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Gene Expression Profile of Primary Gastric Cancer: Towards the Prediction of Lymph Node Status

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Abstract

Background

The identification of gastric tumors associated with a higher risk of lymph node metastasis could help surgeons select patients who may benefit from extended lymph node dissection. The aim of this study was to screen the genome in the search of primary gastric cancer gene expression profiles that might predict lymph node status.

Methods

The gene expression profile was evaluated in frozen tumor samples obtained from 32 patients with primary gastric adenocarcinomas. The array consisted of a duplicated spot panel of 5,541 human genes. To classify node-positive (N+) and node-negative (N−) cases, a logistic regression model was fitted optimizing the Akaike Information Criteria after a stepwise gene selection. The accuracy was evaluated by means of leave-one-out cross validation.

Results

All patients underwent radical gastrectomy and extended lymphadenectomy. Of all the cases, 21 were N+ and 11 demonstrated no lymph node involvement (N−). After quality filtering, the analysis of variance selected a set of 136 genes potentially correlated with nodal involvement (P value <.05). Of these 136 genes, 5 were differentially expressed (adjusted P value <.05). After a stepwise gene selection, only three genes (Bik, aurora kinase B, eIF5A2) were retained in the logistic model, which could correctly predict lymph node status in 30 of 32 cases.

Conclusions

If our findings were confirmed, the identified gene pattern might be used to tailor the extent of lymph node dissection on a single patient basis.

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References

  1. Dicken BJ, Bigam DL, Cass C, et al. Gastric adenocarcinoma: review and considerations for future directions. Ann Surg 2005; 241(1):27–39

    PubMed  Google Scholar 

  2. Hohenberger P, Gretschel S. Gastric cancer. Lancet 2003; 362(9380):305–15

    Article  PubMed  Google Scholar 

  3. Nitti D, Marchet A, Olivieri M, et al. Ratio between metastatic and examined lymph nodes is an independent prognostic factor after D2 resection for gastric cancer: analysis of a large European monoinstitutional experience. Ann Surg Oncol 2003; 10(9):1077–85

    Article  PubMed  Google Scholar 

  4. Jansen EP, Boot H, Verheij M, van de Velde CJ. Optimal locoregional treatment in gastric cancer. J Clin Oncol 2005; 23(20):4509–17

    Article  PubMed  Google Scholar 

  5. McCulloch P, Niita ME, Kazi H, Gama-Rodrigues JJ. Gastrectomy with extended lymphadenectomy for primary treatment of gastric cancer. Br J Surg 2005; 92(1):5–13

    Article  PubMed  CAS  Google Scholar 

  6. Javaid G, Shah OJ, Dar MA, et al. Role of endoscopic ultrasonography in preoperative staging of gastric carcinoma. ANZ J Surg 2004; 74(3):108–11

    Article  PubMed  Google Scholar 

  7. Kim HJ, Kim AY, Oh ST, et al. Gastric cancer staging at multi-detector row CT gastrography: comparison of transverse and volumetric CT scanning. Radiology 2005; 236(3):879–85

    PubMed  Google Scholar 

  8. Kim MC, Kim HH, Jung GJ, et al. Lymphatic mapping and sentinel node biopsy using 99mTc tin colloid in gastric cancer. Ann Surg 2004; 239(3):383–7

    Article  PubMed  Google Scholar 

  9. Ajisaka H, Miwa K. Micrometastases in sentinel nodes of gastric cancer. Br J Cancer 2003; 89(4):676–80

    Article  PubMed  CAS  Google Scholar 

  10. Ryu KW, Lee JH, Kim HS, et al. Prediction of lymph nodes metastasis by sentinel node biopsy in gastric cancer. Eur J Surg Oncol 2003; 29(10):895–99

    Article  PubMed  CAS  Google Scholar 

  11. Ludwig JA, Weinstein JN. Biomarkers in cancer staging, prognosis and treatment selection. Nat Rev Cancer 2005; 5(11):845–56

    Article  PubMed  CAS  Google Scholar 

  12. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med 2004; 10(8):789–99

    Article  PubMed  CAS  Google Scholar 

  13. Songun I, Litvinov SV, van de Velde CJ, et al. Loss of Ep-CAM (CO17–1A) expression predicts survival in patients with gastric cancer. Br J Cancer 2005; 92(9):1767–72

    Article  PubMed  CAS  Google Scholar 

  14. Scartozzi M, Galizia E, Freddari F, et al. Molecular biology of sporadic gastric cancer: prognostic indicators and novel therapeutic approaches. Cancer Treat Rev 2004; 30(5):451–9

    Article  PubMed  CAS  Google Scholar 

  15. Nitti D, Belluco C, Mammano E, et al. Low level of p27(Kip1) protein expression in gastric adenocarcinoma is associated with disease progression and poor outcome. J Surg Oncol 2002; 81(4):167–75; discussion 175–6

    Article  PubMed  Google Scholar 

  16. Wang CS, Lin KH, Chen SL, et al. Overexpression of SPARC gene in human gastric carcinoma and its clinic-pathologic significance. Br J Cancer 2004; 91(11):1924–30

    Article  PubMed  CAS  Google Scholar 

  17. Fan Z, Li J, Dong B, Huang X. Expression of Cdx2 and hepatocyte antigen in gastric carcinoma: correlation with histologic type and implications for prognosis. Clin Cancer Res 2005; 11(17):6162–70

    Article  PubMed  CAS  Google Scholar 

  18. Juttner S, Wissmann C, Jons T, et al. Vascular endothelial growth factor-D and its receptor VEGFR-3: two novel independent prognostic markers in gastric adenocarcinoma. J Clin Oncol 2006; 24(2):228–40

    Article  PubMed  CAS  Google Scholar 

  19. Wang JY, Hsieh JS, Chen CC, et al. Alterations of APC, c-met, and p53 genes in tumor tissue and serum of patients with gastric cancers. J Surg Res 2004; 120(2):242–8

    Article  PubMed  CAS  Google Scholar 

  20. Mocellin S, Provenzano M, Rossi CR, et al. DNA array-based gene profiling: from surgical specimen to the molecular portrait of cancer. Ann Surg 2005; 241(1):16–26

    PubMed  Google Scholar 

  21. Chen CN, Lin JJ, Chen JJ, et al. Gene expression profile predicts patient survival of gastric cancer after surgical resection. J Clin Oncol 2005; 23(29):7286–95

    Article  PubMed  CAS  Google Scholar 

  22. Teramoto K, Tada M, Tamoto E, et al. Prediction of lymphatic invasion/lymph node metastasis, recurrence, and survival in patients with gastric cancer by cDNA array-based expression profiling. J Surg Res 2005; 124(2):225–36

    Article  PubMed  CAS  Google Scholar 

  23. Weiss MM, Kuipers EJ, Postma C, et al. Genomic profiling of gastric cancer predicts lymph node status and survival. Oncogene 2003; 22(12):1872–79

    Article  PubMed  CAS  Google Scholar 

  24. D’Arrigo A, Belluco C, Ambrosi A, et al. Metastatic transcriptional pattern revealed by gene expression profiling in primary colorectal carcinoma. Int J Cancer 2005; 115(2):256–62

    Article  PubMed  CAS  Google Scholar 

  25. Reiner A, Yekutieli D, Benjamini Y. Identifying differentially expressed genes using false discovery rate controlling procedures. Bioinformatics 2003; 19(3):368–75

    Article  PubMed  CAS  Google Scholar 

  26. Dettling M, Buhlmann P. Boosting for tumor classification with gene expression data. Bioinformatics 2003; 19(9):1061–69

    Article  PubMed  CAS  Google Scholar 

  27. Hartgrink HH, van de Velde CJ. Status of extended lymph node dissection: locoregional control is the only way to survive gastric cancer. J Surg Oncol 2005; 90(3):153–65

    Article  PubMed  Google Scholar 

  28. Brennan MF. Current status of surgery for gastric cancer: a review. Gastric Cancer 2005; 8(2):64–70

    Article  PubMed  Google Scholar 

  29. Wu CW, Hsiung CA, Lo SS, et al. Stage migration influences on stage-specific survival comparison between D1 and D3 gastric cancer surgeries. Eur J Surg Oncol 2005; 31(2):153–7

    Article  PubMed  CAS  Google Scholar 

  30. Kazanietz MG. Targeting protein kinase C and “non-kinase” phorbol ester receptors: emerging concepts and therapeutic implications. Biochim Biophys Acta 2005; 1754(1–2):296–304

    PubMed  CAS  Google Scholar 

  31. Levy P, Vidaud D, Leroy K, et al. Molecular profiling of malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1, based on large-scale real-time RT-PCR. Mol Cancer 2004; 3:20

    Article  PubMed  CAS  Google Scholar 

  32. Nottage M, Siu LL. Rationale for Ras and raf-kinase as a target for cancer therapeutics. Curr Pharm Des 2002; 8(25):2231–42

    Article  PubMed  CAS  Google Scholar 

  33. Kasper M, Regl G, Frischauf AM, Aberger F. GLI transcription factors: Mediators of oncogenic Hedgehog signalling. Eur J Cancer 2006; 42(4):437–45

    Article  PubMed  CAS  Google Scholar 

  34. Willis SN, Adams JM. Life in the balance: how BH3-only proteins induce apoptosis. Curr Opin Cell Biol 2005; 17(6):617–25

    Article  PubMed  CAS  Google Scholar 

  35. Keen N, Taylor S. Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer 2004; 4(12):927–936

    Article  PubMed  CAS  Google Scholar 

  36. Clement PM, Henderson CA, Jenkins ZA, et al. Identification and characterization of eukaryotic initiation factor 5A-2. Eur J Biochem 2003; 270(21):4254–63

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was in part supported by the AIRC Regional Grant 2005 and by the grant PRIN (MIUR) 2005.

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Authors and Affiliations

  1. Clinica Chirurgica II, Dipartimento di Scienze Oncologiche e Chirurgiche, Istituto Oncologico Veneto IRCCS and University of Padova, Padova, Italy

    Alberto Marchet MD, Simone Mocellin MD, Alessandro Ambrosi PhD, Enzo Mammano MD, Maura Digito PhD, Mario Lise MD & Donato Nitti MD

  2. Surgical Oncology, Centro di Riferimento Oncologico IRCCS, Aviano, Italy

    Claudio Belluco MD, Francesco De Marchi MD & Mario Lise MD

  3. University Centre of Statistics for the Biomedical Sciences, Vita-Salute San Raffaele University, Milan, Italy

    Alessandro Ambrosi PhD

  4. Research & Innovation (R&I) Company, Padova, Italy

    Alberta Leon PhD & Antonello D’Arrigo PhD

Authors
  1. Alberto Marchet MD
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  2. Simone Mocellin MD
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  3. Claudio Belluco MD
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  4. Alessandro Ambrosi PhD
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  5. Francesco De Marchi MD
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  6. Enzo Mammano MD
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  7. Maura Digito PhD
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  8. Alberta Leon PhD
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  9. Antonello D’Arrigo PhD
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  10. Mario Lise MD
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  11. Donato Nitti MD
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Corresponding author

Correspondence to Donato Nitti MD.

Additional information

Presented at the 59th Annual Cancer Symposium of the Society of Surgical Oncology, San Diego, California, 23–26 March 2006.

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Marchet, A., Mocellin, S., Belluco, C. et al. Gene Expression Profile of Primary Gastric Cancer: Towards the Prediction of Lymph Node Status. Ann Surg Oncol 14, 1058–1064 (2007). https://doi.org/10.1245/s10434-006-9090-0

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  • DOI: https://doi.org/10.1245/s10434-006-9090-0

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