lung tumorigenesis. cancer but more common genetic variants or polymor-
Lung cancer develops through a multistage process in a phisms are more likely to affect lung cancer risk. Inherited
background of increasing genomic instability and inflam- differences in DNA repair capacity in response to tobacco-
mation.10 For example, cytogenetic alterations arise mediated damage have been incriminated as underlying
throughout the airways with monoclonal and trisomic some of this susceptibility. When lymphocytes from lung
clonal patches observed.11 Patches of epithelial cells pre- cancer patients and age-matched controls are exposed to
senting with 2n + 1 number of chromosomes develop dif- bleomycin, the lymphocytes from lung cancer cases develop
fusely in the airway following the distribution of cigarette more chromatid breaks than the control lymphocytes.29 A
smoke exposure and confirm the “field cancerization” similar assay has been developed using benzo(α)pyrene
hypothesis.12 Elucidating the molecular determinants diol-epoxide, a reactive substrate that is derived by in vitro
responsible for the development of lung cancer and identi- processes from benzo(α)pyrene, a major carcinogen in
fying intermediate biomarkers associated with malignant tobacco smoke.30 These results suggest that the DNA repair
progression remain a priority. Cigarette smoking clearly capacity influences risk for lung cancer. Telomere length
contributes to the accumulation of genetic alterations in has also been inversely associated with lung cancer risk.31
lung cancer.13-15 Tobacco is rich in pulmonary carcinogens Nicotinic acetylcholine receptor subunit genes may con-
and causes many genetic changes by inducing DNA muta- tribute to the risk of smoking as well as the risk of lung
tion.16,17 Tobacco-specific nitrosamines induce DNA meth- cancer. In three lung cancer genome-wide association
ylation18; levels of DNA adducts such as methylated DNA studies, polymorphic differences in chromosome 15q25
can, in fact, be used as an index of human tobacco expo- have been associated with the risk of developing lung
sure. Tobacco causes methylation of tumor suppressor cancer.32-34 Single nucleotide polymorphisms mapped to a
genes.19,20 Cigarette smoke has also been shown to induce region of strong linkage disequilibrium within 15q25.1
demethylation of the proto-oncogene synuclein-γ in lung contain nicotinic acetylcholine receptor subunit genes. The
cancer.21 Therefore, cigarette smoke could lead to specific genetic variants were associated both with nicotine depen-
patterns of chromatin structure alterations that may dence as well as with certain lung cancer phenotypes,
promote cancer development. In the future, specific epigen- including lung cancer developing in younger patients and
etic alterations induced by cigarette smoking may be useful in patients with lower amounts of smoking; the variants
as biomarkers of lung cancer development. Chronic expo- were not associated with lung cancer in nonsmokers or
sure to carcinogens initiates a process characterized by with other smoking-related cancers like renal or bladder.35
genetic abnormalities, phenotypic changes, and over- Since then, subsequent analyses have identified additional
growth of clones of genetically altered epithelial cells variants that influence lung cancer risk,36 which will
throughout the lungs.22 Genomic alterations may form a require further investigation in a larger sample size. The
pattern referred to as a “genomic signature.” The signa- relative impact of the nicotinic acetylcholine receptor gene
tures found in NSCLC may contain information about their variants on the propensity to smoke or on the response to
induction by cigarette smoke23 and may reflect the path- the direct carcinogenic effects of smoke is undergoing vali-
ways to cancer development or represent the product of dation in large numbers of smokers and nonsmokers.
competitive selection of clones.24-27 In fact, the clinical Familial risks of lung cancer provide another route for
profile (Table 51-1) and molecular profile of lung tumors uncovering susceptibility genes. In one genome-wide
arising from never-smokers are quite distinct from their linkage analysis, a genomic locus on chromosome 6q23-25
smoker counterparts.28 has now been associated with a familial risk of lung cancer.37
914 PART 3 • Clinical Respiratory Medicine
To date, no tumor suppressor genes inactivated by mutation

have been identified in this locus, although the frequent
inactivation of multiple candidate tumor suppressor genes
within chromosome 6q likely contributes to development of
sporadic lung cancer.38 Finally, a genome-wide association
analysis was conducted to investigate associations between
single nucleotide polymorphisms and the risk of lung
cancer in 194 patients with familial lung cancer and 219
cancer-free control subjects.39 A strong association was
found between common sequence variants at 15q24-25.1
and lung cancer.40 The risk of lung cancer was more than
fivefold higher among those subjects who had both a family
history of lung cancer and two copies of high-risk alleles in
the 15q24-25.1 locus as compared with control subjects.39
Thus, studies into sporadic and familial cancer risk may
identify some of the same genetic predispositions, such as
15q24-25.1 or germline EGFR T790M mutations,41,42 and
have the potential to identify novel genetic predispositions.
Mathematical models integrating clinical, physiologic,
imaging, and biologic variables are now proposed for evalu-
ating risk for lung cancer in clinical practice.43-47 This field
has made tremendous progress, and prediction models are
being proposed for implementation in selecting populations
for screening and/or chemoprevention trials.
EARLY EVENTS IN LUNG

TUMORIGENESIS Figure 51-1 The field of injury. The field of injury could serve as means
for assessing the risk of developing lung cancer, of having lung cancer, or
FIELD CANCERIZATION EFFECT even predicting the behavior of a tumor in the field. In this figure, the lung
epithelial surface area is displayed as if it were a tennis court, known to be
Whereas lung cancer may originate from only one or a few of roughly comparable size. The tumor (red) and associated genetic altera-
airway epithelial cells, it is clear that exposure of the whole tions (red and yellow stars) are shown as stochastic events. Investigations
to understand the role of the field in disease pathogenesis can take advan-
airway mucosa to tobacco smoke can cause the entire bron- tage of the study of tumor samples, and adjacent bronchial biopsies, bron-
chial tree to be at increased risk for development of lung chial brushings, or related serum or plasma (red area surrounding the field)
cancer, leading to the concept of field cancerization (Fig. as well as tumor samples.
51-1). Field cancerization was first proposed in the 1950s,12
and its molecular correlates were later confirmed in the
airways of human smokers.48 Field cancerization is also of lung cancer elsewhere in the airways or with an elevated
demonstrated by the elevated Ki-67 labeling index in the risk for transformation.25,51 Similarly, prevention efforts
airways of smokers at more than one site.49 In addition, should be directed to the entire epithelium, which can then
evidence has been found in a single smoker with diffuse also provide biomarkers for effective prevention. Finally, the
dysplasia that a single identical point mutation of TP53 field cancerization concept has major implications for
could be found diffusely in both lungs, but not in the blood therapy, because one should consider treating the entire
or other solid organs, suggesting that a single progenitor field as opposed to limiting treatment efforts to preinvasive
bronchial epithelial clone populated the bronchial mucosa. lesions that may never develop into lung cancer.52,53
Although the risk of developing lung cancer increases
with the presence of such preinvasive lesions, clearly the GENOMIC INSTABILITY
entire at-risk epithelium does not undergo malignant trans-
formation, and no one has identified the molecular deter- Lung cancer develops along a multistage process in a setting
minants of preinvasive lesions that may predict irreversible of increasing genomic instability. Genomic instability is
progression to lung cancer. Thus, if one considers the total universally found during accumulation of these genetic
number of bronchial epithelial cells and the proliferation abnormalities.54,55 Genome instability is a fundamental
rate of patches of clonal abnormalities, cancer remains a characteristic of cancer initiation and progression. However,
rare event.50 our understanding of the onset of instability, the rate of
The concept of field cancerization has implications for instability, and the mechanisms leading to instability is far
approaching diagnosis, prevention, and treatment of lung from complete. We do know that—from initiation, to pro-
cancer. For example, diagnostic information may be con- motion, to the development of an invasive phenotype—a
tained even in the normal-appearing airway epithelium; in series of molecular changes contribute to a molecular insta-
patients with and without lung cancer, changes in the bility that puts the airway epithelium of some smokers at
airway field have been found to correlate with the presence greater risk for lung cancer.
Two main theories of the genomic changes underlying sion, and this instability may itself be a target for prevention
lung tumorigenesis have emerged: the stochastic (random) or therapy of lung cancer.
and the gene-centric (nonrandom) theories. The stochastic
theory argues that lung cancer arises by genomic aberra- MUCOSAL RESPONSE TO INJURY, THE
tions that are stochastic or random in nature.56 Indeed, in
EMERGENCE OF CRITICAL MUTATIONS
many tumor types, there are relatively few cancer-specific
mutations, whereas there can be a high degree of chromo- Since the late 1970s, somatic mutations have been identi-
somal aberrations.57-59 Some of these low-level aberrations fied and associated with the development of cancer. These
have been called noise but may reflect the underlying insta- mutations, involving those of tumor suppressor genes or
bility. Nonclonal chromosomal alterations such as defective oncogenes, may or may not be critical events in the forma-
mitotic figures, chromosomal fragmentation, or nonrecur- tion of the cancer. Epidemiologic data support the hypoth-
rent genomic alterations indicate a dynamic process leading esis that clones of cells accumulate several key mutations
to instability.56 Nonclonal chromosomal alterations may during oncogenesis. Proposed by Loeb,55 the model of the
provide a survival advantage, whereas clonal chromosomal mutator phenotype, a phenotype in which mutations
alterations at a later stage of progression may confer a develop faster than in normal cells, suggests that this pro-
growth advantage.60 pensity for rapid mutation may be required for multistage
In contrast, the gene-centric theory argues that sequential carcinogenesis and may be acquired by cells early on. This
accumulation of epigenetic and genetic aberrations is phenotype may also be hereditary.
important for lung cancer development.61 This gene-centric DNA mutations may arise from a failure to repair DNA
theory is particularly appealing to explain clonal alterations damage. In addition to damage and mutations due to envi-
in genes implicated in tumor cell growth and survival that ronmental carcinogens, spontaneous errors of replication
represent possible targets for the management of cancer.62 attributed to DNA polymerase take place at a rate of
These alterations include single nucleotide point mutations, 1/10,000 to 1/100,000 base pairs. These intrinsic muta-
changes in chromosome copy number (aneuploidy),63,64 tions may also be an important component underlying
and specific genomic amplifications or deletions.65-67 These genomic instability and eventually tumor development. A
genetic changes are implicated in the pathogenesis of tumor recent analysis of 623 genes in 188 lung adenocarcinomas
development in part through the activation of oncogenes revealed more than 1000 somatic mutations, and those in
and inactivation of tumor suppressor genes and are consid- 26 different genes were found to be mutated at significant
ered one of the key hallmarks of cancer.68 Some genomic frequencies.73 Many of these mutated genes fall into a
signatures seem to persist after tumor development and handful of common signaling pathways. We briefly
throughout their progression and their histologic differen- comment on a few examples of these commonly acquired
tiation. The fact that smoking history leads to specific mutations in KRAS, TP53, p16, BRAF, PIK3CA, epidermal
genomic alterations across different tumors also suggests a growth factor receptor (EGFR), and anaplastic lymphoma
specific pathogenesis with genomic alteration resulting kinase (ALK).
from a series of dysregulations in DNA repair mechanisms KRAS mutations are among the most common muta-
and chromosomal segregation. tions found in lung cancer. The mutations are found in 30%
The two theories are not necessarily mutually exclusive, of adenocarcinomas of the lung,74 but much less frequently
and both random and nonrandom changes may be impor- in other subtypes. Mutations in KRAS lead to activation of
tant. The progressive accumulation of mutations, loss of several pathways. Ras proteins activate the RAF/MEK/ERK
apoptotic control and regulation of cell proliferation, and pathway, which mediates cell growth and cell cycle entry by
the appearance of an abnormal number of chromosomes phosphorylation of transcription factors (e.g., such as
(aneuploidy) are associated with worsening dysplasia c-FOS, ELK1, and MYC); phosphorylation of the RSK (ribo-
phenotypes and may reflect underlying dysregulation of somal protein S6 kinase) and MNK (mitogen-activated protein
mechanisms controlling genomic fidelity. In some lung kinase [MAPK]-interacting serine/threonine kinase) family
tumors, mismatch repair deficiency leads to microsatellite of kinases; and the phosphatidylinositol-3-kinase (PI3K)/
instability at the nucleotide sequence level, whereas in protein kinase B (AKT) pathway, which controls cell sur-
other tumors, aneuploidy is the dominant feature.69 Specific vival, cell growth, and metabolism.75 Mutant KRAS (most
defects in DNA repair may also be present. Polymorphisms frequently, codon 12 G-T transversions) can transform
in DNA repair genes XPD (codon 312 Asp/Asp vs. Asp/Asn) airway epithelial cells76 by activating the extracellular signal-
are associated with impaired efficiency of DNA repair and regulated kinase (ERK)-MAPK and PI3K/AKT pathways.
apoptotic function in lung cancer.70 Measures of genomic Because the KRAS mutation is found early in alveolar atypi-
instability parallel rates of loss of heterozygosity71 and cal hyperplasia, a presumed precursor lesion to adenocar-
accumulation of other genomic abnormalities.69 In the cinomas, KRAS mutation may be an important step in the
airways, progressively more severe and more frequent genesis of this subtype of lung cancer. The fact that mutant
abnormalities are seen in preinvasive lesions. The progres- ras transgenic mice develop adenocarcinomas of the lung
sive accumulation of genomic abnormalities associated supports this hypothesis .77
with clonal growth among populations of tumor cells is TP53 is a prototype tumor suppressor gene that is the
well described. Recent reports use array comparative genomic most common genetic lesion in human cancers78 and is
hybridization (aCGH) to assess genomic instability; in these thus well suited for analysis of the mutational spectrum in
reports, in addition to numerical chromosome changes, human cancers. The gene product p53 is a potent regulator
smaller aberrations are found at specific chromosome loci.72 of cell growth and DNA damage responses, and directly
Clearly, genomic instability itself drives malignant progres- regulates the cell cycle via induction of p21. Mutations of
TP53 are most commonly seen in squamous carcinoma and kinase inhibitors, gefitinib or erlotinib, revealed that most
small cell carcinoma of the lung. Mutations predominantly of them had deletion mutations in exon 19 or point muta-
representing G to T transversions consistent with causation tions in exon 21 of the EGFR kinase domain, but patients
by bulky DNA adducts such as the polycyclic hydrocarbons not responding to these drugs only rarely had these muta-
are frequently found in the lungs of smokers.13 When the tions.90 Inhibition of mutant EGFR is an example of suc-
gene is mutated, the p53 protein can function as an onco- cessful therapeutic targeting of oncogenically activated
gene. Mutated p53 exhibits a prolonged half-life, and the tyrosine kinases in cancer. The presence and type of EGFR
protein can be found to be overexpressed in about 50% of mutations indicate which patients will respond to therapy
lung cancers by immunohistochemistry.79 Although not with EGFR inhibitors. Trials selecting patients on the basis
consistently associated with prognostic significance, there of EGFR mutations have yielded response rates to EGFR
is little doubt that TP53 mutations play a key role in tumor inhibition therapy exceeding 70% and led to median overall
development by dysregulation of cell cycle control and survival exceeding 20 months.91-93
apoptosis. Even though dramatic responses are frequently seen in
p16, a cyclin-dependent kinase inhibitor, functions as a patients with the common EGFR mutations, most patients
tumor suppressor and critical member of the retinoblastoma initially responding to EGFR inhibitors eventually relapse.
(Rb) cell cycle control pathway. The gene is inactivated in These relapses may be explained by additional mutations in
more than 40% of NSCLCs. Previous studies have demon- EGFR or activation of other growth pathways. In certain
strated that point mutations, deletion or loss of heterozy- cases, resistance has been found to be due to an activating
gosity (when one parental copy of a region is lost) on 9p21, mutation of EGFR at a second site. This mutation, T790M,
or hypermethylation of the gene provides alternate mecha- is analogous to the T315I mutation of the murine leukemia
nisms of inactivation in 30% to 50% of NSCLCs. In viral oncogene homolog (ABL) that causes acquired resis-
smokers, the loss of P16 appears to be from different mech- tance in chronic myelogenous leukemia patients who had
anisms than in nonsmokers. In tumors arising in smokers, initially responded to imatinib.94,95 An additional mecha-
P16 was found to be lost due to point mutations or homo- nism of acquired resistance is the de novo amplification of
zygous deletions, whereas in tumors from nonsmokers, the MET receptor tyrosine kinase gene.96,97 Understanding
P16 was lost via promoter hypermethylation.80 The rela- the sources of acquired resistance may reveal strategies for
tionship between the loss of P16 and tobacco points to P16 prevention of resistance.
as another genetic target of cigarette smoke in the patho- The ALK is a receptor tyrosine kinase that is aberrant in
genesis of lung cancer. a variety of malignancies. ALK was originally discovered in
BRAF is a serine/threonine kinase that belongs to the anaplastic large cell lymphoma as part of a chromosomal
RAS/RAF/MEK/ERK/MAPK pathway, and is important for translocation t(2,5), which fuses the C-terminal kinase
transducing mitogenic signals from the cell surface. BRAF domain of ALK encoded on chromosome 2p23 to the
mutations were found in thyroid, colorectal, and lung N-terminus of nucleophosmin on chromosome 5q35.98
cancer as well as in a majority of malignant melanomas.81 Subsequently, a variety of ALK fusion proteins have been
The percentage of BRAF-mutant lung cancers appears to found in multiple malignancies, including inflammatory
be less than 5% and to be limited to lung adenocarcino- myofibroblastic tumor and NSCLC.99,100 ALK fusion proteins
mas.82 This observation has led to drug discovery programs are transforming and are highly susceptible to ALK inhibi-
dedicated to specific targeting of BRAF-dependent tumors. tors.100 Indeed, the ALK tyrosine kinase inhibitor (TKI) crizo-
Trials investigating the efficacy of these agents are ongoing tinib was recently approved for the treatment of ALK
in several tumor types.83 Whether BRAF-mutant lung fusion-positive lung cancer.101 Because crizotinib has “off-
cancer can be successfully treated with inhibitors targeting target” activity against the ROS1 kinase, somatic activating
downstream pathway members of BRAF remains to be ROS1 fusions may also be susceptible to crizotinib.102 Rear-
established. rangements involving another kinase, RET, may be targe-
PIK3CA, the gene encoding the catalytic subunit of the table with RET TKIs.103 Because of their ability to guide
class-1a phosphoinositide-(3,4,5)-kinase, is an important therapeutic decision making, EGFR, KRAS, ALK, ROS1,
component of the AKT antiapoptotic pathway. Mutations RET, BRAF, and PIK3CA mutation testing have become part
in this gene have been found in a large fraction of epithelial of standard pathologic analysis of lung adenocarcinomas
cancers.84 Although the most frequently mutated oncogene in many centers.
in breast cancer, PIK3CA was found to be mutated in less The efforts to characterize the genomes of major human
than 5% of lung cancers. In several functional analyses, cancer types104 have revealed that, beyond known cancer-
these mutations were found to be oncogenic by their ability related genes, many additional genes are mutated in indi-
to activate the AKT survival pathway.85 Most recently, pre- vidual cancers. However, most of these mutations are
clinical studies involving new generation PI3K-kinase found in only a single tumor, suggesting that each tumor
inhibitors suggest that tumors carrying these mutations contains an individual set of mutations contributing to
might be exquisitely sensitive to pathway inhibition.86 tumorigenesis. Ding and coworkers73 found between zero
The gene for the receptor tyrosine kinase EGFR is mutated and 40 mutations in individual lung adenocarcinomas,
in approximately 10% of white and 40% of East Asian with an average of 24.3 for those with a mutant PRKDC
patients with NSCLC,87-89 leading to constitutive activation gene (involved in DNA repair) and 4.7 for those without
of this growth factor receptor. These mutations are more this mutation. The average number of mutations for differ-
common in patients who have never smoked, whose tumors ent tumors range significantly from 0.39 mutations per
are of adenocarcinoma histology, and who are of East Asian one million bases (mut/MB) to the highest in small cell lung
ethnicity. Exon resequencing in responders to the tyrosine cancer (7.34 mut/MB) followed closely by melanoma.105-108
chromosomal abnormalities resulting in clonal expansion

Mutagens of cells that have a growth advantage, whereas in those
Cigarette smoking may account for 85% of lung cancers. who develop COPD, an intense immune response and
Approximately 1 in 10 life-smokers will develop lung cancer, further inflammation predominate. The process by which
suggesting individual differences in susceptibility.109,110 these events diverge is unclear. More likely, heritable genetic
Environmental carcinogenesis resulting from tobacco polymorphisms that influence susceptibility to DNA or con-
smoke exposure is a complex process that can involve acti- nective tissue damage, efficiency of DNA or connective
vation of procarcinogens that lead to DNA adduct forma- tissue repair, the intensity of immune responses to constitu-
tion and subsequent failure of DNA repair, which should ents of tobacco smoke, intrinsic or acquired genomic insta-
normally remove these adducts. Studies comparing DNA bility, or the induction of factors that suppress immune
repair capacity among newly diagnosed lung cancer surveillance likely determine the disease pathway taken.
patients and age-matched controls indicate significant dif- Toll-like receptors (TLRs), which recognize a variety of
ferences between the two groups.111 pathogen-associated molecular patterns, are centrally
The majority of lung cancers are now diagnosed among involved in the initiation of the innate and adaptive immune
ex-smokers.112 This suggests that the accumulation of responses. Recent evidence shows that functional TLRs are
molecular damage during cigarette exposure initiates a also expressed on a wide variety of tumors, suggesting that
cascade of events that lead to cancer even decades after TLRs may play important roles in tumor biology, and are
smoking cessation. Risk factors for lung cancer include being evaluated as therapeutic targets.117,118 Activation of
smoking, including total consumption, age of initiation, tumor cell TLRs not only promotes tumor cell proliferation
and years of smoking; occupational and environmental and resistance to apoptosis but also enhances tumor cell
exposure (asbestos, uranium, radiation), diet (vitamin A, invasion and metastasis by regulating metalloproteinases
vitamin E, cholesterol), and host (familial aggregation) and and integrins. Moreover, the activation of TLR signaling in
genetic factors (see Chapter 52). Cigarette smoke is a tumor cells induces the synthesis of proinflammatory
complex mixture and includes substances that are respon- factors and immunosuppressive molecules, which enhances
sible for DNA adduct formation such as polycyclic aromatic the resistance of tumor cells to attack by cytotoxic lympho-
hydrocarbons, aromatic amines, and tobacco-specific nitro- cytes and leads to immune evasion. Thus, the TLR signaling
samines. These form DNA adducts that may escape normal pathways may be usurped by the neoplastic process to
adduct repair mechanisms and result in heritable altera- advance cancer progression, which suggests that targeting
tions in DNA sequence. For example, the conversion of G-C tumor TLR signaling pathways may open novel therapeutic
base pairs to T-A is involved in the activation of the KRAS avenues.
oncogene and inactivation of the TP53 tumor suppressor Inflammation and tumor-infiltrating inflammatory cells
gene.17 The activated form of benzopyrene is the diol epoxide have been shown to induce and help sustain tumor angio-
benzo(α)pyrene that can cause DNA adducts, leading to genesis and sustain cellular proliferation.119 COPD and its
point mutations and single-strand chromatid breaks.113 A underlying chronic airway inflammation provide support
major concern is that people who start smoking at young of lung cancer growth.120 Chemokines, a component of
ages seem to be have greater amounts of permanent DNA cancer-related inflammation, predispose to cancer by affect-
alterations than smokers who start smoking later.14 ing multiple pathways of tumor progression, including leu-
kocyte recruitment and function; cellular senescence;
ROLE OF INFLAMMATION IN tumor cell proliferation and survival; invasion and metas-
tasis.121 The inflammatory system is expected to provide
LUNG TUMORIGENESIS
valuable targets for the development of innovative thera-
The tumor cell signaling pathways that trigger the uncon- peutic strategies.
trolled proliferation, resistance to apoptosis, metastasis,
and escape from immune surveillance are partially under- ROLE OF VIRUSES IN LUNG TUMORIGENESIS
stood. In contrast, how inflammation and its control may
participate in lung tumorigenesis remains more poorly Viruses can cause lung cancer in animal models; such
understood. viruses, including SV40 large T antigen and polyomavirus
The reason why some smokers develop chronic obstructive large and middle T antigens, cause lung cancer in trans-
pulmonary disease (COPD), some develop lung cancer, and genic models. No common respiratory viruses have been
some develop both diseases remains unclear.114 Cigarette conclusively incriminated in the development of human
smoke contains high concentrations of oxidants and free lung cancer, but several have been implicated. Human pap-
radicals, together with thousands of particles. Local anti- illomavirus, for example, has been associated with lung
oxidant and metabolizing enzymes inactivate many toxic cancer and, in particular, lung cancer arising in women.122
species. Nuclear factor-κB activation and subsequent trans- These results remain controversial because The Cancer
activation of inflammation-related genes appear to play Genome Atlas, a coordinated effort supervised by the
a central role in both COPD and cancer.115 How some National Cancer Institute to apply high-throughput genome
smokers remain free of disease while others develop COPD analysis to the study of cancers, has not reported viral
or cancer may be determined by the activation of genes in sequences in tumors. Similarly, controversy persists on the
response to cigarette smoke.116 Following exposure to the role of other viruses. Simian virus 40 has been suspected in
same toxic smoke, individuals appear to progress toward the development of mesothelioma123; Epstein-Barr virus
disease along different paths. In those who develop lung has been suspected to be involved in the development of
cancer, genomic instability develops that causes further papillomas, mesotheliomas, and lymphomas of the lung;
the Jaagsiekte sheep retrovirus or a variant has been corresponds with tobacco-associated carcinogen exposure.
thought to cause adenocarcinoma in situ in humans as it From these studies, they identified TP53, RB1, CREBBP,
does in sheep.124 However, many polymerase chain reaction– EP300, SLIT2, MLL, COBL, and EPHA7 as potential onco-
based assays have attempted to correlate bronchogenic car- genic drivers, which were classified into five major groups:
cinomas with respiratory viruses without success. Recent (1) receptor tyrosine kinases (RTK), (2) PI3-kinase and p53
advances in proteomics may be useful in studying the role pathways, (3) cell cycle control, (4) histone modifiers, and
of viral infection in airway epithelial cell transformation. (5) SLIT-ROBO signaling. Using reverse phase protein
The proteomic analysis of tumors may allow the identifica- arrays, Byers and associates identified PARP1, a DNA repair
tion of peptide sequences specific to pathogens otherwise protein and E2F1 coactivator, to be highly expressed at the
unknown in tumorigenesis. mRNA and protein levels in SCLCs. PARP inhibition down-
In recent reports, infectious agents associated with dis- regulated key components of the DNA repair machinery
eased human tissues have been discovered by high-throughput and enhanced the efficacy of chemotherapy,131 justifying
sequencing technologies.125 However, identification of a future clinical studies evaluating PARP and EZH2 inhibi-
nucleic acid sequence in a sample does not necessarily tion, together with chemotherapy or other agents. These
implicate an organism as causal in a disease. Viral nucleic gene-centric approaches will have to be complemented by
acid may be found because of contamination of tissues, genome control studies, studies aimed at understanding
because of a subclinical infection unrelated to the disease, or gene regulatory mechanisms by investigating the whole
because it is latent in human tissue but not actively causing genome structure, including chromatin structure and epi-
illness (e.g., human herpesvirus and human papillomavirus). genetic alterations, and function. Understanding both the
genes and their control will be necessary to resolve the
NEUROENDOCRINE TUMOR DEVELOPMENT, molecular networks explaining the heterogeneity found in
tumors and their functional implications.
GENOMICS OF SCLC
Small cell lung cancer has worse clinical outcomes and no
SCLC develops from neuroendocrine cells in the lung. The currently proven personalized therapy. SCLC and NSCLC
evidence for this is best established from mouse studies with account for 15% to 20% and 80% to 85% of annual lung
deletion of Rb and TP53.126,127 In these studies, mouse cancer cases, respectively. SCLC is clinically more aggressive
SCLCs often arise in the lung epithelium, where neuroen- with an untreated median survival of 2 to 4 months.132
docrine cells are located, and the majority of early lesions Despite initial complete responses exceeding 50%, the best
were composed of proliferating neuroendocrine cells. When combinations of chemotherapy and radiation result in less
Rb and TP53 were deleted in nonneuroendocrine lung epi- than 5% of patients surviving 5 years from initial diagno-
thelial cells, mice did not develop SCLC.128,129 sis.132 Efforts to identify driver mutations, gene amplifica-
Recent publications offer new molecular characteriza- tions, or signatures with clinical utility in SCLC have thus far
tion of SCLC. Using comprehensive genomic analysis of not translated to new therapies. In addition, prognostic or
SCLCs130,130a with high-throughput sequencing techniques, diagnostic markers for SCLC are scarce.133-135 Over the past
Rudin and colleagues have demonstrated that SCLCs are decade, several molecular abnormalities have been described
composed of multiple known and new molecular abnor- as indicators of chemotherapy resistance and poor progno-
malities. They confirmed known SCLC molecular alterations sis in NSCLCs.136 As described earlier, recent seminal studies
to genes such as TP53, RB1, PIK3CA, CDKN2A, and PTEN. have identified genomic aberrations in SCLC that will hope-
In addition, they identified other genes coding for proteins fully lead to successful therapeutic strategies.
with a wide array of cellular functions such as the RAS Why is no targeted therapy available in SCLC? The discov-
family regulator, chromatin-modifying enzymes, transcrip- ery of new targets for early detection and for therapeutics
tions regulators, kinases, protein phosphatases of G-protein has been hindered by the fact that SCLC is often detected
coupled receptors. Further genetic mutational clustering late and tissue is rarely obtained for study because surgical
identified specific pathways at the epicenter of SCLC patho- resection is not standard therapy. Another major shortcom-
genesis, which included PI3K, Hedgehog, NOTCH, mediator ing associated with the slow progress has been the lack of
complex, glutamate receptor, DNA repair, and the SOX sensitive and robust technology to detect the signatures
family. This study showed a high mutational frequency of of cancer cells from minute quantities of available tissues
several SOX genes and overexpression of SOX2 in close to or serum. Recently, advances in genomic technology provide
25% of the SCLCs analyzed. Lastly, they identified new muta- high-resolution, high-throughput tools to measure copy
tions to genes coding for tyrosine kinases such as FLT1, FLT4, number, gene expression, DNA methylation, and nucleotide
KDR, and KIT as well as several fusion proteins such as RLF- sequence in cancer have started to move the field
MYCL1 which could be potentially targeted therapeutically. forward.105,130,137 These reports predict rapid evolution in
In another integrative genomic analysis of 99 SCLC the understanding and management of SCLC.
tumors and lines, Peifer and coworkers confirmed recurrent
losses of the tumor suppressor genes TP53 and RB1 and OTHER MOLECULAR
novel amplifications of FGFR1, MYCL1, and MYCN in
SCLC.105 These findings were found to be similar to findings ALTERATIONS DRIVING THE
in TP53/Rb1 conditional knockout mice that, in the absence TUMOR PHENOTYPE
of p53 and RB1 protein expression, developed several SCLCs
expressing amplifications of MYCL1, MYCN, and NFIB. CHROMOSOMAL CHANGES
Exome sequencing, transcriptome sequencing, and genome
sequencing confirmed that SCLCs have a high mutation Cancer cells are characterized not only by mutations but
rate (7.4 protein-altering mutations per MB) that also by a series of other chromosomal aberrations including
deletions and amplifications.138-140 Although chromosomal epithelia but also that cells with these changes may regress
aberrations have been linked to most tumors and are a after smoking cessation and be replaced by cells without
characteristic of cancer,68 chromosomal aberrations are this damage. Patterns of lung cancer allelic loss have been
recognized as increasingly complicated.11,141 Many of the investigated in detail and new regions of allelic loss have
observed alterations have been considered consequences been identified using high-throughput technologies.71
instead of causes of lung cancer development. However, Interestingly, chromosome losses such as LOH and chromo-
there are chromosomal regions with frequent losses found somal gains are more prevalent at all sites in cancers from
in regions coding for essential tumor suppressor genes and smokers than from nonsmokers, indicating a greater chro-
DNA repair genes that may be involved in the pathogenesis mosomal instability in the cancers from smokers.15 aCGH
of several tumor types.142 has been used to discover specific patterns of genomic alter-
Chromosomal alterations in NSCLC have been measured ations found in NSCLC that might be related to smoking
by aCGH.66,67,143 Specific areas of amplification and deletion history. Smoking-related genomic signatures were identi-
can distinguish squamous from adenocarcinoma of the fied in NSCLCs and could be predicted with an overall 88%
lung and other subtypes. Among many areas of genomic accuracy.23 Lung tumors arising from current smokers had
abnormality, amplification of chromosomal region 3q26- the greatest number of copy number alterations. The
3q29 was the most prevalent abnormality in squamous genomic regions most significantly associated with smoking
carcinoma of the lung. These studies confirm and refine were located within 32 regions and functionally associated
previously documented copy number alterations in lung with genes controlling the M phase of the cell cycle, the
cancer using CGH analysis64,144 and show particularly segregation of chromosomes, and the methylation of DNA.
common amplified regions on chromosomal arms 1q, 3q, Understanding chromosomal abnormalities specific to ciga-
5p, 8q, 11q, 12p, 17q, and 20q. rette smoke exposure may point to the etiology of smoking-
Chromosomal abnormalities may have a role in classify- induced lung cancer.
ing tumors. Attempts have been made to look comprehen- Specific translocation is another chromosomal abnor-
sively at the genome to identify tumors with common mality found in lung cancer, but much less commonly
groups of genetic features that might provide biologic or than in hematologic or mesodermal tumors.156,157 Chro-
clinical guidance beyond traditional classification by light mosomal translocations modify gene function through the
microscopy. Single nucleotide polymorphism arrays have deregulated expression of cellular proto-oncogenes
been developed that are able to analyze loss or gain of without altering the structure of the protein product or by
genetic material at very high resolution67 and cancer generating and expressing a chimeric protein with
genome sequencing efforts have uncovered common muta- growth-promoting activities. Unbalanced translocations
tions.106,107,145,146 From genomic analyses, relatively small are also responsible for a large number of LOHs, which is
differences have been observed between squamous and a genetic event known to cause inactivation of tumor sup-
adenocarcinoma of the lung. The most prevalent differ- pressor genes.158 Dang and colleagues159 identified a chro-
ences were found on chromosome 3q and include the p63 mosome 19-15 balanced translocation associated with
gene.143,147,148 Accumulation of specific chromosomal overexpression of NOTCH3, a protein that establishes an
abnormalities has been correlated with clinical and patho- intercellular signaling pathway that plays a key role in
logic data in NSCLC. Chromosomal abnormalities have development. The authors developed a transgenic mouse
been correlated with clinical outcome for a variety of model overexpressing NOTCH3 causing neonatal mortal-
cancers,140 but often, the genes or networks responsible for ity with a phenotype suggestive of alveolar cell hyperpla-
the observed biology are very difficult to define and are only sia. These data suggest that NOTCH3 overexpression
partly understood.146,149-151 prevents epithelial differentiation and this may play a sig-
Chromosomal abnormalities may underlie the progres- nificant role in promoting oncogenesis in a subset of lung
sion of cancer. Loss of chromosomal regions on chromo- cancers.160
somes 3p and 9p have been recognized as early events and Similarly, recent findings are pointing towards new fusion
identified in preinvasive lesions and in the normal-appearing genes such as ALK, ROS1, and RET (discussed earlier) with
epithelium of smokers.152,153 In contrast, TP53 and KRAS rapid translation toward novel therapeutics in lung
mutations have been seen primarily in later stages of pre- cancer.100,102,161-163
neoplasia or frank invasive lesions.154 Amplification of large
regions on the q arm of chromosome 3 has been character-
ized in invasive carcinomas64,66,144,155 and only recently in EPIGENETIC ALTERATIONS OF GENE
preinvasive lesions.147 Patterns of chromosomal change EXPRESSION IN LUNG CANCER
may be specific to cigarette smoke. In fact, lessons have been
learned from the molecular analysis of lung cancers from DNA Adducts
patients with and without a history of smoking. For DNA adducts are covalent modifications of the DNA that
example, loss of heterozygosity (LOH), the loss of a chromo- result from exposure to specific carcinogens and thus, the
some containing a wild-type gene when the gene on the level of DNA adducts in normal cells can serve as a bio-
other allele was previously mutated, at chromosome 3p14 marker for a significant exposure to carcinogens. In addi-
was evaluated in smokers and ex-smokers. LOH at this site tion to being markers of carcinogen exposure, DNA adducts
was found to be more frequent in current smokers (22/25 may directly alter regulation of transcription of tumor sup-
cases) than in former smokers (5/11 cases), and the high pressors or oncogenes.164 Because DNA adduct levels in
frequency in smokers correlated with a high metaplasia tumor tissue and in blood lymphocytes have been associ-
index.152,153 This implies that not only are these chromo- ated with lung cancer165 and because these levels correlate
somal changes frequent in normal-appearing bronchial with daily or lifetime cigarette consumption and do not
reverse after smoking cessation,166 DNA adducts have been promoter region of four genes (TP16, CDH13, RASSFIA,
proposed as potential biomarkers of risk for lung cancer. and APC) in patients with stage I NSCLC was shown to be
In an attempt to identify risk factors associated with the associated with early recurrence.176 The recent effort in The
level of DNA adduct accumulation, Wiencke and associates Cancer Genome Atlas also reported the landscape of altera-
studied DNA adducts in current and former smokers and tions in methylation across a large number of lung
found that, for current smokers, the most important vari- cancers.177
able in determining the level of DNA adducts was the
number of cigarettes smoked per day.164 In contrast, they Histone Deacetylation
found that for ex-smokers, the most important variable was Histone deacetylation is another mechanism of epigenetic
age at initiation. Mechanisms responsible for the relation- control. Histones are nuclear proteins that package DNA
ship between DNA adduct levels and age of initiation are and allow ribosomal access to the DNA. Acetylation of
unknown; the relative contribution of increased adduct for- histone tails on the nucleosome is associated with chro-
mation at younger ages or perhaps decreased adduct matin unfolding and increased regional transcriptional
removal by impaired DNA repair is yet to be determined. activity. Histone deacetylases modulate chromatin struc-
Prospective studies are needed to follow current and ture by regulating acetylation of core histone proteins.
ex-smokers over time to determine the value of adduct Deacetylation of histones is thus associated with compact-
levels in risk assessment. ing the DNA and repressing transcription. In lung cancer
DNA adducts have also been associated with risk of lung cell lines, for example, deacetylation of histone 3 corre-
cancer. In a matched case-control study nested within the lated with refractoriness to retinoic acid, a phenomenon
prospective Physicians’ Health Study, there was an increased related to RARbeta promoter methylation in a subset of
level of DNA adducts in active smokers who later developed cell lines.178 Inhibitors of histone deacetylases have already
lung cancer than in smokers who did not develop lung been shown to decrease the level of a series of oncopro-
cancer.167 The level of adducts has also been found to be teins,179 suggesting a potential role as antitumor thera-
more prevalent among female than male smokers. Women peutic agents.
smokers may be at higher risk of developing lung cancer for
a given tobacco exposure and women also seem to accumu- Regulation by miRNAs
late aromatic/hydrophobic DNA adducts at a faster rate Micro-RNA (miRNA) are a large family of single-stranded
than men.168 (See Chapter 52.) noncoding RNAs that direct the posttranscriptional repres-
sion of protein-coding.180,181 In a study analyzing 104 pairs
DNA Methylation of NSCLC and corresponding normal lung tissues, an
DNA methylation alters gene expression by increasing the expression profile of 43 miRNAs discriminated lung cancers
density of methylation at promoter regions. In contrast to from noncancerous lung tissues.182 Six miRNAs (hsa-mir-
genetic mutations that require two hits to inhibit both 205, hsa-mir-99b, hsa-mir-203, hsa-mir-202, hsa-mir-
alleles, aberrant methylation is a dynamic process over 102, and hsa-mir-204-prec) were differentially expressed in
multiple division cycles and may cause increasing degrees adenocarcinomas when compared with squamous cell car-
of gene function loss over time. “CpG islands,” the major cinomas. Furthermore, high hsa-mir-155 and low hsa-let-
targets of DNA methyltransferase, are associated with the 7a-2 expression correlated with poor survival in lung
transcription start sites in almost half of human genes.169 adenocarcinomas. In another study of 143 surgically
Dense methylation of cytosines within CpG islands can resected NSCLCs, low let-7 expression was also significantly
cause heritable gene silencing.170 Genomic DNA hypo- associated with shorter survival, whereas overexpression of
methylation, leading to genomic instability, as well as pro- let-7 in the A549 lung adenocarcinoma cell line inhibited
moter hypermethylation, leading to inactivation of tumor lung cancer cell growth in vitro.183
suppressor genes, have been shown to be common events Differentially expressed miRNA genes in NSCLC are fre-
in human cancer.171 Gain of methylation in normally quently located in fragile sites of chromosomes highly prone
unmethylated CpG islands surrounding gene transcription to mutation and/or chromosomal regions with frequent
start sites is an increasingly recognized and important copy number alterations, suggesting that differences in
means by which gene expression is altered in tumors.172 miRNA expression may be induced by genomic alterations.
The genes affected include more than half of the tumor Because greater than 50% of miRNAs are present at cancer-
suppressor genes that are known to cause familial cancers. related chromosomal regions, miRNAs are also suspected
Aberrant methylation can begin early in tumor progres- to play a role as oncogenes or tumor suppressor genes.
sion and cause loss of cell cycle control (e.g., p16),173 loss miRNA expression profiles represent potential markers for
of mismatch repair function (e.g., MLH1), and loss of cell- lung cancer diagnosis, classification, and prognosis. Meth-
cell interaction (e.g., E-cadherin). The exact mechanism by odologic issues related to the reproducibility of the analytic
which hypermethylation may cause tumor progression is platforms should be resolved soon.
still unknown. In fact, there is still debate about whether
methylation is a result of or a cause of gene function PROTEOMIC ALTERATIONS
loss.174
Promoter region hypermethylation has also been pro- Changes in DNA and in RNA may not be reflected in
posed as an excellent tumor marker. In lung cancer, methyl- changes in protein expression. In fact, recent advances in
ated loci were found in both tumor and sputum DNA and protein profiling have suggested a poor correlation between
have been detected in the sputum for up to 3 years before gene expression and protein expression. It is now well estab-
the diagnosis of cancer.175 Recently, methylation of the lished that protein activity is often highly regulated by
Cont-1 Cont-2 SCC ADC SCC
12 3412 34 12 34 12 34 1 2 3 4
A
A 3303 protein
groups (62.2%)
2863 protein
groups
D
B
598 protein
groups
0
1.67
3.3
5 (Spectra count)
Figure 51-2 The shotgun proteomic method reproducibly identifies large numbers of proteins from clinical samples. Left, Heat map view of all
identified proteins. Peptides were generated from three different histology pools including two control pools (Cont-1 and Cont-2), squamous cell carci-
noma (SCC), and adenocarcinoma (ADC) pools. The number of protein groups (2863) found across all pools (top), are shown at the upper right side of the
panel. Protein groups present only in the SCC and ADC tumor pools (598) (bottom), are shown at the lower right. Control: Noninvasive lung tissue. Right,
We identified proteins in the SCC pool from four repeated experiments as indicated by the numbers 1 through 4 shown above each row. Out of the 5310
protein groups identified, 3303 (62.2%) protein groups were observed in every experiment (A), and 487 (9.2%) protein groups were observed in three
experiments (B). The number of proteins observed in two experiments (C) and one experiment (D) was 597 (11.2%) and 923 (17.3%), respectively. The blue
lines in each row represent identified protein groups. The intensity of each line is indicative of the spectra counts for each protein group with the scale
shown at the bottom of the figure. (Adapted from Kikuchi T, Hassanein M, Amann JM, et al: In-depth proteomic analysis of nonsmall cell lung cancer to discover
molecular targets and candidate biomarkers. Mol Cell Proteomics 11:916–932, 2012.)
posttranslational modifications such as proteolysis and teomic analysis method, which consists of identifying pro-
phosphorylation. Neither protein expression levels nor teins in complex mixtures using a combination of high
posttranslational modification can be assessed by genomic performance liquid chromatography and mass spectrome-
or cDNA microarray technologies, prompting interest in try, for profiling the two major subtypes of NSCLC and
evaluation of protein expression, commonly referred to as normal lung tissues (Fig. 51-2). With this approach, 3621
“proteomics.” proteins were identified from the analysis of pooled human
Lung cancer has been studied by several proteomic samples of squamous cell carcinoma, adenocarcinoma,
methods including two-dimensional gel electrophoresis, and control specimens. In addition to proteins previously
mass spectrometry, and immunohistochemistry to identify shown to be implicated in lung cancer, multiple new pro-
biomarkers in tumors.184-186 or in biologic fluids such as teins were found of potential interest as therapeutic targets
bronchoalveolar lavage187 of patients with or without or diagnostic biomarkers, including some that were not
cancer. Matrix-assisted laser desorption ionization profiling identified by transcriptome profiling.188 Up-regulation of
is rapid, high throughput, but detects only the most abun- these proteins was confirmed by multiple reaction monitor-
dant proteins of relatively low molecular weight and does ing mass spectrometry. This proteomic technology plat-
not enable direct identification when applied to complex form allows deep mining of lung tumor proteomes,
proteomes. Two-dimensional gel-based analysis suffers enabling the identification of novel, previously undetected
problems of interlaboratory reproducibility and through- biomarker candidates and potential targets for therapy,
put. Mass spectrometry has an even lower throughput, but such as SLC1A5, a neutral amino acid transporter that is
yields confident identification of large numbers of proteins responsible for more than 50% of glutamine transport into
from every cellular compartment. lung cancer cells.189 SLC1A5 is also located at the cytoplas-
Advances in proteomic analysis of human samples are mic membrane and its inhibition decreased cell growth
driving critical aspects of biomarker discovery and the and viability in lung cancer cells. Such approaches may
identification of molecular pathways involved in disease uncover novel and hopefully useful biomarkers of lung
etiology. Our group has used a standardized shotgun pro- cancer.
Reverse phase protein arrays190 are a means to validate

protein biomarkers in biologic specimens. The major Advanced Proteomic Strategies
advantage is that it allows rapid evaluation of known sig- Mass spectrometry-based technologies are capable of very
naling pathways in lung cancer and it requires a minute high throughput, allowing a sample to be analyzed in
amount of tissue.131,191 The limitation is that this method is seconds and with a higher tolerance for salts, buffers, and
a targeted one and dependent on the validation of specific other biologic contaminants. Because of these attributes,
antibodies. matrix-assisted laser desorption ionization mass spectro
scopy has been used to study proteins/peptides in serum,200-203
urine,204 tissue extracts,205,206 whole cells,207 and laser-
captured microdissected cells.208 These profiling experiments
STRATEGIES TO DEEPEN have been applied to a series of biologic specimens. In one
matrix-assisted laser desorption ionization mass spectros-
OUR UNDERSTANDING OF copy study from our group,209 hierarchical clustering of data
LUNG CANCER from lung cancers and normal tissues allowed the identifica-
tion of patterns distinguishing between tumor and normal
HIGH-THROUGHPUT PROFILING TECHNIQUES as well as between histologic subgroups. Shotgun proteomic
approaches allow the survey of increasing numbers of pro-
Expression Arrays to Next Generation Sequencing teins and uncovers new molecular characteristics of lung
Because DNA ultimately affects cellular behavior via pro- cancers, as recently demonstrated in NSCLC.188 Using an
teins translated from the RNA, RNA expression patterns integrative proteomic and transcriptomic analysis, molecu-
may be more relevant than either DNA copy number or lar differences between SCLCs and NSCLCs have been identi-
epigenetic DNA changes. The microarray technology devel- fied, supporting the potential role for PARP1 and EZH2 in
oped in the mid-1990s offers the hope that a fingerprint of SCLC.131 In general, however, because of a lack of reproduc-
the genetic expression of these tumors can be developed ibility between platforms and institutions, proteomic profil-
and then associated with clinical features. Beyond allowing ing, unlike genomic signature profiling, has not yet made a
for better classification of lung cancers, this technical major impact in clinical practice.210-212
advance in profiling gene expression opens a window into Proteomic profiling in biologic fluids or tissue samples
the world of tumor behavior (disease progression, recur- has also been studied, but is not without challenges. The
rence, response to therapy) as well as to the mechanisms of complexity of the sample composition and the predomi-
tumor development. Tumor gene expression profiles are nance of few abundant proteins in the sample that can
also influenced by the surrounding nonmalignant cells and mask lower abundant proteins currently limit the utility of
so profiling both the tumor and nontumor will allow for the this approach. A newer serum proteomic platform has been
study of the regulatory role of both entities.192 tested in retrospective studies and shown to have the ability
Expression array data have provided new ways to distin- to predict whether or not NSCLC patients will benefit from
guish and classify tumors. Selected genes allow the discrim- the EGFR TKI erlotinib.213-215 Future efforts to analyze
ination between primary lung cancer and metastasis of specific proteins or protein signatures in serum or other
extrapulmonary sites.193 Studies of expression profiles of fluids has potential for diagnosis, prediction of therapeutic
adenocarcinomas of the lung using commercially available response and monitoring.
gene chips193 or custom arrays194,195 have identified differ-
ent classes of tumors, albeit with some overlap. For example, MOLECULAR NETWORKS—SYSTEM BIOLOGY
four classes of adenocarcinomas were found to have specific
prognoses and expression signatures. These were charac- To determine the most informative molecular targets from
terized respectively by their (1) expression of cell cycle or high-throughput assays, increasingly sophisticated ana-
proliferation genes, (2) expression of neuroendocrine lytic tools are being developed. These analytic tools help
markers, (3) expression of markers of alveolar origin, and define biologic processes, cellular components, or molecu-
(4) expression of ornithine decarboxylase or glutathione lar pathways as well as provide gene ontology information
S-transferase.193 The neuroendocrine subclass was found to about genes of interest; such analytic tools include WebGe-
have a clinical outcome significantly worse than the others. stalt,216 Pathway Studio, and Ingenuity. The Kyoto Encyclo-
These subclass differences may suggest possible new thera- pedia of Genes and Genomes is a knowledge base for
pies targeted to these subsets and explain why tumors that systematic analysis of gene functions in terms of the net-
superficially seem similar may respond quite differently to works of genes and molecules.217 Although most pathway
therapy. For example, when cDNA microarrays were used and network analysis tools are gene-centric, tools for com-
to study neuroendocrine tumors, a poor correlation was bining and integrating multidimensional information at
found between genes expressed in carcinoid and SCLC,196 various levels are rapidly developing.218 Network analysis
tumors that may be morphologically similar but that behave helps identify central genes or proteins, called hubs, that
very different clinically. link many others in the network. One can assume that
In sum, since the late 1990s, we have learned that the mutations in regulatory (hub) genes or proteins, for
somatic molecular alterations in cancers yield signatures example, are more likely to cause disease than mutations in
that can be used for subclassification193,195 or for predicting those less connected and peripheral in the network.219
patient survival,195,197 risk of recurrence,198 and response to These hubs may also be target sites for therapy. Therefore,
therapy.193 However, these signatures have not always with- quantitative systems biology applied to cancer offers a unique
stood independent validation.199 approach for defining the pathogenesis, and developing
Risk Assessment SNPs, blood and airway Table 51-2 Characteristics of a Successful Diagnostic
epithelium biomarkers
Biomarker
Symptoms Screening Chemoprevention
Measurable, noninvasive, with strong performance characteristics
Noninvasive Diagnosis Serum Proteomics signatures (with emphasis on positive and negative predictive values), robust,
Autoantibodies reproducible, and biologically relevant
miRNAs Proven to add clinical value to current standards and to trigger a
FNA Bronchoscopy Surgical clinical decision
biopsy Adopted by the clinical community for the benefits it affords
Staging Genomic/
Proteomic signatures Competitive in terms of cost and insurance reimbursement
CT chest PET CT Mediastinoscopy

Treatment ERCC1, RMM1
Gene signatures
Surgery Systemic Radiation These characteristics include changes in expression levels
Mutations, NGS, of genes and proteins and their posttranslational modifica-
FISH
Chemo Targeted Therapy
tions. Detection of cancers at early stages maximizes
survival, and identification of blood-borne markers would
Response Recurrence Prognosis lead to minimally invasive tests. The best biomarkers are
Figure 51-3 Future applications envisioned for biomarker-driven per- those that are reproducibly measured, that are related to
sonalized management of lung cancer. At each step in the course of the the disease process, and that trigger a clinical decision
management of lung cancer, important clinical decisions are made. resulting in improved clinical outcomes (Table 51-2).
Biomarkers of risk, diagnosis, prognosis, and response to therapy are
becoming available and are already driving a personalized approach to
Despite an intense search for such biomarkers, there are
lung cancer. Examples of such candidate biomarkers are provided in the none currently validated for the early diagnosis of lung
figure at points in the decision tree where they may affect decision making cancer.222-224
in the near future. ERCC1, excision repair cross-complementation group 1; Biomarkers based on the earliest known molecular
FISH, fluorescent in situ hybridization; FNA, fine needle aspiration; miRNAs, abnormalities found in lung cancer could aid the early
microRNAs; NGS, next generation sequencing; RMM1, ribonucleotide
reductase; SNPs, single nucleotide polymorphisms. detection of lung cancer. Sputum sample analysis for DNA
methylation, miRNAs, or chromosomal abnormalities by
fluorescence in situ hybridization may represent approaches
suitable for early detection. New detection methods such as
exhaled breath condensate for tumor metabolites225,226 may
individualized (personalized) treatment strategies that can be found to be efficient ways of assessing high-risk individu-
take full advantage of modern molecular pathobiology and als. As alluded to earlier, early detection by low-dose CT
the comprehensive data sets that are rapidly becoming scanning has been shown to be effective in lowering both
available for populations and individuals. overall and cancer-specific mortality in the National Lung
Cancer Screening Trial.220 The addition of molecular studies
may significantly increase the sensitivity and specificity of
TRANSLATING LUNG CANCER this new strategy for early detection.
Biomarkers may also provide prognostic and predictive
BIOLOGY TO THE CLINIC information. Expression array signatures and serum pro-
teomic assays have been discussed previously. Polymor-
BIOMARKERS phisms or expression of DNA repair genes (e.g., ERCC and
Biomarkers are measurable products of tumors that can RRM) have been associated with predicting response to che-
assist in the diagnosis (identification of cases), prognosis motherapy,227 but also have been shown to have significant
(correlation with outcome independent of interventions), practical obstacles in terms of the performance reliability
or prediction (associated with outcome after a specific inter- of antibody-based immunohistochemical tests,228 raising
vention). It is clear that lung cancer outcomes could be questions about their clinical utility.229 Cyclooxygenase-2
improved by high-quality biomarkers addressing each of expression and urinary prostaglandins have been associ-
these categories (Fig. 51-3). The biggest strides made to date ated with benefit from COX inhibitors230,231 and are being
have been in choosing treatments for patients with advanced further studied.
lung cancer. However, to decrease lung cancer deaths, we
need to devise biomarker-driven strategies for prevention, PERSONALIZED MEDICINE AND
early detection, and treatment of early-stage lung cancers.
MOLECULAR THERAPEUTICS
The discovery of biomarkers for early-stage lung cancer
has been hampered by the slow onset of lung cancer and The biggest impact of biomarkers in NSCLC clinical care has
the lack of screening tests to identify early disease, although been in testing patients with advanced or metastatic disease
with the recent positive screening trial of low-dose computed for the presence of “driver” genotypes, which can then be
tomography (CT) scans for heavy smokers, we are hopeful matched to corresponding targeted therapies (Fig. 51-4).
that the biologic samples collected from participants will The term driver genotype refers to a crucial, necessary bio-
be a useful resource for discovery for biomarkers.220,221 The logic change, usually a gain-of-function imparted by a gene
assumption underlying the concept of biomarkers is that mutation, amplification, or translocation. This driver is
certain molecular characteristics of the lesions are highly oncogenic and plays a critical role in the signaling that
correlated with specific, clinically-relevant biologic states. drives the malignant phenotype of the cancer. A wide range
of such driver genotypes have been found consistently in notion that genotypic biomarkers can be used to distinguish
NSCLC, predominantly in adenocarcinoma tumors but to one subtype of lung cancer from another. Clinical standards
some extent in squamous cell cancers as well.232,233 Geno- of diagnosis for NSCLC are evolving to take genotyping
type screening of large patient populations has demon- into account at the time of diagnosis; multiplexed platforms
strated that the driver genotypes tend to be mutually are being developed to accomplish testing in a time, money,
exclusive, suggesting that indeed these changes play a role and tissue-efficient manner.234 The genotype information is
in the early development of cancer and confirming the then used to match patients with targeted therapies, typi-
cally small molecular inhibitors that specifically block sig-
naling of the driver pathway. A friendly tool available online
MAP2K1 NRAS at “www.mycancergenome.org” provides such support in
AKT1 ROS1 fusions
an unprecedented way.235
There are several EGFR mutations (most commonly dele-
PIK3CA KIF5B-RET tions in exon 19 and the L858R point mutation in exon 21)
BRAF that have been found in adenocarcinomas among patients
with a low smoking history.87-89 EGFR mutations are much
HER2
more frequent in patients originally from East Asian nations,
ALK for reasons that are unknown; about 10% to 15% of North
fusions
American and European lung cancer patients have EGFR
mutations, whereas in Japan the proportion is 50% or
greater.232 These mutations lead to a constitutive activation
of the EGF receptor and its downstream growth pathways
and patients with EGFR mutations can respond in a dra-
matic way to the approved EGFR TKIs gefitinib, erlotinib,
Unknown
EGFR and afatinib (Fig. 51-5 and Table 51-3).92,211,236 For context,
Table 51-3 Molecular Targets in Lung Cancer

Characteristics of Cancer Possible Molecular Targets
KRAS
Self-sufficient cell growth EGFR, PIK3CA, PDGFR, MAPK, EML4ALK,
ROS1, ALK, RET, HER2, BRAF, MET
Insensitivity to anti-growth SMADs, Rb, cyclin-dependent kinases,
MYC
Limitless replicative p53, Rb, hTERT, EML4-ALK
Figure 51-4 Pie chart showing the percentage distribution of genetic potential
abnormalities in lung adenocarcinoma. Treatment decisions about lung
cancer have shifted from those based only on histology to those incorpo- Evading apoptosis KRAS, p53, BCL-2, caspases, FAS, TNFR,
rating genetic alterations. As seen in this pie chart, the genome of lung DR5, IGF/PI3K/AKT, mTOR, PTEN, MET
cancer is being chipped away, with discovery of driver mutations that lead Sustained angiogenesis NF-κB, VEGF, TGF-β, αvβ3,
to constitutively active signaling proteins and provide a target for therapy. thrombospondin-1, HIF1α
The most recently identified KIF5B-RET fusion subset, which accounts for
approximately 1% of this distribution, is boxed. NRAS, neuroblastoma RAS AKT, protein kinase B; EGFR, epidermal growth factor receptor; EML4-ALK,
viral (v-ras) oncogene homolog; MAP2K1, mitogen-activated protein kinase echinoderm microtubule associated protein like 4-anaplastic lymphoma
kinase 1; AKT1, v-akt murine thymoma viral oncogene homolog 1; PIK3CA, kinase; HIF1α, hypoxia inducible factor 1 alpha; IGF, insulin-like growth
phosphoinositide-3-kinase, catalytic, α polypeptide; BRAF, v-raf murine factor; MAPK, mitogen-activated protein kinase; mTOR, mammalian target
sarcoma viral oncogene homolog B1; HER2, human epidermal growth of rapamycin; NF-κB, nuclear factor-κB; PDGFR, platelet-derived growth
factor receptor 2; EGFR, epidermal growth factor receptor; KRAS, v-Ki-ras2 factor receptor; PI3K, phosphatidylinositol-3-kinase; pRb, retinoblastoma
Kirsten rat sarcoma viral oncogene homolog. (From Pao W, Hutchinson KE: protein; PTEN, phosphatase and tensin homologue gene; TGF-β,
Chipping away at the lung cancer genome. Nature Med 18:349–351, 2012.) transforming growth factor-β; VEGF, vascular endothelial growth factor.
A B
Figure 51-5 A response to anti-epidermal growth factor receptor (EGFR)–targeted therapy. Axial chest CT scan of a woman with chemotherapy-
refractory adenocarcinoma shows a dramatic response to gefitinib (EGFR tyrosine kinase inhibitor) after 2 months of treatment (A, before treatment;
B, after treatment). This woman was a never-smoker of Asian ethnicity with an activating EGFR mutation.
Table 51-4 Targets Identified in Lung Cancer Along with described patients with this genotype who respond to crizo-
Current or Potential Therapies tinib therapy.245
Even though more common in melanoma, BRAF muta-
Driver Genotype Targeted Therapies
tions are also found in about 1% of NSCLC patients.232,246
EGFR mutations Approved EGFR TKIs: gefitinib, erlotinib Both HER2 mutations and HER2 amplification are seen in
and afatinib a small percentage (1% to 2%) of lung cancer patients and
Experimental EGFR TKIs: dacomitinib,
CO-1686, AZD9291 are associated with response to the HER2 monoclonal anti-
ALK translocations Approved ALK TKIs: crizotinib
body trastuzumab and the TKI afatinib.247,248 Other rare
Experimental ALK TKIs: LDK378, AP26113, driver genotypes are emerging in rapid succession.
CH5424802, X-396 KRAS mutations are the most common genotype but
ROS1 translocations Experimental ROS1 TKIs: crizotinib have so far been refractory to therapeutic targeting. In
MET amplification Experimental MET TKIs: crizotinib colon cancer, the presence of KRAS mutation has been a
BRAF mutations Experimental BRAF TKIs: dabrafenib, robust negative predictor for EGFR-targeted therapies
vemurafenib (mainly monoclonal antibodies),249 but in NSCLC it has
HER2 mutations or Experimental HER2 monoclonal antibodies: been less clear that KRAS mutations should disqualify
amplification trastuzumab patients for EGFR therapy.250,251 Development of down-
Experimental HER2 TKIs: afatinib stream signaling inhibitors looks like a potential promising
KRAS Experimental MEK TKIs: selumetinib, strategy for KRAS mutants and a randomized phase 2 study
trametinib of docetaxel chemotherapy with or without the MEK inhibi-
tor selumetinib showed an interesting increase in response
rate and in PFS.252
the response to first-line chemotherapy for lung cancer Harnessing the immune system to attack cancer has long
patients is approximately 20% to 35% and the median been a dream of physicians, but progress has historically
progression-free survival (PFS; how long patients remain on been slow. However, recently, new treatment options in the
treatment without progressing) is about 5 to 6 months.237,238 form of “checkpoint” modulators have emerged as highly
An EGFR mutation-positive patient typically has a 75% promising therapeutic options. Programmed death 1 (PD-1)
response rate to an EGFR TKI with a corresponding PFS of protein, a T-cell coinhibitory receptor, and one of its
10 to 13 months. In a series of prospective randomized ligands, PD-L1, play a pivotal role in the ability of tumor
trials, it has been shown convincingly that initial treatment cells to evade the host’s immune system. Blockade of inter-
of advanced lung cancer in patients with EGFR mutations actions between PD-1 and PD-L1 enhances immune func-
with an EGFR TKI instead of with standard chemotherapy tion in vitro and mediates antitumor activity in preclinical
significantly improves PFS and quality of life; this has now models. In two pivotal phase I trials, antibodies against
become the standard of care.212,239,240 PD-1253 and PD-L1254 have led to remarkably high response
Translocations that result in the apposition of the ALK rates with durable clinical benefit. CTLA-4 is another
receptor tyrosine kinase gene near the EML4 or other protein receptor that down-regulates the immune system.
similar promoter regions have been identified in about 5% The anti-CTLA-4 antibody, ipilimumab, was approved for
of NSCLC cases, again most commonly found in patients use in melanoma255 and is being tested in lung cancer. Com-
with a low smoking history.100,241 ALK rearrangements binations of anti-PD-1 and anti-CTLA-4 antibodies may be
confer sensitivity to the ALK TKI crizotinib with an approxi- even more active, as has been shown in melanoma.256 Anti-
mate 70% response rate and a PFS of 10 months (Table PD-1 and -PD-L1 antibodies may be most effective in tumors
51-4).101,242 Patients with ALK translocations previously expressing the proteins,254,257 but the biomarkers have not
treated with chemotherapy have been randomized to crizo- yet been established as definitive predictors of response.
tinib versus standard second-line chemotherapy; crizotinib
was found to be more effective in term of response and MECHANISMS OF RESISTANCE
PFS.243 In addition, a retrospective analysis suggests that
patients with ALK translocations treated with crizotinib One of the most active areas of research currently in the
have an improved overall survival compared to patients that field of targeted therapy for lung cancer is how to overcome
were unable to receive crizotinib or were diagnosed and acquired resistance. The genotypes with the most proven
treated prior to the availability of crizotinib.244 This is an success in treatment with targeted agents (EGFR mutations
important issue because targeted therapies proven to yield and rearrangements in ALK and ROS1) have also demon-
dramatic responses in a genotype-defined population pose strated that resistance is acquired after 1 to 2 years for most
an ethical dilemma for future randomized trials, because it patients. Resistance is often in the form of a point mutation
is no longer feasible to randomize patients away from the at the gatekeeper location within the RTK,94,95,210,258,259 but
effective targeted therapy without allowing crossover at the may also be in the form of a bypass track, or detour using
time of progression. The ROS1 receptor tyrosine kinase can another cancer signaling pathway.96,97,258,260 Evolution of
undergo an activating translocation in 1% or less of NSCLC the cancer histology from adenocarcinoma to small cell
cases. Given the homology of ROS1 to ALK, the TKI crizo- lung cancer has been noted in some patients with EGFR
tinib also happens to be a specific and effective inhibitor for mutations with acquired resistance to EGFR TKIs but
this subset of lung cancer patients.102 Interestingly, crizo- the mechanism is not well understood.260,261 Several
tinib also inhibits the MET tyrosine kinase, and about 1% therapies for acquired resistance to therapy are being
or less of NSCLC patients have a driver genotype character- studied, primarily in NSCLC with EGFR mutations and ALK
ized by high-level amplification of MET. Case reports have rearrangements.
Hassanein M, Callison JC, Callaway-Lane C, et al: The state of molecular

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Biology of Lung Cancer

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Biology of Lung Cancer

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SECTION J

NEOPLASMS OF THE LUNG

51 BIOLOGY OF LUNG CANCER

INTRODUCTION Role of Inflammation in Lung STRATEGIES TO DEEPEN OUR

INTRODUCTION understanding of driver genes2 and the potential benefit of

To date, no tumor suppressor genes inactivated by mutation

EARLY EVENTS IN LUNG

chromosomal abnormalities resulting in clonal expansion

Cont-1 Cont-2 SCC ADC SCC

Reverse phase protein arrays190 are a means to validate

CT chest PET CT Mediastinoscopy

Table 51-3 Molecular Targets in Lung Cancer

Hassanein M, Callison JC, Callaway-Lane C, et al: The state of molecular

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