Relationships between highly recurrent tumor suppressor alterations in 489 leiomyosarcomas

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Leiomyosarcoma (LMS) is a common sarcoma with no standard therapy for advanced stages.
• Recurrent molecular events include TP53, p16/RB1, and PI3K/mTOR pathway dysregulations.
• Some LMS express estrogen receptor (ER) and/or progesterone receptor (PR).

Purpose of the Study:

• To investigate protein expression in soft tissue and uterine nonprimary LMS (np-LMS).
• To characterize relationships between TP53, p16/RB1, PI3K/mTOR pathway perturbations, and ER/PR expression.
• To compare molecular alterations in primary LMS (p-LMS) and np-LMS.

Main Methods:

• Immunohistochemistry (IHC) for TP53, RB1, p16, and PTEN expression in 227 np-LMS and 262 p-LMS.
• Analysis of matched p-LMS and np-LMS specimens from 35 patients.
• Correlative studies included differentiation scoring, ER/PR IHC, and CDKN2A/p16 fluorescence in situ hybridization.

Main Results:

• TP53, p16/RB1, and PTEN dysregulation observed in 90%, 95%, and 41% of np-LMS, respectively.
• PTEN inactivation was more frequent in soft tissue np-LMS (55%) than uterine np-LMS (31%).
• Moderate-strong ER expression was more common in uterine np-LMS (50%) than soft tissue np-LMS (7%).
• Co-inactivation of TP53 and RB1 occurred in 81% of np-LMS.
• Molecular aberrations were largely conserved between matched p-LMS and np-LMS.

Conclusions:

• Nearly all np-LMS exhibit TP53 and/or RB1 aberrations.
• Therapies targeting cell cycle and DNA damage checkpoints warrant prioritization for LMS treatment evaluations.