J Korean Surg Soc.  2012 May;82(5):288-295.

Clinical significance of insulin-like growth factor gene polymorphisms with survival in patients with gastrointestinal stromal tumors

Affiliations
  • 1Department of Surgery, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Daegu, Korea.
  • 2Department of Pathology, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Daegu, Korea.
  • 3Department of Oncology/Hematology, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Daegu, Korea. bwkang@knu.ac.kr
  • 4Department of Preventive Medicine, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Daegu, Korea.

Abstract

PURPOSE
Insulin-like growth factors (IGFs) regulate a wide range of biological functions including cell proliferation, differentiation, and apoptosis through paracrine and autocrine mechanisms. Accordingly, the present study analyzed polymorphisms of IGF genes and their impact on the prognosis for patients with gastrointestinal stromal tumors (GISTs).
METHODS
Two hundred-thirteen consecutive patients with GISTs who underwent curative surgery from 5 medical centers were enrolled in the present study. The genomic DNA was extracted from paraffin-embedded tumor tissue, and four IGF-1 (+2995C/A, +533C/T, IVS2-16540A/G, Ex4-177G/C) and one IGF-2 (IVS1+1280A/G) gene polymorphisms were determined using a Sequenom MassARRAY system.
RESULTS
With a median follow-up of 18.4 months, the estimated 5-year relapse-free survival and overall survival rates were 69.9% and 86.7%, respectively. In a multivariate analysis including age, gender, primary site of disease, pathology, and risk stratification, no significant association was observed between the polymorphism of the IGF-1 and IGF-2 genes and survival.
CONCLUSION
None of the five IGF-1 and IGF-2 gene polymorphisms investigated in this study was found to be an independent prognostic marker for Korean patients with surgically resected GIST. However, further studies on a larger scale are warranted to clarify the role of IGF-1 and IGF-2 gene polymorphisms as a prognostic biomarker for GIST patients.

Keyword

Gastrointestinal stromal tumor; Insulin-like growth factor; Single nucleotide polymorphism; Prognosis

MeSH Terms

Apoptosis
Cell Proliferation
DNA
Follow-Up Studies
Gastrointestinal Stromal Tumors
Humans
Insulin-Like Growth Factor I
Insulin-Like Growth Factor II
Multivariate Analysis
Polymorphism, Single Nucleotide
Prognosis
Somatomedins
Survival Rate
DNA
Insulin-Like Growth Factor I
Insulin-Like Growth Factor II
Somatomedins

Figure

  • Fig. 1 Survival curves for all patients.

  • Fig. 2 Survival curves of overall survival (A) and relapse-free survival (B) according to National Institutes of Health consensus classification system.


Reference

1. Furstenberger G, Senn HJ. Insulin-like growth factors and cancer. Lancet Oncol. 2002. 3:298–302.
2. Werner H, Le Roith D. New concepts in regulation and function of the insulin-like growth factors: implications for understanding normal growth and neoplasia. Cell Mol Life Sci. 2000. 57:932–942.
3. Giovannucci E. Insulin, insulin-like growth factors and colon cancer: a review of the evidence. J Nutr. 2001. 131:11 Suppl. 3109S–3120S.
4. Kim WY, Jin Q, Oh SH, Kim ES, Yang YJ, Lee DH, et al. Elevated epithelial insulin-like growth factor expression is a risk factor for lung cancer development. Cancer Res. 2009. 69:7439–7448.
5. Ryan PD, Goss PE. The emerging role of the insulin-like growth factor pathway as a therapeutic target in cancer. Oncologist. 2008. 13:16–24.
6. Van der Ven LT, Roholl PJ, Gloudemans T, Van Buul-Offers SC, Welters MJ, Bladergroen BA, et al. Expression of insulin-like growth factors (IGFs), their receptors and IGF binding protein-3 in normal, benign and malignant smooth muscle tissues. Br J Cancer. 1997. 75:1631–1640.
7. Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol. 2002. 33:459–465.
8. Reichardt P, Reichardt A, Pink D. Molecular targeted therapy of gastrointestinal stromal tumors. Curr Cancer Drug Targets. 2011. 11:688–697.
9. Pantaleo MA, Astolfi A, Nannini M, Biasco G. The emerging role of insulin-like growth factor 1 receptor (IGF1r) in gastrointestinal stromal tumors (GISTs). J Transl Med. 2010. 8:117.
10. Braconi C, Bracci R, Bearzi I, Bianchi F, Sabato S, Mandolesi A, et al. Insulin-like growth factor (IGF) 1 and 2 help to predict disease outcome in GIST patients. Ann Oncol. 2008. 19:1293–1298.
11. Giovannucci E. Nutrition, insulin, insulin-like growth factors and cancer. Horm Metab Res. 2003. 35:694–704.
12. Al-Zahrani A, Sandhu MS, Luben RN, Thompson D, Baynes C, Pooley KA, et al. IGF1 and IGFBP3 tagging polymorphisms are associated with circulating levels of IGF1, IGFBP3 and risk of breast cancer. Hum Mol Genet. 2006. 15:1–10.
13. Wong HL, Koh WP, Probst-Hensch NM, Van den Berg D, Yu MC, Ingles SA. Insulin-like growth factor-1 promoter polymorphisms and colorectal cancer: a functional genomics approach. Gut. 2008. 57:1090–1096.
14. Suzuki H, Li Y, Dong X, Hassan MM, Abbruzzese JL, Li D. Effect of insulin-like growth factor gene polymorphisms alone or in interaction with diabetes on the risk of pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2008. 17:3467–3473.
15. Yuan HY, Chiou JJ, Tseng WH, Liu CH, Liu CK, Lin YJ, et al. FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization. Nucleic Acids Res. 2006. 34(Web Server issue):W635–W641.
16. Canzian F, McKay JD, Cleveland RJ, Dossus L, Biessy C, Rinaldi S, et al. Polymorphisms of genes coding for insulin-like growth factor 1 and its major binding proteins, circulating levels of IGF-I and IGFBP-3 and breast cancer risk: results from the EPIC study. Br J Cancer. 2006. 94:299–307.
17. Kim YJ, Yoon JH, Kim CY, Kim LH, Park BL, Shin HD, et al. IGF2 polymorphisms are associated with hepatitis B virus clearance and hepatocellular carcinoma. Biochem Biophys Res Commun. 2006. 346:38–44.
18. Patel AV, Cheng I, Canzian F, Le Marchand L, Thun MJ, Berg CD, et al. IGF-1, IGFBP-1, and IGFBP-3 polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the Breast and Prostate Cancer Cohort Consortium (BPC3). PLoS One. 2008. 3:e2578.
19. Tsuchiya N, Wang L, Suzuki H, Segawa T, Fukuda H, Narita S, et al. Impact of IGF-I and CYP19 gene polymorphisms on the survival of patients with metastatic prostate cancer. J Clin Oncol. 2006. 24:1982–1989.
20. Cho YY, Kim JG, Chae YS, Sohn SK, Kang BW, Moon JH, et al. No association of insulin-like growth factor gene polymorphisms with survival in patients with colorectal cancer. Cancer Res Treat. 2011. 43:189–194.
21. Vashist YK, Uzunoglu G, Cataldegirmen G, Kalinin V, Schurr P, Koenig AM, et al. Haeme oxygenase-1 promoter polymorphism is an independent prognostic marker of gastrointestinal stromal tumour. Histopathology. 2009. 54:303–308.
22. Lai MT, Chen RH, Tsai FJ, Wan L, Chen WC. Glutathione S-transferase M1 gene but not insulin-like growth factor-2 gene or epidermal growth factor gene is associated with prostate cancer. Urol Oncol. 2005. 23:225–229.
23. Ma J, Pollak MN, Giovannucci E, Chan JM, Tao Y, Hennekens CH, et al. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst. 1999. 91:620–625.
24. Janeway KA, Zhu MJ, Barretina J, Perez-Atayde A, Demetri GD, Fletcher JA. Strong expression of IGF1R in pediatric gastrointestinal stromal tumors without IGF1R genomic amplification. Int J Cancer. 2010. 127:2718–2722.
25. Tarn C, Rink L, Merkel E, Flieder D, Pathak H, Koumbi D, et al. Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors. Proc Natl Acad Sci U S A. 2008. 105:8387–8392.
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