Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 13/2016

01-12-2016 | Gastrointestinal Oncology

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

Authors: Kevin K. Chang, MD, Soo-Jeong Cho, MD, PhD, Changhwan Yoon, PhD, Jun Ho Lee, MD, Do Joong Park, MD, PhD, Sam S. Yoon, MD

Published in: Annals of Surgical Oncology | Issue 13/2016

Login to get access

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.
Appendix
Available only for authorised users
Literature
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.CrossRefPubMed
2.
Kumar V, Abbas AK, Aster JC. Robbins and Cotran pathologic basis of disease. 9th ed. 2015.
3.
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.CrossRefPubMed
5.
Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36–46.CrossRefPubMed
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.CrossRefPubMed
7.
Lynch HT, Grady W, Suriano G, Huntsman D. Gastric cancer: new genetic developments. J Surg Oncol. 2005;90:114–33.CrossRefPubMed
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.PubMed
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.
10.
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202–9.CrossRef
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
14.
Thumkeo D, Watanabe S, Narumiya S. Physiological roles of Rho and Rho effectors in mammals. Eur J Cell Biol. 2013;92:303–15.CrossRefPubMed
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.PubMed
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.CrossRef
17.
Washington K. 7th edition of the AJCC cancer staging manual: stomach. Ann Surg Oncol. 2010;17:3077–9.CrossRefPubMed
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.CrossRefPubMed
19.
DerMardirossian C, Bokoch GM. GDIs: central regulatory molecules in Rho GTPase activation. Trends Cell Biol. 2005;15:356–63.CrossRefPubMed
20.
Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53(282):457–81.CrossRef
21.
Cox D. Regression models and life-tables. J R Stat Soc. 1972;34:187–220.
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.CrossRefPubMed
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.PubMedPubMedCentral
24.
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
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.
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.CrossRefPubMed
30.
Karlsson R, Pedersen ED, Wang Z, Brakebusch C. Rho GTPase function in tumorigenesis. Biochim Biophys Acta. 2009;1796:91–8.PubMed
31.
Leve F, Morgado-Diaz JA. Rho GTPase signaling in the development of colorectal cancer. J Cell Biochem. 2012;113:2549–59.CrossRefPubMed
32.
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.CrossRefPubMed
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.CrossRefPubMed
Metadata
Title
Increased RhoA Activity Predicts Worse Overall Survival in Patients Undergoing Surgical Resection for Lauren Diffuse-Type Gastric Adenocarcinoma
Authors
Kevin K. Chang, MD
Soo-Jeong Cho, MD, PhD
Changhwan Yoon, PhD
Jun Ho Lee, MD
Do Joong Park, MD, PhD
Sam S. Yoon, MD
Publication date
01-12-2016
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology / Issue 13/2016
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-016-5357-2

Other articles of this Issue 13/2016

Annals of Surgical Oncology 13/2016 Go to the issue

Gastrointestinal Oncology

Pylorus-Preserving Surgery Based on the Sentinel Node Concept in Early Gastric Cancer

Gastrointestinal Oncology

Pseudomyxoma Peritonei of Extra-Appendiceal Origin: A Comparative Study

Pancreatic Tumors

Evolving Trends Towards Minimally Invasive Surgery for Solid-Pseudopapillary Neoplasms

Head and Neck Oncology

Risk Factors and Survival Associated with Distant Metastasis in Patients with Carcinoma of the Salivary Gland

Colorectal Cancer

Long-Term Outcome of Rectal Cancer With Clinically (EUS/MRI) Metastatic Mesorectal Lymph Nodes Treated by Neoadjuvant Chemoradiation: Role of Organ Preservation Strategies in Relation to Pathologic Response

Bone and Soft Tissue Sarcomas

A Choice of Wine