Biomarkers for Lung Cancer

Sei Hoon Yang

doi:10.6058/jlc.2009.8.2.67

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Yang: Biomarkers for Lung Cancer

Original Article

J Lung Cancer 2009;8(2):67-77.

Published online: 10 January 2009

DOI: https://doi.org/10.6058/jlc.2009.8.2.67

Biomarkers for Lung Cancer

Sei Hoon Yang, M.D., Ph.D.

Department of Internal Medicine, Wonkwang University College of Medicine, Iksan, Korea

Address for correspondence Sei Hoon Yang, M.D., Ph.D. Department of Internal Medicine, Wonkwang University Hospital, 344-2, Shinyong-dong, Iksan 570-711, Korea Tel: 82-63-859-2582 Fax: 82-63-855-2025 E-mail: yshpul@wonkwang.ac.kr

This work was supported by Wonkwang Clinical Medical Research Center Grant in 2006 (WCMRC-2006–01).

This paper was reported to Lung Cancer Symposium 2009 in the Korean Academy for Tuberculosis and Respiratory Diseases.

Received 13 November 2009 Accepted 20 November 2009

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Over the last decade, intense interest has been focused on discovery of biomarkers and their clinical uses. Lung cancer biomarker discovery has particular eminence in this field due to its anticipated critical role in risk stratification, early detection, treatment selection, prognostication, and monitoring for recurrence of cancer. Significant progress has been made in our understanding of the steps involved in lung carcinogenesis and in development of novel technologies for biomarker discovery. The most active areas of research have been in promoter hypermethylation, proteomics, and genomics. Many investigators have adopted panels of serum biomarkers in an attempt to increase sensitivity. Markers for identification of lung cancer patients who may benefit from targeted therapy have been developed more rapidly. Development of targeted lung cancer therapy has engendered interest in markers for identification of optimal candidates for these therapies. Despite extensive study to date, few have turned out to be useful in the clinic. Even those used in the clinic do not show enough sensitivity, specificity, and reproducibility for general use. All biomarkers identified so far must be validated in larger clinical cohorts.

Keywords: Biological markers, Lung neoplasms

References

1. Kim YC, Kwon YS, Oh IJ, et al. National survey of lung cancer in Korea, 2005. J Lung Cancer. 2007; 6:67–73.

2. Mulshine JL, Sullivan DC. Clinical practice. Lung cancer screening. N Engl J Med. 2005; 352:2714–2720.

3. Dalton WS, Friend SH. Cancer biomarkers: an invitation to the table. Science. 2006; 312:1165–1168.

4. Biomarker Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001; 69:89–95.

5. Oh P, Li Y, Yu J, et al. Subtractive proteomic mapping of the endothelial surface in lung and solid tumours for tissue-specific therapy. Nature. 2004; 429:629–635.

6. Park HJ, Kim BG, Lee SJ, et al. Proteomic profiling of endothelial cells in human lung cancer. J Proteome Res. 2008; 7:1138–1150.

7. Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E. Collaborators from 14 Countries; World Health Organization. International histological classification of tumors. Histological typing of lung and pleural tumors. 3rd ed.New York: Sprin-ger-Verlag;1999.

8. Greenberg AK, Yee H, Rom WN. Preneoplastic lesions of the lung. Respir Res. 2002; 3:20.

9. Belinsky SA. Gene-promoter hypermethylation as a biomarker in lung cancer. Nat Rev Cancer. 2004; 4:707–717.

10. Brabender J, Metzger R, Salonga D, et al. Comprehensive expression analysis of retinoic acid receptors and retinoid X receptors in nonsmall cell lung cancer: implications for tumor development and prognosis. Carcinogenesis. 2005; 26:525–530.

11. Ardizzoni A, Cafferata MA, Tiseo M, et al. Decline in serum carcinoembryonic antigen and cytokeratin 19 fragment during chemotherapy predicts objective response and survival in patients with advanced nonsmall cell lung cancer. Cancer. 2006; 107:2842–2849.

12. Okada M, Nishio W, Sakamoto T, et al. Prognostic significance of perioperative serum carcinoembryonic antigen in nonsmall cell lung cancer: analysis of 1,000 consecutive resections for clinical stage I disease. Ann Thorac Surg. 2004; 78:216–221.

13. Schneider J. Tumor markers in detection of lung cancer. Adv Clin Chem. 2006; 42:1–41.

14. Haam SJ, Kim GD, Cho SH, Lee DY. Clinical effectiveness of tumor markers (CEA, NSE, Cyfra 21–1) in completely resected nonsmall cell lung cancer. J Lung Cancer. 2006; 5:75–83.

15. Kulpa J, Wojcik E, Reinfuss M, Kolodziejski L. Carcinoembryonic antigen, squamous cell carcinoma antigen, CYFRA 21–1, and neuron-specific enolase in squamous cell lung cancer patients. Clin Chem. 2002; 48:1931–1937.

16. Ferrigno D, Buccheri G, Giordano C. Neuron-specific enolase is an effective tumour marker in nonsmall cell lung cancer (NSCLC). Lung Cancer. 2003; 41:311–320.

17. Pujol JL, Quantin X, Jacot W, Boher JM, Grenier J, Lamy PJ. Neuroendocrine and cytokeratin serum markers as prognostic determinants of small cell lung cancer. Lung Cancer. 2003; 39:131–138.

18. Molina R, Filella X, Auge JM. ProGRP: a new biomarker for small cell lung cancer. Clin Biochem. 2004; 37:505–511.

19. Siemes C, Visser LE, Coebergh JW, et al. C-reactive protein levels, variation in the C-reactive protein gene, and cancer risk: the Rotterdam Study. J Clin Oncol. 2006; 24:5216–5222.

20. Dziadziuszko R, Witta SE, Cappuzzo F, et al. Epidermal growth factor receptor messenger RNA expression, gene dosage, and gefitinib sensitivity in nonsmall cell lung cancer. Clin Cancer Res. 2006; 12:3078–3084.

21. Barak V, Goike H, Panaretakis KW, Einarsson R. Clinical utility of cytokeratins as tumor markers. Clin Biochem. 2004; 37:529–540.

22. Xue X, Zhu YM, Woll PJ. Circulating DNA and lung cancer. Ann N Y Acad Sci. 2006; 1075:154–164.

23. Jahr S, Hentze H, Englisch S, et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res. 2001; 61:1659–1665.

24. Chen HY, Yu SL, Chen CH, et al. A five-gene signature and clinical outcome in nonsmall-cell lung cancer. N Engl J Med. 2007; 356:11–20.

25. Sozzi G, Musso K, Ratcliffe C, Goldstraw P, Pierotti MA, Pastorino U. Detection of microsatellite alterations in plasma DNA of nonsmall cell lung cancer patients: a prospect for early diagnosis. Clin Cancer Res. 1999; 5:2689–2692.

26. Ludwig JA, Weinstein JN. Biomarkers in cancer staging, prognosis and treatment selection. Nat Rev Cancer. 2005; 5:845–856.

27. Brambilla C, Fievet F, Jeanmart M, et al. Early detection of lung cancer: role of biomarkers. Eur Respir J Suppl. 2003; 39:36s–44s.

28. Chung GT, Sundaresan V, Hasleton P, Rudd R, Taylor R, Rabbitts PH. Sequential molecular genetic changes in lung cancer development. Oncogene. 1995; 11:2591–2598.

29. Kishimoto Y, Sugio K, Hung JY, et al. Allele-specific loss in chromosome 9p loci in preneoplastic lesions accompanying nonsmall-cell lung cancers. J Natl Cancer Inst. 1995; 87:1224–1229.

30. Rodenhuis S, Slebos RJ. Clinical significance of ras oncogene activation in human lung cancer. Cancer Res. 1992; 52:2665S–2669S.

31. Sugio K, Ishida T, Yokoyama H, Inoue T, Sugimachi K, Sasazuki T. Ras gene mutations as a prognostic marker in adenocarcinoma of the human lung without lymph node metastasis. Cancer Res. 1992; 52:2903–2906.

32. Brambilla E, Gazzeri S, Lantuejoul S, et al. p53 mutant immunophenotype and deregulation of p53 transcription pathway (Bcl2, Bax, and Waf1) in precursor bronchial lesions of lung cancer. Clin Cancer Res. 1998; 4:1609–1618.

33. Gazzeri S, Brambilla E, Caron de Fromentel C, et al. p53 genetic abnormalities and myc activation in human lung carcinoma. Int J Cancer. 1994; 58:24–32.

34. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997; 88:323–331.

35. Aviel-Ronen S, Blackhall FH, Shepherd FA, Tsao MS. K-ras mutations in nonsmall-cell lung carcinoma: a review. Clin Lung Cancer. 2006; 8:30–38.

36. Belinsky SA, Nikula KJ, Palmisano WA, et al. Aberrant methylation of p16 (INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. Proc Natl Acad Sci U S A. 1998; 95:11891–11896.

37. Chaussade L, Eymin B, Brambilla E, Gazzeri S. Expression of p15 and p15.5 products in neuroendocrine lung tumours: relationship with p15 (INK4b) methylation status. Oncogene. 2001; 20:6587–6596.

38. Esteller M, Sanchez-Cespedes M, Rosell R, Sidransky D, Baylin SB, Herman JG. Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from nonsmall cell lung cancer patients. Cancer Res. 1999; 59:67–70.

39. Kurakawa E, Shimamoto T, Utsumi K, Hirano T, Kato H, Ohyashiki K. Hypermethylation of p16 (INK4a) and p15 (INK4b) genes in nonsmall cell lung cancer. Int J Oncol. 2001; 19:277–281.

40. Palmisano WA, Divine KK, Saccomanno G, et al. Predicting lung cancer by detecting aberrant promoter methylation in sputum. Cancer Res. 2000; 60:5954–5958.

41. 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; 92:1303–1307.

42. Zochbauer-Muller S, Fong KM, Virmani AK, Geradts J, Gazdar AF, Minna JD. Aberrant promoter methylation of multiple genes in nonsmall cell lung cancers. Cancer Res. 2001; 61:249–255.

43. Usadel H, Brabender J, Danenberg KD, et al. Quantitative adenomatous polyposis coli promoter methylation analysis in tumor tissue, serum, and plasma DNA of patients with lung cancer. Cancer Res. 2002; 62:371–375.

44. Ramirez JL, Sarries C, de Castro PL, et al. Methylation patterns and K-ras mutations in tumor and paired serum of resected nonsmall-cell lung cancer patients. Cancer Lett. 2003; 193:207–216.

45. Belinsky SA, Klinge DM, Dekker JD, et al. Gene promoter methylation in plasma and sputum increases with lung cancer risk. Clin Cancer Res. 2005; 11:6505–6511.

46. 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; 66:3338–3344.

47. Marsit CJ, Okpukpara C, Danaee H, Kelsey KT. Epigenetic silencing of the PRSS3 putative tumor suppressor gene in nonsmall cell lung cancer. Mol Carcinog. 2005; 44:146–150.

48. Yano M, Toyooka S, Tsukuda K, et al. Aberrant promoter methylation of human DAB2 interactive protein (hDAB2IP) gene in lung cancers. Int J Cancer. 2005; 113:59–66.

49. Zhang Z, Tan S, Zhang L. Prognostic value of apoptosis-associated speck-like protein containing a CARD gene promoter methylation in resectable nonsmall-cell lung cancer. Clin Lung Cancer. 2006; 8:62–65.

50. Maruyama R, Sugio K, Yoshino I, Maehara Y, Gazdar AF. Hypermethylation of FHIT as a prognostic marker in nonsmall cell lung carcinoma. Cancer. 2004; 100:1472–1477.

51. Kim JS, Kim JW, Han J, Shim YM, Park J, Kim DH. Cohypermethylation of p16 and FHIT promoters as a prognostic factor of recurrence in surgically resected stage I non-small cell lung cancer. Cancer Res. 2006; 66:4049–4054.

52. Grote HJ, Schmiemann V, Geddert H, et al. Methylation of RAS association domain family protein 1A as a biomarker of lung cancer. Cancer. 2006; 108:129–134.

53. Ehrich M, Field JK, Liloglou T, et al. Cytosine methylation profiles as a molecular marker in nonsmall cell lung cancer. Cancer Res. 2006; 66:10911–10918.

54. Lee SH, Kim YT, Sung SW, Kim JH. Correlation between aberrant promoter hypermethylation of CpG islands and the clinical outcome of nonsmall cell lung cancer after curative resection. J Lung Cancer. 2004; 3:77–85.

55. Yoon KA, Hwangbo B, Kim IJ, et al. Novel polymorphisms in the SUV39H2 histone methyltransferase and the risk of lung cancer. Carcinogenesis. 2006; 27:2217–2222.

56. Omenn GS. Strategies for plasma proteomic profiling of cancers. Proteomics. 2006; 6:5662–5673.

57. Rifai N, Gillette MA, Carr SA. Protein biomarker discovery and validation: the long and uncertain path to clinical utility. Nat Biotechnol. 2006; 24:971–983.

58. Miura N, Nakamura H, Sato R, et al. Clinical usefulness of serum telomerase reverse transcriptase (hTERT) mRNA and epidermal growth factor receptor (EGFR) mRNA as a novel tumor marker for lung cancer. Cancer Sci. 2006; 97:1366–1373.

59. Lin X, Gu J, Lu C, Spitz MR, Wu X. Expression of telomere-associated genes as prognostic markers for overall survival in patients with nonsmall cell lung cancer. Clin Cancer Res. 2006; 12:5720–5725.

60. El-Zein RA, Schabath MB, Etzel CJ, Lopez MS, Franklin JD, Spitz MR. Cytokinesis-blocked micronucleus assay as a novel biomarker for lung cancer risk. Cancer Res. 2006; 66:6449–6456.

61. Jakupciak JP, Wang W, Markowitz ME, et al. Mitochondrial DNA as a cancer biomarker. J Mol Diagn. 2005; 7:258–267.

62. McCulloch M, Jezierski T, Broffman M, Hubbard A, Turner K, Janecki T. Diagnostic accuracy of canine scent detection in early- and late-stage lung and breast cancers. Integr Cancer Ther. 2006; 5:30–39.

63. Poli D, Carbognani P, Corradi M, et al. Exhaled volatile organic compounds in patients with nonsmall cell lung cancer: cross sectional and nested short-term follow-up study. Respir Res. 2005; 6:71.

64. Wang YC, Hsu HS, Chen TP, Chen JT. Molecular diagnostic markers for lung cancer in sputum and plasma. Ann N Y Acad Sci. 2006; 1075:179–184.

65. Greenberg AK, Lee MS. Biomarkers for lung cancer: clinical uses. Curr Opin Pulm Med. 2007; 13:249–255.

Tables

Table 1.

Potential Biomarkers from Specimens of Human Various Cancers

MGMT (methylguanine methyltransferase), hnRNP (heterogeneous nuclear ribonucleoprotein), LOH (loss of heterozygosity), FHIT (fragile histidine triad), TMS-1 (target of methylation inducing silencing), RASSF1A (ras association domain family 1A gene), DAPK (death-associated protein kinase), APC (adenomatous polyposis coli), hTERT (human telomerase catalytic subunit), CEA (carcinoembryonic antigen) NSE (neuron-specific enolase)

Sputum:

Mutations of K-ras and p53; epigenetic changes; methylayion of p16 and MGMT; overexpression of hnRNP A2/B1 and other members of hnRNP family

Circulating genes in plasma/serum:

Mutations of K-ras, p53 and β-tubulin genes; LOH of FHIT; promoter hypermethylation of TMS-1, RASSF1A, DAPK, APC genes; detection of hTERT mRNA; presence of elevated cell-free circulating DNA and RNA levels in cancer as compared with healthy controls and patients with benign diseases; detecting abnormal proteins/peptides, for example CEA and NSE

Autoantibodies in serum:

Detection of antibodies against p53: glycosylated annexins I and/or II; anti-p40; antineural and antinuclear antibodies; MUCI; livin and survivin; c-Myc and L-myc

Breath analysis:

Detection of volatile organic compounds (VOCs), mainly alkanes and aromatic compounds

Table 2.

Characteristics of the Ideal Tumor Marker

* Specific production by premalignant or malignant tissue early in the progression of disease

* Produced at detectable levels in all patients with a specific malignancy

* Expression in an organ site-specific manner

* Evidence of presence in bodily fluids obtained non-invasively or in easily accessible tissue

* Levels related quantitatively to tumor volume, biological behavior, or disease progression

* Relatively short half-life, reflecting temporal changes in tumor burden and response to therapy

* Existence of a standardized, reproducible, and validated objective and quantitative assay.

Table 3.

Protein-Based Biomarkers in Detection of Lung Cancer: Currently Available

	Diagnosis	Therapy monitoring	Prognosis monitoring	Ontology	Details
CEA	AdenoCA, LCLC (＞10 μ g/L)	AdenoCA, Advanced NSCLC	AdenoCA, NSCLC	Cellular component Cell membrane: lipid anchor Immunoglobulin superfamily	Use in combination with CYFRA. Often elevated in smokers.
CYFRA21–1	NSCLC, SCC (Sensitivity for NSCLC varies between 23 and 70%)	Advanced NSCLC	NSCLC, SCC	Structural constitutent of cytoskeleton	Often elevated in patients with benign lung diseases.
TPA	NSCLC, SCC	−	NSCLC		−
ProGRP	SCLC (＞200 ng/L=Highly suspicious) (Sensitivities for SCLC range 47∼86%)	SCLC	−	Neuropeptide hormone activity	Increased in renal failure and some benign lung diseases. Use in combination with NSE
NSE	SCLC (＞100 μ g/L=High probability) (Sensitivities for SCLC as high as 74%)	SCLC	SCLC	Phosphoglycerate dehydrogenase activity Subcellular location (cytoplasm)	Use in combination with ProGRP May correlates with short survival Increased in inflammatory diseases
Tumor M2-pyruvate kinase	AdenoCA (Sensitivities for SCLC range 50∼71%)	−	AdenoCA	Pyruvate kinase activity Glycolysis Cytoplasm	Increased in multiple malignant diseases and some inflammatory diseases

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

Table 4.

Gene-Based Biomarkers in Detection of Lung Cancer: Potential

Groups	Types of genes
Chromosomal changes	Deletion of the short arm of chromosome 3 (3p)	27∼88% in circulating DNA of lung cancer
Hypermethylation	Serine protease family member-trypsinogen IV (PRSS3)	−
	Tissue inhibitor of metalloproteinase (TIMP)-3	−
	Death associated protein (DAP)-kinase	−
	P16, FHIT	Associated with an increased risk of lung cancer recurrence after therapy
Genetic changes	K-ras	20∼30% in circulating DNA of lung cancer
	p53	27% in circulating DNA of lung cancer

Table 5.

Protein-Based Biomarkers for the Detection of Lung Cancer: Potential

	Diagnosis	Ontology	Details
Serum amyloid A	Lung cancer	Lipid transporter activity	Elevated to 62.4 μ g/mL
		Acute phase response	(2 μ g/mL in healthy control)
		Immune cell chemotaxis
		Extracellular region
Haptoglobin-α 2	AdenoCA	Serine-type endopeptidase activity	−
		Defense response
		Proteolysis
		Extracellular region
APOA1	AdenoCA	Lipid transporter activity	Apolipoprotein A-1 fragment:
		Lipase inhibitor activity	downregulated in cancer pateients
		Cholesterol efflux, homeostasis, metabolic
		process, transport
		Extracellular region
KLKB1	AdenoCA	Peptidase activity	17∼18 kDa fragment of plasma
		Proteolysis	kallikrein B1

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