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The quantification of HER2 and MYC gene fragments in cell-free plasma as putative biomarkers for gastric cancer diagnosis

  • Kyoung Un Park , Hee Eun Lee , Soo Kyung Nam , Kyung Han Nam , Do Joong Park , Hyung-Ho Kim , Woo Ho Kim and Hye Seung Lee EMAIL logo
Published/Copyright: March 26, 2014

Abstract

Background: This study aimed to investigate the significance of circulating HER2 and MYC gene fragments quantification in the diagnosis of gastric cancer.

Methods: Levels of HER2 and MYC genes were evaluated by fluorescence in situ hybridization and real-time PCR in 81 gastric cancer tissues, and by real-time PCR in 36 gastritis tissues. Real-time PCR for HER2 and MYC products was also performed on 184 plasma samples from 81 gastric cancers, eight gastric adenomas, 63 gastritis patients, and 32 healthy individuals.

Results:HER2/HBB and MYC/HBB ratios in tissue and cell-free plasma from gastric cancer patients were significantly higher than those of gastritis tissue and cancer-free individuals. An optimized cut-off value of plasma target gene to HBB ratio, used to differentiate cancer patients from cancer-free individuals, was evaluated using receiver operating characteristic (ROC) curves. Values of 2.0 were calculated for HER2 [area under the ROC curve (AUC), 0.760] and 2.725 for MYC (AUC, 0.767). A combination model of HER2 and MYC provided a better differentiation condition than that for HER2 or MYC only (AUC, 0.850). HER2/HBB ratios in plasma from gastric cancer patients correlated with MYC/HBB ratios.

Conclusions: Our findings suggest that the measurement of plasma HER2 and MYC gene levels could improve the screening of gastric cancer.


Corresponding author: Hye Seung Lee, MD, PhD, Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 463-707, South Korea, Phone: +82 31 7877714, Fax: +82 31 7874012, E-mail:
aKyoung Un Park and Hee Eun Lee contributed equally to this work.

Acknowledgments

This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology [2010-0023625].

Conflict of interest statement

Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article. Research support played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

References

1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69–90.10.3322/caac.20107Search in Google Scholar PubMed

2. Edge S, Bird DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC cancer staging manual, 7th ed. New York, NY: Springer, 2010.Search in Google Scholar

3. Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO Classification of tumours of the digestive system, 4th ed. Lyon, France: IARC, 2010.Search in Google Scholar

4. Gold P, Freedman SO. Specific carcinoembryonic antigens of the human digestive system. J Exp Med 1965;122:467–81.10.1084/jem.122.3.467Search in Google Scholar PubMed PubMed Central

5. Gold P, Freedman SO. Demonstration of tumor-specific antigens in human colonic carcinomata by immunological tolerance and absorption techniques. J Exp Med 1965;121:439–62.10.1084/jem.121.3.439Search in Google Scholar PubMed PubMed Central

6. Perkins GL, Slater ED, Sanders GK, Prichard JG. Serum tumor markers. Am Fam Physician 2003;68:1075–82.Search in Google Scholar

7. Stroun M, Anker P, Maurice P, Lyautey J, Lederrey C, Beljanski M. Neoplastic characteristics of the DNA found in the plasma of cancer patients. Oncology 1989;46:318–22.10.1159/000226740Search in Google Scholar PubMed

8. Sai S, Ichikawa D, Tomita H, Ikoma D, Tani N, Ikoma H, et al. Quantification of plasma cell-free DNA in patients with gastric cancer. Anticancer Res 2007;27:2747–51.Search in Google Scholar

9. Usadel H, Brabender J, Danenberg KD, Jeronimo C, Harden S, Engles J, et al. Quantitative adenomatous polyposis coli promoter methylation analysis in tumor tissue, serum, and plasma DNA of patients with lung cancer. Cancer Res 2002;62:371–5.Search in Google Scholar

10. Diehl F, Li M, Dressman D, He Y, Shen D, Szabo S, et al. Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci USA 2005;102:16368–73.10.1073/pnas.0507904102Search in Google Scholar PubMed PubMed Central

11. Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer 2011;11:426–37.10.1038/nrc3066Search in Google Scholar PubMed

12. Lo YM, Chan WY, Ng EK, Chan LY, Lai PB, Tam JS, et al. Circulating Epstein-Barr virus DNA in the serum of patients with gastric carcinoma. Clin Cancer Res 2001;7:1856–9.Search in Google Scholar

13. Lee TL, Leung WK, Chan MW, Ng EK, Tong JH, Lo KW, et al. Detection of gene promoter hypermethylation in the tumor and serum of patients with gastric carcinoma. Clin Cancer Res 2002;8:1761–6.Search in Google Scholar

14. Nawroz H, Koch W, Anker P, Stroun M, Sidransky D. Microsatellite alterations in serum DNA of head and neck cancer patients. Nat Med 1996;2:1035–7.10.1038/nm0996-1035Search in Google Scholar PubMed

15. Castells A, Puig P, Mora J, Boadas J, Boix L, Urgell E, et al. K-ras mutations in DNA extracted from the plasma of patients with pancreatic carcinoma: diagnostic utility and prognostic significance. J Clin Oncol 1999;17:578–84.10.1200/JCO.1999.17.2.578Search in Google Scholar PubMed

16. Park KU, Lee HE, Park do J, Jung EJ, Song J, Kim HH, et al. MYC quantitation in cell-free plasma DNA by real-time PCR for gastric cancer diagnosis. Clin Chem Lab Med 2009;47:530–6.10.1515/CCLM.2009.126Search in Google Scholar PubMed

17. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2:127–37.10.1038/35052073Search in Google Scholar PubMed

18. Henriksson M, Luscher B. Proteins of the Myc network: essential regulators of cell growth and differentiation. Adv Cancer Res 1996;68:109–82.10.1016/S0065-230X(08)60353-XSearch in Google Scholar

19. Vita M, Henriksson M. The Myc oncoprotein as a therapeutic target for human cancer. Semin Cancer Biol 2006;16:318–30.10.1016/j.semcancer.2006.07.015Search in Google Scholar PubMed

20. Tse C, Brault D, Gligorov J, Antoine M, Neumann R, Lotz JP, et al. Evaluation of the quantitative analytical methods real-time PCR for HER-2 gene quantification and ELISA of serum HER-2 protein and comparison with fluorescence in situ hybridization and immunohistochemistry for determining HER-2 status in breast cancer patients. Clin Chem 2005;51:1093–101.10.1373/clinchem.2004.044305Search in Google Scholar PubMed

21. Kindich R, Florl AR, Jung V, Engers R, Muller M, Schulz WA, et al. Application of a modified real-time PCR technique for relative gene copy number quantification to the determination of the relationship between NKX3.1 loss and MYC gain in prostate cancer. Clin Chem 2005;51:649–52.10.1373/clinchem.2004.045013Search in Google Scholar PubMed

22. Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 1965;64:31–49.10.1111/apm.1965.64.1.31Search in Google Scholar PubMed

23. Lee HS, Lee HK, Kim HS, Yang HK, Kim WH. Tumour suppressor gene expression correlates with gastric cancer prognosis. J Pathol 2003;200:39–46.10.1002/path.1288Search in Google Scholar PubMed

24. Lee HE, Park KU, Yoo SB, Nam SK, Park do J, Kim HH, et al. Clinical significance of intratumoral HER2 heterogeneity in gastric cancer. Eur J Cancer 2013;49:1448–57.10.1016/j.ejca.2012.10.018Search in Google Scholar PubMed

25. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001;25:402–8.10.1006/meth.2001.1262Search in Google Scholar PubMed

26. Andolfo I, Petrosino G, Vecchione L, De Antonellis P, Capasso M, Montanaro D, et al. Detection of erbB2 copy number variations in plasma of patients with esophageal carcinoma. BMC Cancer 2011;11:126.10.1186/1471-2407-11-126Search in Google Scholar PubMed PubMed Central

27. Bechmann T, Andersen RF, Pallisgaard N, Madsen JS, Maae E, Jakobsen EH, et al. Plasma HER2 amplification in cell-free DNA during neoadjuvant chemotherapy in breast cancer. J Cancer Res Clin Oncol 2013;139:995–1003.10.1007/s00432-013-1413-5Search in Google Scholar PubMed

28. Galmozzi E, Casalini P, Iorio MV, Casati B, Olgiati C, Menard S. HER2 signaling enhances 5′UTR-mediated translation of c-Myc mRNA. J Cell Physiol 2004;200:82–8.10.1002/jcp.20012Search in Google Scholar PubMed

29. Neve RM, Sutterluty H, Pullen N, Lane HA, Daly JM, Krek W, et al. Effects of oncogenic ErbB2 on G1 cell cycle regulators in breast tumour cells. Oncogene 2000;19:1647–56.10.1038/sj.onc.1203470Search in Google Scholar PubMed

30. Park K, Kwak K, Kim J, Lim S, Han S. c-myc amplification is associated with HER2 amplification and closely linked with cell proliferation in tissue microarray of nonselected breast cancers. Hum Pathol 2005;36:634–9.10.1016/j.humpath.2005.04.016Search in Google Scholar PubMed

31. Takehana T, Kunitomo K, Kono K, Kitahara F, Iizuka H, Matsumoto Y, et al. Status of c-erbB-2 in gastric adenocarcinoma: a comparative study of immunohistochemistry, fluorescence in situ hybridization and enzyme-linked immuno-sorbent assay. Int J Cancer 2002;98:833–7.10.1002/ijc.10257Search in Google Scholar PubMed

32. Li X, Tu J, Zhang D, Xu Z, Yang G, Gong L, et al. The clinical significance of HER-2 and NF-kappaB expression in gastric cancer. Hepatogastroenterology 2013;60:1519–23.Search in Google Scholar

33. Dai SQ, An X, Wang F, Shao Q, Chen YC, Kong YN, et al. Serum HER 2 extracellular domain level is correlated with tissue HER 2 status in metastatic gastric or gastro-oesophageal junction adenocarcinoma. PLoS One 2013;8:e63458.10.1371/journal.pone.0063458Search in Google Scholar PubMed PubMed Central

Received: 2013-11-14
Accepted: 2014-1-21
Published Online: 2014-3-26
Published in Print: 2014-7-1

©2014 by Walter de Gruyter Berlin/Boston

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