Prognostic value of loss of heterozygosity and sub-cellular localization of SMAD4 varies with tumor stage in colorectal cancer
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Xu Jia1, Chandrakumar Shanmugam1,6, Ravi K. Paluri2, Nirag C. Jhala1,7, Michael P. Behring3, Venkat R. Katkoori1,8, Shajan P. Sugandha2, Sejong Bae2,5, Temesgen Samuel4, Upender Manne1,5
1Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
2Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
3Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
4College of Veterinary Medicine, Tuskegee University, Tuskegee, AL, USA
5Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
6Current address: Department of Pathology, ESIC Medical College and Hospital, Sanathnagar, Hyderabad, Telangana, India
7Current address: Pathology & Laboratory Medicine, Temple University, Philadelphia, PA, USA
8Current address: Department of Surgery, Michigan State University, College of Human Medicine, Lansing, MI, USA
Upender Manne, email: [email protected]
Keywords: colorectal cancer, tumor stage, 18q21 LOH, nuclear/cytoplasmic SMAD4, survival
Received: August 31, 2016 Accepted: January 24, 2017 Published: February 21, 2017
Background: Although loss of heterozygosity (LOH) at chromosome location 18q21 and decreased expression of SMAD4 in invasive colorectal cancers (CRCs) correlate with poor patient survival, the prognostic value of LOH at 18q21 and sub-cellular localization of SMAD4 have not been evaluated in relation to tumor stage.
Methods: Genomic DNA samples from 209 formalin-fixed, paraffin-embedded sporadic CRC tissues and their matching controls were analyzed for 18q21 LOH, and corresponding tissue sections were evaluated by immunohistochemistry for expression of SMAD4 and assessed for its sub-cellular localization (nuclear vs. cytoplasmic). In addition, 53 frozen CRCs and their matching control tissues were analyzed for their mutational status and mRNA expression of SMAD4. The phenotypic expression pattern and LOH status were evaluated for correlation with patient survival by the use of Kaplan-Meier and Cox regression models.
Results: LOH of 18q21 was detected in 61% of the informative cases. In 8% of the cases, missense point mutations were detected in Smad4. In CRCs, relative to controls, there was increased SMAD4 staining in the cytoplasm (74%) and decreased staining in the nuclei (37%). LOH of 18q21 and high cytoplasmic localization of SMAD4 were associated with shortened overall survival of Stage II patients, whereas low nuclear expression of SMAD4 was associated with worse survival, but only for patients with Stage III CRCs.
Conclusions: LOH of 18q21 and high cytoplasmic localization of SMAD4 in Stage II CRCs and low nuclear SMAD4 in Stage III CRCs are predictors of shortened patient survival.
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