M6P/IGF2R loss of heterozygosity in head and neck cancer associated with poor patient prognosis.

Timothy A Jamieson,J Keith Killian,Yoshihiko Oka,Robert W Clough,David M Brizel,Hong-Seok Jang,Mitchell S Anscher,Robin T Vollmer,Randy L Jirtle,Xiaolong Fu

doi:10.1186/1471-2407-3-4

Abstract

BackgroundThe mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) encodes for a multifunctional receptor involved in lysosomal enzyme trafficking, fetal organogenesis, cytotoxic T cell-induced apoptosis and tumor suppression. The purpose of this investigation was to determine if the M6P/IGF2R tumor suppressor gene is mutated in human head and neck cancer, and if allelic loss is associated with poor patient prognosis.MethodsM6P/IGF2R loss of heterozygosity in locally advanced squamous cell carcinoma of the head and neck was assessed with six different gene-specific nucleotide polymorphisms. The patients studied were enrolled in a phase 3 trial of twice daily radiotherapy with or without concurrent chemotherapy; median follow-up for surviving patients is 76 months.ResultsM6P/IGF2R was polymorphic in 64% (56/87) of patients, and 54% (30/56) of the tumors in these informative patients had loss of heterozygosity. M6P/IGF2R loss of heterozygosity was associated with a significantly reduced 5 year relapse-free survival (23% vs. 69%, p = 0.02), locoregional control (34% vs. 75%, p = 0.03) and cause specific survival (29% vs. 75%, p = 0.02) in the patients treated with radiotherapy alone. Concomitant chemotherapy resulted in a better outcome when compared to radiotherapy alone only in those patients whose tumors had M6P/IGF2R loss of heterozygosity.ConclusionsThis study provides the first evidence that M6P/IGF2R loss of heterozygosity predicts for poor therapeutic outcome in patients treated with radiotherapy alone. Our findings also indicate that head and neck cancer patients with M6P/IGF2R allelic loss benefit most from concurrent chemotherapy.

Highlights

The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) encodes for a multifunctional receptor involved in lysosomal enzyme trafficking, fetal organogenesis, cytotoxic T cell-induced apoptosis and tumor suppression
M6P/IGF2R Loss of Heterozygosity Analysis The study population consisted of 116 patients enrolled in a phase III randomized clinical trial comparing radiation alone versus radiation plus concurrent chemotherapy for advanced head and neck cancer [31] plus an additional 23 patients who met all the entrance criteria but declined enrollment
M6P/IGF2R loss of heterozygosity was associated with significant reductions in 5 year relapse-free survival {37% vs. 65%; p = 0.05}, locoregional control {46% vs. 76%; p = 0.03} and a non-significant reduction in cause-specific survival {43% vs. 69%; p = 0.1}

Summary

Introduction

The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) encodes for a multifunctional receptor involved in lysosomal enzyme trafficking, fetal organogenesis, cytotoxic T cell-induced apoptosis and tumor suppression. The purpose of this investigation was to determine if the M6P/IGF2R tumor suppressor gene is mutated in human head and neck cancer, and if allelic loss is associated with poor patient prognosis. Analysis of X-chromosome inactivation in female patients with multiple head and neck cancers shows that distinct tumors arise from regional clonal growths of phenotypically normal, mutated preneoplastic cells [3,4,5], a phenomenon similar to that observed in liver cancer patients with cirrhosis [6]. Long-term smoking and alcohol abuse are strongly associated with these clonal growths in the upper aerodigestive tract (reviewed in [7])

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