Open access peer-reviewed chapter

Tumour Suppressor Genes with Oncogenic Roles in Lung Cancer

Written By

Mateus Camargo Barros-Filho, Florian Guisier, Leigha D. Rock, Daiana D. Becker-Santos, Adam P. Sage, Erin A. Marshall and Wan L. Lam

Submitted: January 15th, 2019 Reviewed: February 7th, 2019 Published: April 16th, 2019

DOI: 10.5772/intechopen.85017

Chapter metrics overview

1,294 Chapter Downloads

View Full Metrics

Abstract

Lung cancer is one of the most common cancers and the leading cause of cancer-related deaths worldwide. High-throughput sequencing efforts have uncovered the molecular heterogeneity of this disease, unveiling several genetic and epigenetic disruptions driving its development. Unlike oncogenes, tumour suppressor genes negatively regulate cell cycle control and exhibit loss-of-function alterations in cancer. Although tumour suppressor genes are more frequently disrupted, oncogenes are more likely to be drug-targeted. Many genes are described as presenting both tumour suppressive and oncogenic functions in different tumour types or even within the natural history of the disease in a single tumour. In this chapter, we describe current knowledge of tumour suppressor genes in lung tissues, focusing on tumour suppressor/oncogene duality.

Keywords

  • tumour-suppressor genes
  • oncogenes
  • dual roles
  • lung cancer
  • targeted therapy

1. Introduction

Cancer cells arise in non-malignant tissue due to the sequential acquisition of molecular alterations that drive proliferation, permit the evasion of growth suppression and apoptosis signals and promote angiogenesis, invasion and metastasis [1]. This process is stochastic, and over time the tumour continues to evolve in a dynamic manner, generating a group of cells harbouring different genetic and epigenetic features [2]. The resulting heterogeneity is the basis of tumour evolution and leads to the selection of tumour cells. These cells often present with rewired signalling networks and often oncogene addiction [3].

The uncontrolled growth of cancer cells can in part be explained by their aberrant gene expression patterns. While most cancer genes are characterized as either oncogenes or tumour suppressors based on their typical behaviour in tumours, some genes display dual oncogenic and tumour suppressive functions [4, 5]. The majority of these genes encode multiple isoforms, which are further post-translationally modified and form a variety of protein complexes, generating a context-dependent cellular network [6]. In diploid organisms, gain-of-function (GOF) mutations in oncogenes are typically dominant (single events are sufficient to promote tumourigenesis), while loss-of-function alterations are recessive in TSGs (requires two inactivation events) [7]. For example, for a TSG with dual oncogenic roles, one gain-of-function mutation can potentially cease its tumour suppressive function and turn on oncogenic signalling [5].

Recently, genes with both oncogenic and tumour-suppressive functions were described across 12 main cancer types using The Cancer Genome Atlas (TCGA) database [5]. Using a text mining approach, the authors identified genes mainly represented by kinases (e.g. BCR, CHEK2, MAP2K4, NTRK3 and SYK) or transcription factors (e.g. BRCA1, EZH2, NOTCH1, NOTCH2, STAT3 and TP53) and evaluated them at the genomic and gene expression levels. Using an in silico analysis, it was shown that genes with dual functions interact with more partners and are more important hub-genes in protein-protein interaction networks.

In this chapter, we discuss TSGs with both tumour suppressive and oncogenic functions in lung cancer.

1.1 Lung cancer classification

Lung cancer is one of the most common cancers and the leading cause of cancer-related deaths worldwide [8]. In the United States, lung cancer accounts for 13.5% of all new cancer cases and 25.3% of all cancer deaths. The five-year survival rate is dismal, with only 18.6% of patients surviving 5 years [9]. The majority of lung cancer cases (approximately 80%) are attributed to cigarette smoking [10]. About 10–25% of cases occur in people who have never smoked [11]. The aetiology behind these cases is most likely a combination of genetic factors, as well as the effects of exposure to environmental carcinogens such as asbestos, radon gas or other forms of pollution [12].

Lung cancer is classified according to histological type. There are two major types: small cell lung cancer (SCLC), which accounts for 15–20% of lung cancer patients, and non-small cell lung cancer (NSCLC), comprising the remaining 80–85% (Figure 1) [13]. SCLC, primarily originating from the central airways, is thought to be derived from neuroendocrine cells [14]. NSCLC is composed of three major histological subtypes: adenocarcinoma (LUAD), squamous cell carcinoma (LUSC) and large cell carcinoma (LCC). LUAD is the most common, accounting for approximately 40% of all lung cases [15]. LUAD typically arises from glandular epithelium, from bronchioalveolar stem cells, club (Clara) cells or type II pneumocytes in the lung periphery [13]. LUAD is also the predominant subtype that arises in patients who have never smoked [15]. LUSC develops primarily in the central airways and segmental bronchi, strongly associates with a history of smoking and accounts for approximately 20% of all lung cancer cases. LCC may arise anywhere in the lung and are classified as tumours without general features associated with SCLC, LUAD or LUSC [13].

Figure 1.

Histological classification of lung cancer. (A) Lung cancer histological types. (B) Location of the tumours and cell origins. SCLC, small cell lung cancer; NSCLC, non-small cell lung cancer; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; LCC, large cell carcinoma.

1.2 TSG mutation spectrum in lung cancer

Beyond the histological heterogeneity of lung cancer, genomic studies of large cohorts have uncovered the complex molecular landscape of lung tumours. Indeed, it has been observed that a wide variety of oncogenes and TSGs can be altered in lung cancer, and these molecular events are vastly different between histological subtypes [16, 17].

Clinical studies have shown that molecularly defined lung cancer subgroups can correlate with characteristics such as ethnicity [18], smoking history [19], treatment sensitivity [20] or prognosis [21]. Many of the commonly identified gain-of-function alterations in proto-oncogenes have been actively investigated for therapeutic purposes. For example, EGFR, ALK, ROS1, BRAF, MET, RET and HER2 are routinely assessed in the clinic to offer targeted therapy for eligible LUAD patients [22].

Three TSGs are frequently mutated in all three major lung cancer subtypes: TP53, LRP1B and CSMD3. Other TSGs of particular interest in lung cancer are as follows RB1 and CREBBP in SCLC, KEAP1 and STK11 in LUAD, CDKN2A in LUSC, NOTCH1 and PTEN in both SCLC and LUSC and NF1 in both LUAD and LUSC (Figure 2). Mutations in these TSGs are usually mutually exclusive, indicating that individual genes are capable of driving lung cancer progression.

Figure 2.

Mutational frequency of TSGs in small cell lung cancer (SCLC; n = 110) [16], lung adenocarcinoma (LUAD; n = 660) [23] and lung squamous cell carcinoma (LUSC; n = 484) [23]. TSGs were defined according to COSMIC Cancer Gene Census (https://cancer.sanger.ac.uk/census) and mutation frequency of the most commonly disrupted TSGs in these subtypes of lung cancer were retrieved using cBioPortal (http://www.cbioportal.org/).

Advertisement

2. TSGs with oncogenic roles in lung cancer

Several TSGs in lung cancer have also been shown to behave as oncogenes, depending on the molecular context and/or the mechanism by which they are altered (Table 1). Among them are TP53, NFIB, members of the NOTCH family, NKX2-1, NFE2L2, as well as some non-coding RNAs (MALAT1, mir-125, and mir-378), which will be discussed in detail below.

Gene Main function Role as TSG Role as oncogene
TP53 TF: regulates cell cycle, DNA repair, senescence and apoptosis TSG in several tissues: frequently lost through mutations [24] Missense mutations confer gain-of-function oncogenic properties [31]
NFIB TF: crucial in lung development Underexpressed in NSCLC and associated with poor survival in LUAD [32] Amplified and OE in SCLC: inducing chromatin reprogramming during metastasis [33]
NOTCH1/NOTCH2 Transmembrane receptors: proliferation, differentiation and survival Inactivated by inhibitor ligands and through mutations, especially in SCLC [34] Maintains stem cell features; promotes proliferation in LUAD [35]
NFE2L2 TF: cellular defense mechanism against oxidative stress Protects lung tissue against exposure to oxidative stress [36] Mutational activation: aids cells to escape from endogenous tumour suppression [37]
NKX2-1 TF: essential for lung development Acts as a TSG in KRAS-driven p53-mutant LUAD [38] Enhanced oncogenic signals in EGFR-driven LUAD [39]
STK11 Serine-threonine kinase: regulation of energetic metabolism and cell polarity Mutational inactivation promotes cancer development [40] OE maintains metabolic homeostasis and attenuates oxidative stress [40]
TGFB Cytokine: regulates development, differentiation and homeostasis Expression loss leads to growth arrest in early-stage lung and other cancers [41] OE promotes tumour growth in advanced cancer stages [42]
TUSC3 Endoplasmic reticulum protein in magnesium uptake, glycosylation and embryonic development Hypermethylation; expression loss in NSCLC; inhibits cell proliferation and promotes apoptosis [43] OE in NSCLC accelerates cancer growth; induces EMT [44]
WT1 TF: role in urogenital system development Loss of function enhances cell viability and proliferation in Wilms’ tumour [45] OE promotes survival in KRAS-mutated NSCLC [46]
MALAT1 Long non-coding RNA OE reduces invasiveness in PTEN expressing tumours [47] OE associated with chemotherapy resistance in NSCLC [48]
miR-125b microRNA OE induces apoptosis [49] OE promotes metastasis [50]
miR-378 microRNA OE reverses chemoresistance to cisplatin in LUAD [51] OE is associated with invasion and brain metastasis [52]

Table 1.

Main TSGs with dual functions reported in lung cancer.

TF, transcription factor; OE, overexpression; EMT, epithelial-mesenchymal transition. Numbers in brackets refer to the list of reference.

2.1 TP53

TP53 is a well-known TSG, representing the most common somatically mutated gene in human cancer, especially in lung tumours [24]. The classic functions of the encoded p53 protein are cell cycle regulation, DNA repair, senescence mediated by stress, apoptosis and angiogenesis. These functions mainly occur through the binding of a p53 tetramer to the promoter of target genes [25]. In many cancer types, TP53 mutation is associated with poor prognosis, including local and distant metastases events, resistance to treatment and decreased survival [26, 27].

Despite having a reputation as a ‘guardian of the genome’, recent work has shown that activating TP53 alterations can act to promote cancer development and progression [25, 28]. Depending on the location of the mutation within the TP53 gene, protein structure and subsequent DNA binding activity can be lost or altered, resulting in either loss or gain of function [25]. In contrast to the majority of TSGs, TP53 is not commonly inactivated by deletions or truncating mutations. Indeed, 74% of mutations within the TP53 locus are missense point mutations, which can be found in proteins in human tumours [25]. In fact, altered TP53 was initially considered as a cancer antigen with putative oncogenic properties [25]. Together, this highlights the dichotomous role of TP53 disruptions, in that both the loss of wild-type p53 and gain-of-function mutations can provide a growth advantage to tumours [28].

Lung cancer is commonly associated with tobacco use, where the prolonged exposure to carcinogens damages the DNA of the exposed cells. These alterations are especially enriched in missense mutations in TP53, leading to GOF-p53 [29]. The oncogenic GOF mutation in p53 was previously shown to be related with the inactivation of AMP-activated protein kinase (AMPK) signalling in head and neck cancer and another tobacco-related cancer [30]. AMPK is a master regulator of metabolic homeostasis and GOF-mutated p53 is able to physically interact and inhibit AMPK, stimulating aerobic glycolysis under energetic stress conditions and leading to invasive growth.

In lung cancer mouse models, prevention of tumour formation by inhibiting GOF p53 mutants has been demonstrated [53]. Although the highly aberrant genomes in p53-mutated tumours should lead to unfeasible mitosis, these mutations facilitate the survival and proliferation of these cells through stabilizing replication forks and promoting micronuclei arrangement [31].

GOF p53 mutants are most likely involved in multiple mechanisms that coordinate tumour progression. For example, GOF-p53 (R175H, R273H and D281G) was demonstrated to upregulate CXCL5, CXCL8 and CXCL12 through its transcription factor activity, promoting migration of lung cancer cell lines [54]. CXCL5 expression was shown to be elevated in human lung tumour samples harbouring GOF-p53, and its inhibition could reverse cell motility in lung cancer and melanoma cell lines [54]. In NSCLC, it was recently reported that GOF-p53 can physically interact with HIF-1 and binds to the SWI/SNF chromatin remodelling complex, inducing the expression of hypoxia-responsive genes [55]. Importantly, specific extracellular matrix components are upregulated by this process and mediate pro-tumourigenic features in NSCLC [55].

2.2 NFIB

Nuclear factor I (NFI) is a transcription factor family, comprising NFIA, NFIB, NFIC and NFIX, that plays important roles in normal development and in numerous diseases [56]. These proteins bind to specific DNA sequences leading to repression or activation of gene expression in a context-dependent manner, regulating cell differentiation and proliferation through their target genes [57]. NFIB, in particular, has been implicated in a wide range of malignancies, being described as both an oncogene and a potential TSG [58].

Using an in vivo model, it was demonstrated that NFIB is a metastatic driver in SCLC, inducing global chromatin reprogramming during metastasis [33]. The authors isolated tumour cells from primary and metastatic sites of genetically engineered mice, and using genome-wide analysis, they showed a pronounced increase in chromatin accessibility during tumour progression, resulting from NFIB copy number amplifications. Interestingly, the distal regions that became accessible upon NFIB upregulation were similar to open regions found in neural tissue. Recently, the same group described two metastatic models in SCLC, one dependent and other independent of NFIB amplification [59]. NFIB was likewise reported as amplified and/or overexpressed in melanoma [60], breast [61], oesophagus [62] and salivary gland malignancies [63].

A gene fusion involving NFIB (MYB-NFIB) is frequently found in adenoid cystic carcinomas from salivary glands [64] and in adenoid cystic carcinoma from other topologies [65]. Despite the putative oncogenic function of NFIB, studies have focused on its fusion partner MYB as the main oncogenic driver in these cancers [66]. Given the fact that other fusion partners of NFIB have been reported in adenoid cystic carcinomas [67] and that MYB-NFIB fusions lead to NFIB truncation [68], NFIB may have a possible independent role as a TSG in these malignancies.

While the MYB-NFIB fusion is not observed in lung cancers, NFIB is frequently underexpressed in NSCLC tissues [32] and during epithelial-to-mesenchymal transition in NSCLC cell lines [69]. NFIB is an essential transcriptional factor in lung development [70] and was demonstrated to be targeted by many microRNAs that recapitulate their foetal lung expression patterns in NSCLC [32]. Lower expression of this gene was associated with shorter overall survival, less-differentiated tumour features and repressed expression of cell differentiation markers in LUAD patients [32]. Therefore, contrary to the established oncogenic role of NFIB in SCLC, these observations suggest a tumour suppressive role in NSCLC.

2.3 NOTCH gene family

The Notch signalling pathway is important in the regulation of cell fate during embryogenesis and maintenance of homeostasis in adult tissues [71]. It includes Notch receptors (NOTCH1, NOTCH2, NOTCH3 and NOTCH4) and ligands from the DSL family, which suppress or induce tumour-related mechanisms under specific cellular contexts [71].

In SCLC, Notch signalling is frequently inactivated by either a mutation in Notch receptors or the overexpression of ligands that inhibit downstream signalling [34]. Despite this potential role as a TSG, Notch signalling in lung tumours is complex, as it has also been shown to be related to chemoresistance in SCLC [72]. In addition, the overactivation of this pathway through several mechanisms acts like an oncogene in LUAD by preserving stem cell features and promoting proliferation [35, 73]. Notch1 expression is required in Kras-driven LUAD carcinogenesis, suppressing apoptosis via the p53 pathway [35]. The inhibition of the Notch pathway is able to restrain lung cancer stem cell maintenance, which is characterized by subpopulations of cells expressing aldehyde dehydrogenase [74].

Conversely, loss-of-function mutations of Notch receptors generating truncated receptors imply a TSG role in LUSC [75]. Although functional studies to further corroborate this hypothesis are still needed, reports in other squamous cell carcinomas substantiate the idea that the inactivation of this signalling pathway promotes tumourigenesis [76].

2.4 NKX2-1 (also known as TTF-1)

Nkx2-1 is a homeobox-containing transcription factor that is essential for lung development and is expressed in type II pneumocytes and bronchiolar cells in adults [77]. It is expressed in 40–50% of lung cancers and is amplified and overexpressed in 6–11% of LUAD [78].

Nkx2-1 acts as a lineage-specific oncogene in some LUAD cases [79], enhancing cell viability and proliferation in lung cancer cell lines [78]. This function relies on the activation of (i) the pro-survival PI3K-AKT pathway, through ROR1 kinase-dependent c-Src activation as well as maintaining the EGFR-ERBB3 association [80], and (ii) LMO3, a member of the LMO family of oncogenes that is translocated in T-ALL [81].

On the other hand, Nkx2-1 expression has been associated with good patient outcome [82] and the loss of Nkx2-1 expression was associated with the aggressive behaviour of NSCLCs [83]. Mechanistically, tumour suppressive functions of Nkx2-1 in lung adenocarcinoma rely on the restriction of cell motility, invasion and metastatic ability, through the inhibition of the TGF-β [41] and IKK-B/NFk-B [39] pathways. The dual role of Nkx2-1 is dependent on EGFR, KRAS and TP53 status in LUAD: NKX2-1 acts as a TSG in KRAS-driven and TP53-mutant tumours, whereas it enhances EGFR-driven tumourigenesis [84, 85].

2.5 NFE2L2

NFE2L2 encodes a transcription factor that regulates proteins involved in cellular defense mechanisms against metabolic, xenobiotic and oxidative stress [86]. NFE2L2 has been often considered a TSG due to its protective role against genome-damaging agents, the higher propensity to cancer development in NFE2L2-deficient mice and its protective effects in cancer chemoprevention [87].

Due to the constant exposure to oxidative stress in the lung, the NFE2L2 pathway is important to guarantee the genomic stability of these cells [88]. However, once transformation of normal to cancer cells occurs, NFE2L2 favours tumour development by acting to protect against oxidative stress resulting from the tumour microenvironment and exposure to genotoxic agents during patient treatment [86]. In fact, mutations in NFE2L2 and KEAP1, an important member of the NFE2L2 signalling, are very common and mutually exclusive in NSCLC [89]. Curiously, a recent study demonstrated that lung cancer patients presenting NFE2L2 or KEAP1 mutations are highly resistant to chemotherapy [89]. However, the relation between the NFE2L2 pathway and treatment response prediction needs further investigation.

2.6 MALAT1 and other non-coding RNAs

While large-scale genomic sequencing efforts have uncovered an invaluable number of genetic alterations related to cancer biology, in the past, they were commonly focused on the 2% of the genome that encodes protein [90]. In the last decade, non-coding RNA transcripts have been shown to have important regulatory functions in normal and disease biology [91]. Indeed, many non-coding genes have been shown to play tumour-suppressive or oncogenic roles in numerous cancer types [92].

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was one of the first cancer-related long non-coding RNAs to be described [93]. MALAT1 is broadly expressed in normal cells, where it has been shown to regulate the alternative splicing of pre-mRNAs by changing the distribution of splicing regulators in nuclear speckles [94]. MALAT1 was primarily identified as an oncogenic transcript in lung cancer and has since been widely considered a marker of metastasis, poor patient survival [93] and chemotherapy resistance in NSCLC [48]. Mechanistically, MALAT1 has been shown to promote carcinogenesis through P53 deacetylation [95] and enhance cell migration through Akt/mTOR signalling [96] and TGF-β-induced endothelial-to-mesenchymal transition [97]. Conversely, MALAT1 has also been shown to reduce invasiveness by modulating the expression of EpCAM and ITGB4 in PTEN-expressing tumours [47] and by downregulation of MMP2 and inactivation of ERK/MAPK signalling [98]. MALAT1 also binds the nuclear p65/p50 heterodimer and thus inhibits NF-κB-dependent pathways [99] and is thought to be involved in the response to DNA damage [100]. Furthermore, MALAT1 reduces the invasiveness of cerebral metastases by sustaining the blood-brain barrier [101]. MALAT1 expression and subcellular location is finely tuned through various regulatory mechanisms [102], which may drive its pro- or anti-tumour effects [103]. Analysis of the dual role of MALAT1 highlights not only the complexity of non-coding RNA function but also their relevance to broad areas of cancer biology and management.

MicroRNAs (miRNAs) are short transcripts that typically regulate coding genes post-transcriptionally through direct interaction with mRNA transcripts. Many are deregulated in lung cancer [104], where they have documented tumour-suppressive and oncogenic roles [105]. For example, miRNA-125b has been shown to have a multifaceted function as a tumour suppressor and oncogene, being underexpressed in bladder [106] and ovarian cancer [107] and overexpressed in glioma [108] and prostate cancer [109]. It was shown that miRNA-125b induces apoptosis in cancer cell lines exposed to nutrient starvation and chemotherapy, including in lung cancer [49]. On the other hand, miRNA-125b may also function as an oncogene in NSCLC, as it is able to promote metastasis by targeting TP53INP1 [50]. In addition, inhibition of miR-125b can also decrease the invasive potential and leads to cell cycle arrest and apoptosis in NSCLC [110]. Similarly, miR-378 was reported to be overexpressed in lung cancer and other tumour types, inducing cell migration, invasion and tumour angiogenesis [111]. However, it was previously demonstrated that upregulation of this miRNA sensitizes lung cancer cell lines to cisplatin [51].

Advertisement

3. Conclusions and future directions

Here, we summarize the commonly disrupted genes in lung cancer with dual roles as both tumour suppressors and oncogenes. These conflicting roles are a result from the complexity of biological pathways and the heterogeneity of cancer cells.

Most of the current molecular therapies are based on hyperactivated oncogene inhibitors. In lung cancer, only a fraction of the cases exhibit alterations in targetable genes, such as EGFR, BRAF and MET mutations and ALK, RET and ROS1 fusions [112]. Therefore, there is an urgent need for the development of novel therapeutic strategies exploiting non-oncogene alterations of lung tumour cells.

Considering that TSGs are found altered more frequently than oncogenes in human tumours [113], the existence of TSGs with dual oncogenic roles opens a new window of opportunities for the development of new targeted therapies. However, therapeutic action against TSGs remains challenging, as many are not amenable to current pharmacologic inactivation strategies. Most of the TSGs are not a kinase that can be pharmacologically blocked and are not located at the cell surface to be targeted by an antibody.

In summary, there is an unmet need to clarify the ambiguity found within genes, both coding and non-coding, with both pro- and anti-tumour functions. Broadening our understanding of these features may enable the development of novel and specific therapeutic strategies that consider both molecular and tissue contexts.

Advertisement

Acknowledgments

This work was supported by grants from the Canadian Institutes for Health Research (CIHR FDN-143345) and scholarships from CIHR, the BC Cancer Foundation, the Ligue nationale contre le cancer, the Fonds de Recherche en Santé Respiratoire (appel d’offres 2018 emis en commun avec la Fondation du Souffle), the Fondation Charles Nicolle and the São Paulo Research Foundation (FAPESP 2015/17707-5 and 2018/06138-8). D.D.B.S. and E.A.M. are Vanier Canada Scholars.

Advertisement

Conflict of interest

The authors have no conflicts to declare.

References

  1. 1. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144(5):646-674
  2. 2. Gupta PB, Fillmore CM, Jiang G, Shapira SD, Tao K, Kuperwasser C, et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell. 2011;146(4):633-644
  3. 3. Dagogo-Jack I, Shaw AT. Tumour heterogeneity and resistance to cancer therapies. Nature Reviews Clinical Oncology. 2018;15(2):81-94
  4. 4. Stepanenko AA, Vassetzky YS, Kavsan VM. Antagonistic functional duality of cancer genes. Gene. 2013;529(2):199-207
  5. 5. Shen L, Shi Q , Wang W. Double agents: Genes with both oncogenic and tumor-suppressor functions. Oncogene. 2018;7(3):25
  6. 6. Aranko AS, Oeemig JS, Kajander T, Iwai H. Intermolecular domain swapping induces intein-mediated protein alternative splicing. Nature Chemical Biology. 2013;9(10):616-622
  7. 7. Knudson AG. Two genetic hits (more or less) to cancer. Nature Reviews Cancer. 2001;1(2):157-162
  8. 8. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer. 2015;136(5):E359-E386
  9. 9. Noone AM, Cronin KA, Altekruse SF, Howlader N, Lewis DR, Petkov VI, et al. Cancer incidence and survival trends by subtype using data from the surveillance epidemiology and end results program, 1992-2013. Cancer Epidemiology, Biomarkers & Prevention. 2017;26(4):632-641
  10. 10. Ridge CA, McErlean AM, Ginsberg MS. Epidemiology of lung cancer. Seminars in Interventional Radiology. 2013;30(2):93-98
  11. 11. Thun MJ, Hannan LM, Adams-Campbell LL, Boffetta P, Buring JE, Feskanich D, et al. Lung cancer occurrence in never-smokers: An analysis of 13 cohorts and 22 cancer registry studies. PLoS Medicine. 2008;5(9):e185
  12. 12. Dela Cruz CS, Tanoue LT, Matthay RA. Lung cancer: Epidemiology, etiology, and prevention. Clinics in Chest Medicine. 2011;32(4):605-644
  13. 13. Pikor LA, Ramnarine VR, Lam S, Lam WL. Genetic alterations defining NSCLC subtypes and their therapeutic implications. Lung Cancer. 2013;82(2):179-189
  14. 14. Gazdar AF, Bunn PA, Minna JD. Small-cell lung cancer: What we know, what we need to know and the path forward. Nature Reviews Cancer. 2017;17(12):725-737
  15. 15. Chen Z, Fillmore CM, Hammerman PS, Kim CF, Wong KK. Non-small-cell lung cancers: A heterogeneous set of diseases. Nature Reviews Cancer. 2014;14(8):535-546
  16. 16. George J, Lim JS, Jang SJ, Cun Y, Ozretic L, Kong G, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524(7563):47-53
  17. 17. Lockwood WW, Wilson IM, Coe BP, Chari R, Pikor LA, Thu KL, et al. Divergent genomic and epigenomic landscapes of lung cancer subtypes underscore the selection of different oncogenic pathways during tumor development. PLoS One. 2012;7(5):e37775
  18. 18. Heath EI, Lynce F, Xiu J, Ellerbrock A, Reddy SK, Obeid E, et al. Racial disparities in the molecular landscape of cancer. Anticancer Research. 2018;38(4):2235-2240
  19. 19. Govindan R, Ding L, Griffith M, Subramanian J, Dees ND, Kanchi KL, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell. 2012;150(6):1121-1134
  20. 20. Zhu CQ , Cutz JC, Liu N, Lau D, Shepherd FA, Squire JA, et al. Amplification of telomerase (hTERT) gene is a poor prognostic marker in non-small-cell lung cancer. British Journal of Cancer. 2006;94(10):1452-1459
  21. 21. Shi J, Hua X, Zhu B, Ravichandran S, Wang M, Nguyen C, et al. Somatic genomics and clinical features of lung adenocarcinoma: A retrospective study. PLoS Medicine. 2016;13(12):e1002162
  22. 22. Barlesi F, Mazieres J, Merlio JP, Debieuvre D, Mosser J, Lena H, et al. Routine molecular profiling of patients with advanced non-small-cell lung cancer: Results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT). Lancet. 2016;387(10026):1415-1426
  23. 23. Campbell JD, Alexandrov A, Kim J, Wala J, Berger AH, Pedamallu CS, et al. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nature Genetics. 2016;48(6):607-616
  24. 24. Bailey MH, Tokheim C, Porta-Pardo E, Sengupta S, Bertrand D, Weerasinghe A, et al. Comprehensive characterization of cancer driver genes and mutations. Cell. 2018;173(2):371-385.e18
  25. 25. Brosh R, Rotter V. When mutants gain new powers: News from the mutant p53 field. Nature Reviews Cancer. 2009;9(10):701-713
  26. 26. Campling BG, El-Deiry WS. Clinical implication of p53 mutation in lung cancer. Molecular Biotechnology. 2003;24(2):141-156
  27. 27. Zhou G, Liu Z, Myers JN. TP53 mutations in head and neck squamous cell carcinoma and their impact on disease progression and treatment response. Journal of Cellular Biochemistry. 2016;117(12):2682-2692
  28. 28. Soussi T, Wiman KG. TP53: An oncogene in disguise. Cell Death and Differentiation. 2015;22(8):1239-1249
  29. 29. Barta JA, McMahon SB. Lung-enriched mutations in the p53 tumor suppressor: A paradigm for tissue-specific gain of oncogenic function. Molecular Cancer Research. 2019;17(1):3-9
  30. 30. Zhou G, Wang J, Zhao M, Xie TX, Tanaka N, Sano D, et al. Gain-of-function mutant p53 promotes cell growth and cancer cell metabolism via inhibition of AMPK activation. Molecular Cell. 2014;54(6):960-974
  31. 31. Singh S, Vaughan CA, Frum RA, Grossman SR, Deb S, Palit DS. Mutant p53 establishes targetable tumor dependency by promoting unscheduled replication. The Journal of Clinical Investigation. 2017;127(5):1839-1855
  32. 32. Becker-Santos DD, Thu KL, English JC, Pikor LA, Martinez VD, Zhang M, et al. Developmental transcription factor NFIB is a putative target of oncofetal miRNAs and is associated with tumour aggressiveness in lung adenocarcinoma. The Journal of Pathology. 2016;240(2):161-172
  33. 33. Denny SK, Yang D, Chuang CH, Brady JJ, Lim JS, Gruner BM, et al. Nfib promotes metastasis through a widespread increase in chromatin accessibility. Cell. 2016;166(2):328-342
  34. 34. Meder L, Konig K, Ozretic L, Schultheis AM, Ueckeroth F, Ade CP, et al. NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas. International Journal of Cancer. 2016;138(4):927-938
  35. 35. Licciulli S, Avila JL, Hanlon L, Troutman S, Cesaroni M, Kota S, et al. Notch1 is required for Kras-induced lung adenocarcinoma and controls tumor cell survival via p53. Cancer Research. 2013;73(19):5974-5984
  36. 36. Tong YH, Zhang B, Fan Y, Lin NM. Keap1-Nrf2 pathway: A promising target towards lung cancer prevention and therapeutics. Chronic Diseases and Translational Medicine. 2015;1(3):175-186
  37. 37. Menegon S, Columbano A, Giordano S. The dual roles of NRF2 in cancer. Trends in Molecular Medicine. 2016;22(7):578-593
  38. 38. Winslow MM, Dayton TL, Verhaak RG, Kim-Kiselak C, Snyder EL, Feldser DM, et al. Suppression of lung adenocarcinoma progression by Nkx2-1. Nature. 2011;473(7345):101-104
  39. 39. Chen PM, Wu TC, Cheng YW, Chen CY, Lee H. NKX2-1-mediated p53 expression modulates lung adenocarcinoma progression via modulating IKKbeta/NF-kappaB activation. Oncotarget. 2015;6(16):14274-14289
  40. 40. Kottakis F, Bardeesy N. LKB1-AMPK axis revisited. Cell Research. 2012;22(12):1617-1620
  41. 41. Saito RA, Watabe T, Horiguchi K, Kohyama T, Saitoh M, Nagase T, et al. Thyroid transcription factor-1 inhibits transforming growth factor-beta-mediated epithelial-to-mesenchymal transition in lung adenocarcinoma cells. Cancer Research. 2009;69(7):2783-2791
  42. 42. Pirozzi G, Tirino V, Camerlingo R, Franco R, La Rocca A, Liguori E, et al. Epithelial to mesenchymal transition by TGFbeta-1 induction increases stemness characteristics in primary non small cell lung cancer cell line. PLoS One. 2011;6(6):e21548
  43. 43. Peng Y, Cao J, Yao XY, Wang JX, Zhong MZ, Gan PP, et al. TUSC3 induces autophagy in human non-small cell lung cancer cells through Wnt/beta-catenin signaling. Oncotarget. 2017;8(32):52960-52974
  44. 44. Feng S, Zhai J, Lu D, Lin J, Dong X, Liu X, et al. TUSC3 accelerates cancer growth and induces epithelial-mesenchymal transition by upregulating claudin-1 in non-small-cell lung cancer cells. Experimental Cell Research. 2018;373(1-2):44-56
  45. 45. Huff V. Wilms’ tumours: About tumour suppressor genes, an oncogene and a chameleon gene. Nature Reviews Cancer. 2011;11(2):111-121
  46. 46. Wu C, Wang S, Xu C, Tyler A, Li X, Andersson C, et al. WT1 enhances proliferation and impedes apoptosis in KRAS mutant NSCLC via targeting cMyc. Cellular Physiology and Biochemistry. 2015;35(2):647-662
  47. 47. Kwok ZH, Roche V, Chew XH, Fadieieva A, Tay Y. A non-canonical tumor suppressive role for the long non-coding RNA MALAT1 in colon and breast cancers. International Journal of Cancer. 2018;143(3):668-678
  48. 48. Cui Y, Li G, Zhang X, Dai F, Zhang R. Increased MALAT1 expression contributes to cisplatin resistance in non-small cell lung cancer. Oncology Letters. 2018;16(4):4821-4828
  49. 49. Gong J, Zhang JP, Li B, Zeng C, You K, Chen MX, et al. MicroRNA-125b promotes apoptosis by regulating the expression of Mcl-1, Bcl-w and IL-6R. Oncogene. 2013;32(25):3071-3079
  50. 50. Li Q , Han Y, Wang C, Shan S, Wang Y, Zhang J, et al. MicroRNA-125b promotes tumor metastasis through targeting tumor protein 53-induced nuclear protein 1 in patients with non-small-cell lung cancer. Cancer Cell International. 2015;15:84
  51. 51. Chen X, Jiang Y, Huang Z, Li D, Cao M, Meng Q , et al. miRNA-378 reverses chemoresistance to cisplatin in lung adenocarcinoma cells by targeting secreted clusterin. Scientific Reports. 2016;6:19455
  52. 52. Chen LT, Xu SD, Xu H, Zhang JF, Ning JF, Wang SF. MicroRNA-378 is associated with non-small cell lung cancer brain metastasis by promoting cell migration, invasion and tumor angiogenesis. Medical Oncology. 2012;29(3):1673-1680
  53. 53. Vaughan CA, Singh S, Windle B, Sankala HM, Graves PR, Andrew Yeudall W, et al. p53 mutants induce transcription of NF-kappaB2 in H1299 cells through CBP and STAT binding on the NF-kappaB2 promoter and gain of function activity. Archives of Biochemistry and Biophysics. 2012;518(1):79-88
  54. 54. Yeudall WA, Vaughan CA, Miyazaki H, Ramamoorthy M, Choi MY, Chapman CG, et al. Gain-of-function mutant p53 upregulates CXC chemokines and enhances cell migration. Carcinogenesis. 2012;33(2):442-451
  55. 55. Amelio I, Mancini M, Petrova V, Cairns RA, Vikhreva P, Nicolai S, et al. p53 mutants cooperate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumor progression. Proceedings of the National Academy of Sciences of the United States of America. 2018;115(46):e10869-e10878
  56. 56. Mason S, Piper M, Gronostajski RM, Richards LJ. Nuclear factor one transcription factors in CNS development. Molecular Neurobiology. 2009;39(1):10-23
  57. 57. Gronostajski RM. Roles of the NFI/CTF gene family in transcription and development. Gene. 2000;249(1-2):31-45
  58. 58. Becker-Santos DD, Lonergan KM, Gronostajski RM, Lam WL. Nuclear factor I/B: A master regulator of cell differentiation with paradoxical roles in cancer. eBioMedicine. 2017;22:2-9
  59. 59. Yang D, Denny SK, Greenside PG, Chaikovsky AC, Brady JJ, Ouadah Y, et al. Intertumoral heterogeneity in SCLC is influenced by the cell type of origin. Cancer Discovery. 2018;8(10):1316-1331
  60. 60. Fane ME, Chhabra Y, Hollingsworth DEJ, Simmons JL, Spoerri L, Oh TG, et al. NFIB mediates BRN2 driven melanoma cell migration and invasion through regulation of EZH2 and MITF. eBioMedicine. 2017;16:63-75
  61. 61. Moon HG, Hwang KT, Kim JA, Kim HS, Lee MJ, Jung EM, et al. NFIB is a potential target for estrogen receptor-negative breast cancers. Molecular Oncology. 2011;5(6):538-544
  62. 62. Yang ZQ , Imoto I, Pimkhaokham A, Shimada Y, Sasaki K, Oka M, et al. A novel amplicon at 9p23-24 in squamous cell carcinoma of the esophagus that lies proximal to GASC1 and harbors NFIB. Japanese Journal of Cancer Research. 2001;92(4):423-428
  63. 63. Andreasen S, Persson M, Kiss K, Homoe P, Heegaard S, Stenman G. Genomic profiling of a combined large cell neuroendocrine carcinoma of the submandibular gland. Oncology Reports. 2016;35(4):2177-2182
  64. 64. Warner KA, Oklejas AE, Pearson AT, Zhang Z, Wu W, Divi V, et al. UM-HACC-2A: MYB-NFIB fusion-positive human adenoid cystic carcinoma cell line. Oral Oncology. 2018;87:21-28
  65. 65. Brill LB 2nd, Kanner WA, Fehr A, Andren Y, Moskaluk CA, Loning T, et al. Analysis of MYB expression and MYB-NFIB gene fusions in adenoid cystic carcinoma and other salivary neoplasms. Modern Pathology. 2011;24(9):1169-1176
  66. 66. Persson M, Andren Y, Mark J, Horlings HM, Persson F, Stenman G. Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(44):18740-18744
  67. 67. Geurts JM, Schoenmakers EF, Roijer E, Astrom AK, Stenman G, van de Ven WJ. Identification of NFIB as recurrent translocation partner gene of HMGIC in pleomorphic adenomas. Oncogene. 1998;16(7):865-872
  68. 68. Ho AS, Kannan K, Roy DM, Morris LG, Ganly I, Katabi N, et al. The mutational landscape of adenoid cystic carcinoma. Nature Genetics. 2013;45(7):791-798
  69. 69. Du L, Yamamoto S, Burnette BL, Huang D, Gao K, Jamshidi N, et al. Transcriptome profiling reveals novel gene expression signatures and regulating transcription factors of TGFbeta-induced epithelial-to-mesenchymal transition. Cancer Medicine. 2016;5(8):1962-1972
  70. 70. Steele-Perkins G, Plachez C, Butz KG, Yang G, Bachurski CJ, Kinsman SL, et al. The transcription factor gene Nfib is essential for both lung maturation and brain development. Molecular and Cellular Biology. 2005;25(2):685-698
  71. 71. Hori K, Sen A, Artavanis-Tsakonas S. Notch signaling at a glance. Journal of Cell Science. 2013;126(Pt 10):2135-2140
  72. 72. Lim JS, Ibaseta A, Fischer MM, Cancilla B, O'Young G, Cristea S, et al. Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer. Nature. 2017;545(7654):360-364
  73. 73. Ntziachristos P, Lim JS, Sage J, Aifantis I. From fly wings to targeted cancer therapies: A centennial for notch signaling. Cancer Cell. 2014;25(3):318-334
  74. 74. Sullivan JP, Spinola M, Dodge M, Raso MG, Behrens C, Gao B, et al. Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling. Cancer Research. 2010;70(23):9937-9948
  75. 75. Wang NJ, Sanborn Z, Arnett KL, Bayston LJ, Liao W, Proby CM, et al. Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(43):17761-17766
  76. 76. Zhang M, Biswas S, Qin X, Gong W, Deng W, Yu H. Does Notch play a tumor suppressor role across diverse squamous cell carcinomas? Cancer Medicine. 2016;5(8):2048-2060
  77. 77. Maeda Y, Dave V, Whitsett JA. Transcriptional control of lung morphogenesis. Physiological Reviews. 2007;87(1):219-244
  78. 78. Kwei KA, Kim YH, Girard L, Kao J, Pacyna-Gengelbach M, Salari K, et al. Genomic profiling identifies TITF1 as a lineage-specific oncogene amplified in lung cancer. Oncogene. 2008;27(25):3635-3640
  79. 79. Yamaguchi T, Hosono Y, Yanagisawa K, Takahashi T. NKX2-1/TTF-1: An enigmatic oncogene that functions as a double-edged sword for cancer cell survival and progression. Cancer Cell. 2013;23(6):718-723
  80. 80. Yamaguchi T, Yanagisawa K, Sugiyama R, Hosono Y, Shimada Y, Arima C, et al. NKX2-1/TITF1/TTF-1-induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma. Cancer Cell. 2012;21(3):348-361
  81. 81. Watanabe H, Francis JM, Woo MS, Etemad B, Lin W, Fries DF, et al. Integrated cistromic and expression analysis of amplified NKX2-1 in lung adenocarcinoma identifies LMO3 as a functional transcriptional target. Genes & Development. 2013;27(2):197-210
  82. 82. Berghmans T, Paesmans M, Mascaux C, Martin B, Meert AP, Haller A, et al. Thyroid transcription factor 1-a new prognostic factor in lung cancer: A meta-analysis. Annals of Oncology. 2006;17(11):1673-1676
  83. 83. Tan D, Li Q , Deeb G, Ramnath N, Slocum HK, Brooks J, et al. Thyroid transcription factor-1 expression prevalence and its clinical implications in non-small cell lung cancer: A high-throughput tissue microarray and immunohistochemistry study. Human Pathology. 2003;34(6):597-604
  84. 84. Maeda Y, Tsuchiya T, Hao H, Tompkins DH, Xu Y, Mucenski ML, et al. Kras(G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung. The Journal of Clinical Investigation. 2012;122(12):4388-4400
  85. 85. Snyder EL, Watanabe H, Magendantz M, Hoersch S, Chen TA, Wang DG, et al. Nkx2-1 represses a latent gastric differentiation program in lung adenocarcinoma. Molecular Cell. 2013;50(2):185-199
  86. 86. Motohashi H, Yamamoto M. Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends in Molecular Medicine. 2004;10(11):549-557
  87. 87. Hayes JD, McMahon M, Chowdhry S, Dinkova-Kostova AT. Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway. Antioxidants & Redox Signaling. 2010;13(11):1713-1748
  88. 88. Siegel D, Franklin WA, Ross D. Immunohistochemical detection of NAD(P)H:quinone oxidoreductase in human lung and lung tumors. Clinical Cancer Research. 1998;4(9):2065-2070
  89. 89. Frank R, Scheffler M, Merkelbach-Bruse S, Ihle MA, Kron A, Rauer M, et al. Clinical and pathological characteristics of KEAP1- and NFE2L2-mutated non-small cell lung carcinoma (NSCLC). Clinical Cancer Research. 2018;24(13):3087-3096
  90. 90. Carninci P, Kasukawa T, Katayama S, Gough J, Frith MC, Maeda N, et al. The transcriptional landscape of the mammalian genome. Science. 2005;309(5740):1559-1563
  91. 91. Esteller M. Non-coding RNAs in human disease. Nature Reviews Genetics. 2011;12(12):861-874
  92. 92. Zhang W, Bojorquez-Gomez A, Velez DO, Xu G, Sanchez KS, Shen JP, et al. A global transcriptional network connecting noncoding mutations to changes in tumor gene expression. Nature Genetics. 2018;50(4):613-620
  93. 93. Ji P, Diederichs S, Wang W, Boing S, Metzger R, Schneider PM, et al. MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene. 2003;22(39):8031-8041
  94. 94. Tripathi V, Ellis JD, Shen Z, Song DY, Pan Q , Watt AT, et al. The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Molecular Cell. 2010;39(6):925-938
  95. 95. Chen R, Liu Y, Zhuang H, Yang B, Hei K, Xiao M, et al. Quantitative proteomics reveals that long non-coding RNA MALAT1 interacts with DBC1 to regulate p53 acetylation. Nucleic Acids Research. 2017;45(17):9947-9959
  96. 96. Tang Y, Xiao G, Chen Y, Deng Y. LncRNA MALAT1 promotes migration and invasion of non-small-cell lung cancer by targeting miR-206 and activating Akt/mTOR signaling. Anti-Cancer Drugs. 2018;29(8):725-735
  97. 97. Xiang Y, Zhang Y, Tang Y, Li Q. MALAT1 modulates TGF-beta1-induced endothelial-to-mesenchymal transition through downregulation of miR-145. Cellular Physiology and Biochemistry. 2017;42(1):357-372
  98. 98. Han Y, Wu Z, Wu T, Huang Y, Cheng Z, Li X, et al. Tumor-suppressive function of long noncoding RNA MALAT1 in glioma cells by downregulation of MMP2 and inactivation of ERK/MAPK signaling. Cell Death & Disease. 2016;7:e2123
  99. 99. Zhao G, Su Z, Song D, Mao Y, Mao X. The long noncoding RNA MALAT1 regulates the lipopolysaccharide-induced inflammatory response through its interaction with NF-kappaB. FEBS Letters. 2016;590(17):2884-2895
  100. 100. Gao C, He Z, Li J, Li X, Bai Q , Zhang Z, et al. Specific long non-coding RNAs response to occupational PAHs exposure in coke oven workers. Toxicology Reports. 2016;3:160-166
  101. 101. Ma J, Wang P, Yao Y, Liu Y, Li Z, Liu X, et al. Knockdown of long non-coding RNA MALAT1 increases the blood-tumor barrier permeability by up-regulating miR-140. Biochimica et Biophysica Acta. 2016;1859(2):324-338
  102. 102. Gutschner T, Hammerle M, Diederichs S. MALAT1—A paradigm for long noncoding RNA function in cancer. Journal of Molecular Medicine. 2013;91(7):791-801
  103. 103. Guo F, Guo L, Li Y, Zhou Q , Li Z. MALAT1 is an oncogenic long non-coding RNA associated with tumor invasion in non-small cell lung cancer regulated by DNA methylation. International Journal of Clinical and Experimental Pathology. 2015;8(12):15903-15910
  104. 104. Cinegaglia NC, Andrade SC, Tokar T, Pinheiro M, Severino FE, Oliveira RA, et al. Integrative transcriptome analysis identifies deregulated microRNA-transcription factor networks in lung adenocarcinoma. Oncotarget. 2016;7(20):28920-28934
  105. 105. Svoronos AA, Engelman DM, Slack FJ. OncomiR or tumor suppressor? The duplicity of micrornas in cancer. Cancer Research. 2016;76(13):3666-3670
  106. 106. Ichimi T, Enokida H, Okuno Y, Kunimoto R, Chiyomaru T, Kawamoto K, et al. Identification of novel microRNA targets based on microRNA signatures in bladder cancer. International Journal of Cancer. 2009;125(2):345-352
  107. 107. Guan Y, Yao H, Zheng Z, Qiu G, Sun K. MiR-125b targets BCL3 and suppresses ovarian cancer proliferation. International Journal of Cancer. 2011;128(10):2274-2283
  108. 108. Pogue AI, Cui JG, Li YY, Zhao Y, Culicchia F, Lukiw WJ. Micro RNA-125b (miRNA-125b) function in astrogliosis and glial cell proliferation. Neuroscience Letters. 2010;476(1):18-22
  109. 109. Ozen M, Creighton CJ, Ozdemir M, Ittmann M. Widespread deregulation of microRNA expression in human prostate cancer. Oncogene. 2008;27(12):1788-1793
  110. 110. Wang X, Zhang Y, Fu Y, Zhang J, Yin L, Pu Y, et al. MicroRNA-125b may function as an oncogene in lung cancer cells. Molecular Medicine Reports. 2015;11(5):3880-3887
  111. 111. Ho CS, Yap SH, Phuah NH, In LL, Hasima N. MicroRNAs associated with tumour migration, invasion and angiogenic properties in A549 and SK-Lu1 human lung adenocarcinoma cells. Lung Cancer. 2014;83(2):154-162
  112. 112. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511(7511):543-550
  113. 113. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer genome landscapes. Science. 2013;339(6127):1546-1558

Written By

Mateus Camargo Barros-Filho, Florian Guisier, Leigha D. Rock, Daiana D. Becker-Santos, Adam P. Sage, Erin A. Marshall and Wan L. Lam

Submitted: January 15th, 2019 Reviewed: February 7th, 2019 Published: April 16th, 2019