Phosphorylated Mcl-1 Expression on the Prognosis of Head and Neck Cancer Open Access

Hooda, Sharjeel Mehdi (2012)

Permanent URL: https://etd.library.emory.edu/concern/etds/h128nf791?locale=en
Published

Abstract

ABSTRACT
Phosphorylated Mcl-1 Expression on the Prognosis of Head and Neck Cancer

Background: Head and neck cancer (HNC) accounts for an estimated 350,000 deaths internationally each year. Mcl-1 is an anti-apoptotic Bcl-2 family protein and recent studies have shown that phosphorylating Mcl-1 can enhance cancer cell survival activity. However, the effect of phosphorylated Mcl-1 (pMcl-1) has not yet been studied on clinical outcome variables for HNC.

Methods: A pilot, retrospective, cohort study was conducted with 49 patients that presented to Emory University with HNC between 2002 and 2007. Selection criteria included subjects who presented with Stage III, IVa, or IVb disease and underwent surgical excision prior to radiation or chemotherapy. Protein expression levels of pMcl-1 and total Mcl-1 were evaluated via immunohistochemical staining of tumor tissue. Expression levels, scored by a blinded pathologist, were categorized as either absent, low (below median) or high (above median) and were correlated with disease free survival (DFS) and overall survival (OS). Data analysis was completed with Kaplan Meier survival analysis and Cox modeling.

Results: The median duration of follow up was 3.63 years. Tumors with undetectable pMcl-1 levels correlated with worse DFS (p=0.0490) and OS (p=0.0162). Survival curves were significantly different between subjects with high vs. low vs. absent expression for OS (p=0.0368), but not for DFS (p=0.0765). Multivariate analysis for DFS revealed a hazard ratio (HR) of 0.127 (p=0.0136) for high pMcl-1 versus absent pMcl-1 expression and a HR of 0.232 (p=0.0276) for low pMcl-1 versus absent pMcl-1 expression.

Conclusions: Increased pMcl-1 expression was associated with improved DFS and OS. This result was counter to the initial hypothesis and most likely related to antibody binding selectively at the serine 159 site on Mcl-1. This suggests that upregulating Mcl-1 phosphorylation at serine 159 may improve survival for HNC patients.

Table of Contents

TABLE OF CONTENTS
INTRODUCTION...1
BACKGROUND...3
METHODS...7
RESULTS...13
DISCUSSION...17
REFERENCES...25
TABLES...28
FIGURES...35


LIST OF TABLES
Table 1: Baseline patient characteristics...28
Table 2: Extended Cox model for DFS evaluating phosphorylated Mcl-1 expression level as a median based categorical variable...29
Table 3: Extended Cox model for OS evaluating phosphorylated Mcl-1 expression level as a median based categorical variable...30
Table 4: Extended Cox model for DFS evaluating phosphorylated Mcl-1 expression level as a quartile based categorical variable...31
Table 5: Extended Cox model for OS evaluating phosphorylated Mcl-1 expression level as a quartile based categorical variable...32
Table 6: Extended Cox model for DFS evaluating phosphorylated Mcl-1 expression level as a continuous variable...33
Table 7: Extended Cox model for OS evaluating phosphorylated Mcl-1 expression level as a continuous variable...34


LIST OF FIGURES
Figure 1: Representative sample of IHC staining for phosphorylated Mcl-1...35
Figure 2: Survival curves for DFS by tumor classification...36
Figure 3: Survival curves for DFS by node classification...37
Figure 4: Survival curves for DFS by gender...38
Figure 5: Survival curves for DFS by age...39
Figure 6: Survival curves for DFS by tumor differentiation...40
Figure 7: Survival curves for DFS by smoking status...41
Figure 8: Survival curves for DFS by total Mcl-1 expression...42
Figure 9: Survival curves for OS by total Mcl-1 expression...43
Figure 10: Survival curves for DFS by phosphorylated Mcl-1 expression as a categorical variable based upon detectable expression...44
Figure 11: Survival curves for OS by phosphorylated Mcl-1 expression as a categorical variable based upon detectable expression...45
Figure 12: Survival curves for DFS by phosphorylated Mcl-1 expression as a categorical variable based upon detectable expression and a median cutpoint...46
Figure 13: Survival curves for OS by phosphorylated Mcl-1 expression as a categorical variable based upon detectable expression and a median cutpoint...47
Figure 14: Survival curves for DFS by phosphorylated Mcl-1 expression as a quartile based categorical variable...48
Figure 15: Survival curves for OS by phosphorylated Mcl-1 expression as a quartile based categorical variable...49

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