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

Abstract

Background: 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. 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.

Results: Our 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.

Conclusions: Although 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.

Figure 1

Gender dimorphism in age of MPNST onset in genetically engineered murine model. Female mice (black squares) developed MPNST 20 days later than male mice (black circles) (p = 0.015). Gray line symbolizes median age of diagnosis for each cohort.

Figure 2

Gender disparity in age of MPNST initial diagnosis in UCLA cohort. Dashed lines represent spontaneous MPNST cases. Male patients are represented in red, female patients are represented in blue.

Figure 3

Age of MPNST diagnosis. Distribution of age at MPNST diagnosis in (A) all MPNST patients including UCLA (B) North American cohort (C) European cohort (D) Asian cohort. Spontaneous MPNST patients are depicted with a dashed line, NF-1 associated MPNST patients are depicted with a solid line. Males are represented in red, females are represented in blue.