Advertisement

Annals of Surgical Oncology

, Volume 23, Issue 13, pp 4238–4246 | Cite as

Increased RhoA Activity Predicts Worse Overall Survival in Patients Undergoing Surgical Resection for Lauren Diffuse-Type Gastric Adenocarcinoma

  • Kevin K. Chang
  • Soo-Jeong Cho
  • Changhwan Yoon
  • Jun Ho Lee
  • Do Joong Park
  • Sam S. YoonEmail author
Gastrointestinal Oncology

Abstract

Background

Several studies have reported a high rate of RHOA mutations in the Lauren diffuse-type gastric adenocarcinoma (GA) but not in intestinal-type GA. The aim of this study was to determine if RhoA activity is prognostic for overall survival (OS) in patients with resectable GA.

Methods

Retrospective review was performed on a prospective database of GA patients who underwent potentially curative resection between 2003 and 2012 at a single institution. Tissue microarrays were constructed from surgical specimens and analyzed for phosphorylated RhoA, a marker of inactive RhoA signaling. OS was estimated by the Kaplan–Meier method, and multivariate analysis was performed by Cox proportional hazards regression modeling.

Results

One hundred thirty-six patients with diffuse-type GA and 129 patients with intestinal-type GA were examined. Compared to intestinal-type GA, diffuse-type GA tumors were significantly associated with increased tumor size and advanced tumor, node, metastasis (TNM) classification system stage. In patients with diffuse-type GA, high RhoA activity was associated with significantly worse OS when compared to low RhoA activity (5-year OS 52.5 vs. 81.0 %, p = 0.017). This difference in OS was not observed in patients with intestinal-type GA (5-year OS 83.9 vs. 81.6 %, p = 0.766). On multivariate analysis of diffuse-type GA patients, high RhoA activity was an independent negative prognostic factor for OS (hazard ratio 2.38, 95 % confidence interval 1.07–5.28).

Conclusions

Increased RhoA activity is predictive of worse OS in patients with diffuse-type GA who undergo potentially curative surgical resection. Along with findings from genomic studies, these results suggest RhoA may be a novel therapeutic target in diffuse-type GA.

Keywords

Gastric Cancer Overall Survival Gastric Adenocarcinoma RhoA Activity Gastric Adenocarcinoma Cell Line 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgment

Funded in part through National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748.

Disclosure

The authors declare no conflict of interest.

Supplementary material

10434_2016_5357_MOESM1_ESM.docx (13 kb)
Supplementary material 1 (DOCX 13 kb)
10434_2016_5357_MOESM2_ESM.pptx (635 kb)
Supplementary material 2 (PPTX 635 kb)

References

  1. 1.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRefPubMedGoogle Scholar
  2. 2.
    Kumar V, Abbas AK, Aster JC. Robbins and Cotran pathologic basis of disease. 9th ed. 2015.Google Scholar
  3. 3.
    Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol. 2006;12:354–62.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Pozzo C, Barone C. Is there an optimal chemotherapy regimen for the treatment of advanced gastric cancer that will provide a platform for the introduction of new biological agents? Oncologist. 2008;13:794–806.CrossRefPubMedGoogle Scholar
  5. 5.
    Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36–46.CrossRefPubMedGoogle Scholar
  6. 6.
    Cervantes A, Roda D, Tarazona N, Rosello S, Perez-Fidalgo JA. Current questions for the treatment of advanced gastric cancer. Cancer Treat Rev. 2013;39:60–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Lynch HT, Grady W, Suriano G, Huntsman D. Gastric cancer: new genetic developments. J Surg Oncol. 2005;90:114–33.CrossRefPubMedGoogle Scholar
  8. 8.
    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.PubMedGoogle Scholar
  9. 9.
    Bosman FT. World Health Organization; International Agency for Research on Cancer. WHO classification of tumours of the digestive system. 4th ed. Lyon: International Agency for Research on Cancer; 2010.Google Scholar
  10. 10.
    Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202–9.CrossRefGoogle Scholar
  11. 11.
    Wang K, Yuen ST, Xu J, et al. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat Genet. 2014;46:573–82.CrossRefPubMedGoogle Scholar
  12. 12.
    Kakiuchi M, Nishizawa T, Ueda H, et al. Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. Nat Genet. 2014;46:583–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Guan R, Xu X, Chen M, et al. Advances in the studies of roles of Rho/Rho-kinase in diseases and the development of its inhibitors. Eur J Med Chem. 2013;70:613–22.CrossRefPubMedGoogle Scholar
  14. 14.
    Thumkeo D, Watanabe S, Narumiya S. Physiological roles of Rho and Rho effectors in mammals. Eur J Cell Biol. 2013;92:303–15.CrossRefPubMedGoogle Scholar
  15. 15.
    Su XJ, Tang ZF, Li Q, et al. [Expression and significance of RhoA and NF-KappaB in human gastric carcinoma]. Zhonghua Zhong Liu Za Zhi. 2011;33:276–9.PubMedGoogle Scholar
  16. 16.
    Siewert JR, Feith M, Werner M, Stein HJ. Adenocarcinoma of the esophagogastric junction: results of surgical therapy based on anatomical/topographic classification in 1,002 consecutive patients. Ann Surg. 2000;232:353–61.CrossRefGoogle Scholar
  17. 17.
    Washington K. 7th edition of the AJCC cancer staging manual: stomach. Ann Surg Oncol. 2010;17:3077–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Kononen J, Bubendorf L, Kallioniemi A, et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med. 1998;4:844–7.CrossRefPubMedGoogle Scholar
  19. 19.
    DerMardirossian C, Bokoch GM. GDIs: central regulatory molecules in Rho GTPase activation. Trends Cell Biol. 2005;15:356–63.CrossRefPubMedGoogle Scholar
  20. 20.
    Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53(282):457–81.CrossRefGoogle Scholar
  21. 21.
    Cox D. Regression models and life-tables. J R Stat Soc. 1972;34:187–220.Google Scholar
  22. 22.
    Qiao J, Huang F, Lum H. PKA inhibits RhoA activation: a protection mechanism against endothelial barrier dysfunction. Am J Physiol Lung Cell Mol Physiol. 2003;284:L972–80.CrossRefPubMedGoogle Scholar
  23. 23.
    Lang P, Gesbert F, Delespine-Carmagnat M, Stancou R, Pouchelet M, Bertoglio J. Protein kinase A phosphorylation of RhoA mediates the morphological and functional effects of cyclic AMP in cytotoxic lymphocytes. EMBO J. 1996;15:510–9.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Liu M, Bi F, Zhou X, Zheng Y. Rho GTPase regulation by miRNAs and covalent modifications. Trends Cell Biol. 2012;22:365–73.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Tan IB, Ivanova T, Lim KH, et al. Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy. Gastroenterology. 2011;141:476–85.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Lei Z, Tan IB, Das K, et al. Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil. Gastroenterology. 2013;145:554–65.CrossRefPubMedGoogle Scholar
  27. 27.
    Cristescu R, Lee J, Nebozhyn M, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21:449–56.CrossRefPubMedGoogle Scholar
  28. 28.
    Maeda M, Ushijima T. RHOA mutation may be associated with diffuse-type gastric cancer progression, but is it gain or loss? Gastric Cancer. In press.Google Scholar
  29. 29.
    Kantak SS, Kramer RH. E-cadherin regulates anchorage-independent growth and survival in oral squamous cell carcinoma cells. J Biol Chem. 1998;273:16953–61.CrossRefPubMedGoogle Scholar
  30. 30.
    Karlsson R, Pedersen ED, Wang Z, Brakebusch C. Rho GTPase function in tumorigenesis. Biochim Biophys Acta. 2009;1796:91–8.PubMedGoogle Scholar
  31. 31.
    Leve F, Morgado-Diaz JA. Rho GTPase signaling in the development of colorectal cancer. J Cell Biochem. 2012;113:2549–59.CrossRefPubMedGoogle Scholar
  32. 32.
    Orgaz JL, Herraiz C, Sanz-Moreno V. Rho GTPases modulate malignant transformation of tumor cells. Small GTPases. 2014;5:e29019.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Takami Y, Higashi M, Kumagai S, et al. The activity of RhoA is correlated with lymph node metastasis in human colorectal cancer. Dig Dis Sci. 2008;53:467–73.CrossRefPubMedGoogle Scholar
  34. 34.
    Pan Y, Bi F, Liu N, et al. Expression of seven main Rho family members in gastric carcinoma. Biochem Biophys Res Commun. 2004;315:686–91.CrossRefPubMedGoogle Scholar

Copyright information

© Society of Surgical Oncology 2016

Authors and Affiliations

  • Kevin K. Chang
    • 1
  • Soo-Jeong Cho
    • 1
  • Changhwan Yoon
    • 1
  • Jun Ho Lee
    • 1
  • Do Joong Park
    • 2
  • Sam S. Yoon
    • 1
    Email author
  1. 1.Department of SurgeryMemorial Sloan Kettering Cancer CenterNew YorkUSA
  2. 2.Department of SurgerySeoul National University Bundang Hospital, Seoul National University College of MedicineSeongnamSouth Korea

Personalised recommendations