Skip to main content
SpringerLink
Log in

Epigenetics and Biomarkers in Lung Cancer: Emerging Blood-Based Molecular Biomarkers for Detection and Monitoring

  • Reference work entry
Biomarkers in Cancer

  • 1951 Accesses

Abstract

Early detection and precise diagnosis of lung cancer are critical to select proper therapeutic treatments as early as possible. Toward this direction, the discovery and exploitation of novel innovative, non-invasive, and reliable tumor biomarkers are of vital importance. In this review, we present emerging blood-based molecular biomarkers that have been evaluated for the detection and monitoring of lung cancer. We specially focus on biomarkers based on a non-invasive liquid biopsy approach, such as circulating tumor cells (CTCs), circulating miRNAs, gene promoter methylation, and DNA mutations in cell-free circulating DNA.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Abbreviations

5-Aza-dC:

5-Aza-2′-deoxycytidine

AD:

Adenocarcinoma

ALK:

Anaplastic Lymphoma Kinase

cfDNA:

Cell-Free DNA

CTCs:

Circulating Tumor Cells

DFI:

Disease-Free Interval

EGFR:

Epidermal Growth Factor Receptor

EGFR-TKIs:

EGFR Tyrosine Kinase Inhibitors

LCM:

Laser Cell Microdissection

miRNA:

MicroRNA

MSP:

Methylation-Specific PCR

NSCLC:

Non-small Cell Lung Cancer

OS:

Overall Survival

RT-qPCR:

Reverse Transcription Quantitative PCR

SCC:

Squamous Cell Carcinoma

SCLC:

Small-Cell Lung Cancer

References

  • Ahrendt SA, Chow JT, Xu LH, et al. Molecular detection of tumor cells in bronchoalveolar lavage fluid from patients with early stage lung cancer. J Natl Cancer Inst. 1999;91:332–9.

    Article  CAS  PubMed  Google Scholar 

  • Alix-Panabières C, Pantel K. Circulating tumor cells: liquid biopsy of cancer. Clin Chem. 2013;59:110–8.

    Article  PubMed  Google Scholar 

  • Anglim PP, Alonzo TA, Laird-Offringa IA. DNA methylation-based biomarkers for early detection of non-small cell lung cancer: an update. Mol Cancer. 2008;7:81.

    Article  PubMed  PubMed Central  Google Scholar 

  • Bagga S, Bracht J, Hunter S, et al. Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell. 2005;122:553–63.

    Article  CAS  PubMed  Google Scholar 

  • Bearzatto A, Conte D, Frattini M, et al. p16(INK4A) hypermethylation detected by fluorescent methylation-specific PCR in plasmas from non-small cell lung cancer. Clin Cancer Res. 2002;8:3782–7.

    CAS  PubMed  Google Scholar 

  • Begum S, Brait M, Dasgupta S, et al. An epigenetic marker panel for detection of lung cancer using cell-free serum DNA. Clin Cancer Res. 2011;17:4494–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Belinsky SA, Klinge DM, Dekker JD, et al. Gene promoter methylation in plasma and sputum increases with lung cancer risk. Clin Cancer Res. 2005;11:6505–11.

    Article  CAS  PubMed  Google Scholar 

  • Belinsky SA, Liechty KC, Gentry FD, et al. Promoter hypermethylation of multiple genes in sputum precedes lung cancer incidence in a high risk cohort. Cancer Res. 2006;66:3338–44.

    Article  CAS  PubMed  Google Scholar 

  • Belinsky SA, Grimes MJ, Casas E, et al. Predicting gene promoter methylation in non small cell lung cancer by evaluating sputum and serum. Br J Cancer. 2007;96:1278–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bianchi F, Nicassio F, Marzi M, et al. A serum circulating miRNA diagnostic test to identify asymptomatic high-risk individuals with early stage lung cancer. EMBO Mol Med. 2011;3:495–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boeri M, Verri C, Conte D, et al. MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proc Natl Acad Sci U S A. 2011;108:3713–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brock MV, Hooker CM, Ota-Machida E, et al. DNA methylation markers and early recurrence in stage I lung cancer. N Engl J Med. 2008;358:1118–28.

    Article  CAS  PubMed  Google Scholar 

  • Buchen L. Missing the mark. Nature. 2011;471:428–32.

    Article  CAS  PubMed  Google Scholar 

  • Cardarella S, Ogino A, Nishino M, Butaney M, Shen J, Lydon C, et al. Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. Clin Cancer Res. 2013;19:4532–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carmona FJ, Esteller M. DNA methylation in early neoplasia. Cancer Biomark. 2011;9:101–11.

    Google Scholar 

  • Chen X, Ba Y, Ma L, et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 2008;18:997–1006.

    Article  CAS  PubMed  Google Scholar 

  • Chen X, Hu Z, Wang W, et al. Identification of ten serum microRNAs from a genome-wide serum microRNA expression profile as novel noninvasive biomarkers for nonsmall cell lung cancer diagnosis. Int J Cancer. 2012;130:1620–8.

    Article  CAS  PubMed  Google Scholar 

  • Crowley E, Di Nicolantonio F, Loupakis F, et al. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013;10:472–84.

    Article  CAS  PubMed  Google Scholar 

  • Cui EH, Li HJ, Hua F, et al. Serum microRNA 125b as a diagnostic or prognostic biomarker for advanced NSCLC patients receiving cisplatin-based chemotherapy. Acta Pharmacol Sin. 2013;34:309–13.

    Article  CAS  PubMed  Google Scholar 

  • Damman R, Strunnikova M, Schagdarsurengin U, et al. CpG island methylation and expression of tumor-associated genes in lung carcinoma. Eur J Cancer. 2005;41:1223–36.

    Article  Google Scholar 

  • Daskalos A, Nikolaidis G, Xinarianos G, et al. Hypomethylation of retrotransposable elements correlates with genomic instability in non-small cell lung cancer. Int J Cancer. 2009;124:81–7.

    Article  CAS  PubMed  Google Scholar 

  • Diamandis EP. Cancer biomarkers: can we turn recent failures into success? J Natl Cancer Inst. 2010;102:1462–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Diamandis EP, Bast RC, Lopez-Otín C. Conquering cancer in our lifetime: new diagnostic and therapeutic trends. Clin Chem. 2013;59:1–3.

    Article  CAS  PubMed  Google Scholar 

  • Dietrich D, Kneip C, Raji O, et al. Performance evaluation of the DNA methylation biomarker SHOX2 for the aid in diagnosis of lung cancer based on the analysis of bronchial aspirates. Int J Oncol. 2012;40:825–32.

    CAS  PubMed  Google Scholar 

  • Duffy MJ, Crown J. Companion biomarkers: paving the pathway to personalized treatment for cancer. Clin Chem. 2013;59:1447–56.

    Article  CAS  PubMed  Google Scholar 

  • Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358:1148–59.

    Article  CAS  PubMed  Google Scholar 

  • Esteller M, Sanchez-Cespedes M, Rosell R, et al. Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from non-small cell lung cancer patients. Cancer Res. 1999;59:67–70.

    CAS  PubMed  Google Scholar 

  • Fischer JR, Ohnmacht N, Rieger N, et al. Prognostic significance of RASSF1A promoter methylation on survival of non-small cell lung cancer patients treated with gemcitabine. Lung Cancer. 2007;56:115–23.

    Article  PubMed  Google Scholar 

  • Gainor JF, Varghese AM, Ou SH, Kabraji S, Awad MM, Katayama R, et al. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res. 2013;19:4273–81.

    Article  CAS  PubMed  Google Scholar 

  • Gao W, Lu X, Liu L, et al. MiRNA-21: a biomarker predictive for platinum-based adjuvant chemotherapy response in patients with non-small cell lung cancer. Cancer Biol Ther. 2012;13:330–40.

    Article  CAS  PubMed  Google Scholar 

  • Gormally E, Caboux E, Vineis P, et al. Circulating free DNA in plasma or serum as biomarker of carcinogenesis: practical aspects and biological significance. Mutat Res. 2007;635:105–17.

    Article  CAS  PubMed  Google Scholar 

  • Hanash SM, Baik CS, Kallioniemi O. Emerging molecular biomarkers–blood-based strategies to detect and monitor cancer. Nat Rev Clin Oncol. 2011;8:142–50.

    Article  PubMed  Google Scholar 

  • Hennessey PT, Sanford T, Choudhary A, et al. Serum microRNA biomarkers for detection of non-small cell lung cancer. PLoS One. 2012;7:e32307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herman JG, Baylin SB, Brock MV, Rudin CM. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 2011;1(7):598–607.

    Article  PubMed  PubMed Central  Google Scholar 

  • Heyn H, Esteller M. DNA methylation profiling in the clinic: applications and challenges. Nat Rev Genet. 2012;13:679–92.

    Article  CAS  PubMed  Google Scholar 

  • Hsu HS, Chen TP, Wen CK, et al. Multiple genetic and epigenetic biomarkers for lung cancer detection in cytologically negative sputum and a nested case–control study for risk assessment. J Pathol. 2007;213:412–9.

    Article  CAS  PubMed  Google Scholar 

  • Hu Z, Chen X, Zhao Y, et al. Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small-cell lung cancer. J Clin Oncol. 2010;28:1721–6.

    Article  PubMed  Google Scholar 

  • Hui A, How C, Ito E, et al. Micro-RNAs as diagnostic or prognostic markers in human epithelial malignancies. BMC Cancer. 2011;11:500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iorio MV, Croce CM. MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med. 2012;4:143–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Juergens RA, Wrangle J, Vendetti FP, et al, Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 2011;1(7):598–607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Keller A, Leidinger P, Gislefoss R, et al. Stable serum miRNA profiles as potential tool for non-invasive lung cancer diagnosis. RNA Biol. 2011;8:506–16.

    Article  CAS  PubMed  Google Scholar 

  • Kim DS, Cha SI, Lee JH, et al. Aberrant DNA methylation profiles of non-small cell lung cancers in a Korean population. Lung Cancer. 2007;58:1–6.

    Article  PubMed  Google Scholar 

  • Kneip C, Scmhidt B, Seegenbarth A, et al. SHOX2 DNA methylation is a biomarker for the diagnosis of lung cancer in plasma. J Thorac Surg. 2011;6:1632.

    Google Scholar 

  • Le HB, Zhu WY, Chen DD, et al. Evaluation of dynamic change of serum miR-21 and miR-24 in pre- and post-operative lung carcinoma patients. Med Oncol. 2012;29:3190–7.

    Article  CAS  PubMed  Google Scholar 

  • Lee JA, Bubendorf L, Stahel R, Peters S. Testing for anaplastic lymphoma kinase rearrangement to target crizotinib therapy: oncology, pathology and health economic perspectives. Expert Rev Anticancer Ther. 2013;13:625–36.

    Article  CAS  PubMed  Google Scholar 

  • Lin Q, Mao W, Shu Y, et al. A cluster of specified microRNAs in peripheral blood as biomarkers for metastatic non-small-cell lung cancer by stem-loop RT-PCR. J Cancer Res Clin Oncol. 2012;138:85–93.

    Article  CAS  PubMed  Google Scholar 

  • Liu CG, Calin GA, Meloon B, et al. An oligonucleotide microchip for genome-wide microRNA profiling in human and mouse tissues. Proc Natl Acad Sci U S A. 2004;101:9740–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maheswaran S, Sequist LV, Nagrath S, et al. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med. 2008;359(4):366–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maia BM, Rocha RM, Calin GA. Clinical significance of the interaction between non-coding RNAs and the epigenetics machinery: challenges and opportunities in oncology. Epigenetics. 2013;9:75–80.

    Article  PubMed  PubMed Central  Google Scholar 

  • Markou A, Liang Y, Lianidou E. Prognostic, therapeutic and diagnostic potential of microRNAs in non-small cell lung cancer. Clin Chem Lab Med. 2011;49:1591–603.

    Article  CAS  PubMed  Google Scholar 

  • Markou A, Sourvinou I, Vorkas PA, et al. Clinical evaluation of microRNA expression profiling in non small cell lung cancer. Lung Cancer. 2013;81:388–96.

    Article  CAS  PubMed  Google Scholar 

  • Murtaza M, Dawson SJ, Tsui DW, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013;497:108–12.

    Article  CAS  PubMed  Google Scholar 

  • Nygaard AD, Garm Spindler KL, Pallisgaard N, et al. The prognostic value of KRAS mutated plasma DNA in advanced non-small cell lung cancer. Lung Cancer. 2013;79:312–7.

    Article  PubMed  Google Scholar 

  • Ong FS, Das K, Wang J, et al. Personalized medicine and pharmacogenetic biomarkers: progress in molecular oncology testing. Expert Rev Mol Diagn. 2012;12:593–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pailler E, Adam J, Barthélémy A, et al. Detection of circulating tumor cells harboring a unique ALK rearrangement in ALK-positive non-small-cell lung cancer. J Clin Oncol. 2013;31(18):2273–81.

    Article  PubMed  Google Scholar 

  • Palmisiano WA, Divine KK, Saccomano G, et al. Predicting lung cancer by detecting aberrant promoter methylation in sputum. Cancer Res. 2000;60:5954–8.

    Google Scholar 

  • Pavlou MP, Diamandis EP, Blasutig IM. The long journey of cancer biomarkers from the bench to the clinic. Clin Chem. 2013;59:147–57.

    Article  CAS  PubMed  Google Scholar 

  • Peters S, Taron M, Bubendorf L, Blackhall F, Stahel R. Treatment and detection of ALK-rearranged NSCLC. Lung Cancer. 2013;81:145–54.

    Article  PubMed  Google Scholar 

  • Ponomaryova AA, Rykova EY, Cherdyntseva NV, et al. Potentialities of aberrantly methylated circulating DNA for diagnostics and post-treatment follow-up of lung cancer patients. Lung Cancer. 2013;81:397–403.

    Article  PubMed  Google Scholar 

  • Saito K, Kawakami K, Matsumoto I, et al. Long interspersed nuclear element 1 hypomethylation is a marker of poor prognosis in stage IA non-small cell lung cancer. Clin Cancer Res. 2010;16:2418–26.

    Article  CAS  PubMed  Google Scholar 

  • Sakai K, Horiike A, Irwin DL, et al. Detection of epidermal growth factor receptor T790M mutation in plasma DNA from patients refractory to epidermal growth factor receptor tyrosine kinase inhibitor. Cancer Sci. 2013;104:1198–204.

    Article  CAS  PubMed  Google Scholar 

  • Schmidt B, Liebenberg V, Diethrich D, et al. SHOX2 DNA methylation is a biomarker for the diagnosis of lung cancer based on bronchial aspirates. BMC Cancer. 2010;3:600.

    Article  Google Scholar 

  • Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011;11:426–37.

    Article  CAS  PubMed  Google Scholar 

  • Shen J, Todd NW, Zhang H, et al. Plasma microRNAs as potential biomarkers for non-small-cell lung cancer. Lab Invest. 2011;91:579–87.

    Article  CAS  PubMed  Google Scholar 

  • Silva J, García V, Zaballos Á, et al. Vesicle-related microRNAs in plasma of nonsmall cell lung cancer patients and correlation with survival. Eur Respir J. 2011;37:617–23.

    Article  CAS  PubMed  Google Scholar 

  • Stenman UH. Validating serum markers for monitoring of cancer. Clin Chem. 2013;59:4–5.

    Article  CAS  PubMed  Google Scholar 

  • Tang D, Shen Y, Wang M, et al. Identification of plasma microRNAs as novel noninvasive biomarkers for early detection of lung cancer. Eur J Cancer Prev. 2013;22:540–8.

    Article  CAS  PubMed  Google Scholar 

  • Vallée A, Marcq M, Bizieux A, et al. Plasma is a better source of tumor-derived circulating cell-free DNA than serum for the detection of EGFR alterations in lung tumor patients. Lung Cancer. 2013;82:373–4.

    Article  PubMed  Google Scholar 

  • Van der Drift M, Prinsen C, Knuiman J, et al. Diagnosing peripheral lung cancer: the additional value of RASSF1A methylation and KRAS mutation analyses in washings in non diagnostic bronchoscopy. Chest. 2012;141:169–75.

    Article  PubMed  Google Scholar 

  • Vincent MD, Kuruvilla MS, Leighl NB, et al. Biomarkers that currently affect clinical practice: EGFR, ALK, MET, KRAS. Curr Oncol. 2012;19:S33–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Virmani AK, Rathi A, Zochbauer-Muller S, et al. Promoter methylation and silencing of the retinoic acid receptor-beta gene in lung carcinomas. J Natl Cancer Inst. 2000;92:1303–7.

    Article  CAS  PubMed  Google Scholar 

  • Volinia S, Calin GA, Liu CG, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A. 2006;103:2257–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang T, Nelson RA, Bogardus A, et al. Five-year lung cancer survival: which advanced stage non small cell lung cancer patients attain long term survival? Cancer. 2010;116:1518–25.

    Article  PubMed  Google Scholar 

  • Yang J, Shen Y, Liu B, et al. Promoter methylation of BRMS1 correlates with smoking history and poor survival in non small cell lung cancer patients. Lung Cancer. 2011;74:305–9.

    Article  PubMed  Google Scholar 

  • Yuxia M, Zhennan T, Wei Z. Circulating miR-125b is a novel biomarker for screening non-small-cell lung cancer and predicts poor prognosis. J Cancer Res Clin Oncol. 2012;138:2045–50.

    Article  PubMed  Google Scholar 

  • Zhang Y, Wang R, Song H, Huang G, Yi J, et al. Methylation of multiple genes as a candidate biomarker in non-small cell lung cancer. Cancer Lett. 2011;303:21–8.

    Article  CAS  PubMed  Google Scholar 

  • Zheng D, Haddadin S, Wang Y, et al. Plasma microRNAs as novel biomarkers for early detection of lung cancer. Int J Clin Exp Pathol. 2011;4:575–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu W, Liu X, He J, et al. Overexpression of members of the microRNA-183 family is a risk factor for lung cancer: a case control study. BMC Cancer. 2011;11:393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zöchbauer-Müller S. Genome-wide miRNA expression profiling identifies miR-9-3 and miR-193a as targets for DNA methylation in non-small cell lung cancers. Clin Cancer Res. 2012;18:1619–29.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Analysis of Circulating Tumor Cells Lab, Laboratory of Analytical Chemistry, Department of Chemistry, University of Athens, Athens, Greece

    Athina Markou, Ioanna Sourvinou, Ioanna Balkouranidou & Evi S. Lianidou

Authors
  1. Athina Markou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ioanna Sourvinou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ioanna Balkouranidou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Evi S. Lianidou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Evi S. Lianidou .

Editor information

Editors and Affiliations

  1. Faculty of Life Sciences & Medicine King’s College London, Department of Nutrition and Dietetics Division of Diabetes & Nutritional Scien, London, United Kingdom

    Victor R. Preedy

  2. Faculty of Science & Technology, Department of Biomedical Sciences, University of Westminster, London, United Kingdom

    Vinood B. Patel

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media Dordrecht

About this entry

Cite this entry

Markou, A., Sourvinou, I., Balkouranidou, I., Lianidou, E.S. (2015). Epigenetics and Biomarkers in Lung Cancer: Emerging Blood-Based Molecular Biomarkers for Detection and Monitoring. In: Preedy, V., Patel, V. (eds) Biomarkers in Cancer. Biomarkers in Disease: Methods, Discoveries and Applications. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7681-4_35

Download citation

Publish with us

Policies and ethics

Search

Navigation