Accepted Manuscript LGR5 expression in oral epithelial dysplasia and oral squamous cell carcinoma Andrew J. Dalley , PhD, Ahmad A. AbdulMajeed , PhD, Luke P. Pitty , BDSc, Aidan G. Major , BDSc, Camile S. Farah , PhD, FRACDS (OralMed) PII:

S2212-4403(14)01398-4

DOI:

10.1016/j.oooo.2014.11.014

Reference:

OOOO 1073

To appear in:

Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology

Received Date: 5 August 2014 Revised Date:

10 November 2014

Accepted Date: 19 November 2014

Please cite this article as: Dalley AJ, AbdulMajeed AA, Pitty LP, Major AG, Farah CS, LGR5 expression in oral epithelial dysplasia and oral squamous cell carcinoma, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2015), doi: 10.1016/j.oooo.2014.11.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT LGR5 expression in oral epithelial dysplasia and oral squamous cell carcinoma.

Andrew J. Dalley, PhD a, Ahmad A. AbdulMajeed, PhD a, Luke P. Pitty, BDSc a,b, Aidan G.

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Major, BDSca,b , Camile S. Farah, PhD, FRACDS (OralMed) a,b,c* a

The University of Queensland, UQ Centre for Clinical Research, Brisbane, Queensland,

Australia; bThe University of Queensland, School of Dentistry, Brisbane, Queensland,

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Australia; cThe Australian Centre for Oral Oncology Research & Education, Brisbane,

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Queensland, Australia.

* Correspondence: Camile S. Farah, Australian Centre for Oral Oncology Research & Education (ACORE), PO Box 88, Royal Brisbane & Women’s Hospital, Herston 4029 Queensland, Australia. Email: [email protected]. Tel: +61 7 3012 8760 Fax: +61 7

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3012 7960.

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Keywords:

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Oral Cancer; Oral Precancer; LGR5; Wnt; P53; Immunohistochemistry;

Financial Support:

This work was supported by the Australian Dental Research Foundation Inc, NSW, Australia and the Cancer Council Queensland, QLD, Australia via Grant#1034345. The authors have no conflicts of interest to declare.

Submission details: Abstract: 144 words. Manuscript: 1472 words, including figure legends. No tables, Two colour figures. One supplementary element (positive IHC control).

ACCEPTED MANUSCRIPT Abstract: (144 words) Objective. LGR5 is pivotal to oral cavity development and is implicated in epithelial malignancy whereby stimulation of LGR5 potentiates canonical Wnt signalling. This investigation tested

dysplasia (OED) and oral squamous cell carcinoma (OSCC). Study Design.

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our hypothesis of a correlation between LGR5 expression and the severity of oral epithelial

Immunoreactive LGR5 protein expression was quantified in 342 tissue samples ranging in

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disease severity from normal through mild and moderate/severe OED to OSCC.

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Results.

LGR5 was restricted to the basal layers for normal tissues, projected to the stratum granulosum in severe dysplasia, was intense in carcinoma nests of well differentiated OSCC, but

uniformly

diffuse

throughout

poorly

differentiated

OSCC.

Median

LGR5

immunoreactivity index scores increased with disease severity: mild dysplasia = 1
500 cells. Cells were firstly evaluated as positive or negative for LGR5, then positive cells were graded for intensity of immunoreactivity. Stain intensity was scaled: 0 = no stain, 1 = weak intensity, 2 = moderate intensity, 3 = strong intensity. The percent positively stained epithelial cells were calculated (numerator = number of positively stained cells; denominator = total number of cells observed) and categorised: 0% positive= score 0; 1-25% positive = score 1; 25-49% positive = score 2; 50-74% positive= score 3; and 75-100% positive = score 4. The final index score, which ranged from 0 to 12, was the product of categorised percentage positive score and the scaled stain intensity score.

ACCEPTED MANUSCRIPT Statistical analysis: Non-parametric analysis and presentation used IBM SPSS Statistics V.20 software (IBM Corporation, Armonk, NY, USA) and the R computing language ([http://www.R-project.org]). Median (Q2) and inter-quartile range (IQR) have been presented. The proportion of positively stained sections has been reported for each pathology (numerator = number of positively stained sections; denominator = total number

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of sections observed). Immunolocalisation score data for disease groups were compared to normal using Mann-Whitney U tests with Bonferroni correction for n=3 comparisons

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EP

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M AN U

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(*p

LGR5 expression in oral epithelial dysplasia and oral squamous cell carcinoma.

LGR5 is pivotal to oral cavity development and is implicated in epithelial malignancy whereby stimulation of LGR5 potentiates canonical Wnt signaling...
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