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

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.

Phenotypic heterogeneity of neurofibromatosis type 1 in a large international registry

“…Our cohort has a higher prevalence of scoliosis, possibly because our cohort had an older average age, whereas other studies included pediatric populations, in whom scoliosis was less common. Similarly, the prevalence of MPNST in our study may be slightly lower than in prior studies because of the older age distribution of our cohort, as MPNST has both a young age of onset (median of 28 years) and a tendency for early mortality (5-year survival rate of 39%) (23). Compared with data from the French Clinical Research Program NF1 database published in 2009 with 750 patients, we have a greater prevalence of plexiform neurofibromas (43% vs. 34%), cNFs (91% vs. 62%), and neoplasm (18% optic gliomas vs. 10% any neoplasm), likely due to the older age of our adult-only cohort (24).…”

Giant Malignant Peripheral Nerve Sheath Tumor of the Head and Neck: A Case Report and Literature Review

“…[5][6][7] At the same time, patients with NF1 had an earlier onset age of MPNST compared with non-NF1 patients (median age: 28 vs 41). 8 So far, the pathogenesis of MPNST has not been clarified. The NF1-MPNST is mainly related to NF1 gene mutation, and the changes in X-linked alpha thalassemia/mental retardation syndrome (ATRX), polycomb repressive complex 2 (PRC2), MET-c-MET, gene of phosphate and tension homology deleted on chromsome 10 (PTEN), insulin-like growth factor 1 receptor (IGF1R), epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK), and other levels are also related to the progression of MPNST.…”

“…5 -7 At the same time, patients with NF1 had an earlier onset age of MPNST compared with non-NF1 patients (median age: 28 vs 41). 8…”

Peripheral nerve tumors of the hand: Clinical features, diagnosis, and treatment

“…They can originate from peripheral nerves or extraneural soft tissues and manifest as nerve sheath differentiation. MPNSTs mostly occur in 20-50-year-old individuals[ 5 , 78 ], and 22%-50% of MPNSTs occur in patients with NF1. About 8%–13% of patients with NF1 are diagnosed with MPNSTs[ 35 , 79 ].…”