Gender dimorphism and age of onset in malignant peripheral nerve sheath tumor preclinical models and human patients.

Elizabeth Shurell,William D Tap,Noah Federman,Brenna M Tam,Linh M Tran,Fritz C Eilber,Kathleen B Smith,Jonathan Nakashima,Sarah M Dry,Yunfeng Li,Hong Wu

doi:10.1186/1471-2407-14-827

Abstract

BackgroundGender-based differences in disease onset in murine models of malignant peripheral nerve sheath tumor (MPNST) and in patients with Neurofibromatosis type-1-(NF-1)-associated or spontaneous MPNST has not been well studied.MethodsForty-three mGFAP-Cre+;Ptenloxp/+;LSL-K-rasG12D/+ mice were observed for tumor development and evaluated for gender disparity in age of MPNST onset. Patient data from the prospectively collected UCLA sarcoma database (1974–2011, n = 113 MPNST patients) and 39 published studies on MPNST patients (n = 916) were analyzed for age of onset differences between sexes and between NF-1 and spontaneous MPNST patients.ResultsOur murine model showed gender-based differences in MPNST onset, with males developing MPNST significantly earlier than females (142 vs. 162 days, p = 0.015). In the UCLA patient population, males also developed MPNST earlier than females (median age 35 vs. 39.5 years, p = 0.048). Patients with NF-1-associated MPNST had significantly earlier age of onset compared to spontaneous MPNST (median age 33 vs. 39 years, p = 0.007). However, expanded analysis of 916 published MPNST cases revealed no significant age difference in MPNST onset between males and females. Similar to the UCLA dataset, patients with NF-1 developed MPNST at a significantly younger age than spontaneous MPNST patients (p < 0.0001, median age 28 vs. 41 years) and this disparity was maintained across North American, European, and Asian populations.ConclusionsAlthough our preclinical model and single-institution patient cohort show gender dimorphism in MPNST onset, no significant gender disparity was detected in the larger MPNST patient meta-dataset. NF-1 patients develop MPNST 13 years earlier than patients with spontaneous MPNST, with little geographical variance.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-827) contains supplementary material, which is available to authorized users.

Highlights

Gender-based differences in disease onset in murine models of malignant peripheral nerve sheath tumor (MPNST) and in patients with Neurofibromatosis type-1-(NF-1)-associated or spontaneous MPNST has not been well studied
Our study focused on age of MPNST diagnosis, as this data is consistently reported in the published MPNST literature
Engineered murine model of MPNST demonstrates gender dimorphism in disease onset In our previous study, we developed a murine neurofibroma model by conditional deletion of one allele of the Pten tumor suppressor gene and activation of the K-rasG12D oncogene in the Schwann progenitor cells [21]

Summary

Introduction

Gender-based differences in disease onset in murine models of malignant peripheral nerve sheath tumor (MPNST) and in patients with Neurofibromatosis type-1-(NF-1)-associated or spontaneous MPNST has not been well studied. Methods: Forty-three mGFAP-Cre+;Ptenloxp/+;LSL-K-rasG12D/+ mice were observed for tumor development and evaluated for gender disparity in age of MPNST onset. MPNST is an aggressive soft tissue sarcoma (STS) that accounts for up to 10 percent of all STS [10,11,12]. It is often associated with the autosomal dominant syndrome of Neurofibromatosis type 1 (NF-1), but arise sporadically as well. MPNSTs carry a poor prognosis, with a 5year survival of 15-45% in NF-1 patients compared to 43-75% for non-NF-1 patients [10,13,14,15]

Objectives

Methods

Results

Conclusion