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Published on: September 13, 2019
Relationships between highly recurrent tumor suppressor alterations in 489 leiomyosarcomas
Inga-Marie Schaefer1, Meijun Z Lundberg1, Elizabeth G Demicco2,3
1Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Background:
Leiomyosarcoma (LMS) is the most common soft tissue and uterine sarcoma, but no standard therapy is available for recurrent or metastatic LMS. TP53, p16/RB1, and PI3K/mTOR pathway dysregulations are recurrent events, and some LMS express estrogen receptor (ER) and/or progesterone receptor (PR). To characterize relationships between these pathway perturbations, the authors evaluated protein expression in soft tissue and uterine nonprimary leiomyosarcoma (np-LMS), including local recurrences and distant metastases.
Methods:
TP53, RB1, p16, and PTEN expression aberrations were determined by immunohistochemistry (IHC) in tissue microarrays (TMAs) from 227 np-LMS and a comparison group of 262 primary leiomyosarcomas (p-LMS). Thirty-five of the np-LMS had a matched p-LMS specimen in the TMAs. Correlative studies included differentiation scoring, ER and PR IHC, and CDKN2A/p16 fluorescence in situ hybridization.
Results:
Dysregulation of TP53, p16/RB1, and PTEN was demonstrated in 90%, 95%, and 41% of np-LMS, respectively. PTEN inactivation was more common in soft tissue np-LMS than uterine np-LMS (55% vs 31%; P = .0005). Moderate-strong ER expression was more common in uterine np-LMS than soft tissue np-LMS (50% vs 7%; P < .0001). Co-inactivation of TP53 and RB1 was found in 81% of np-LMS and was common in both soft tissue and uterine np-LMS (90% and 74%, respectively). RB1, p16, and PTEN aberrations were nearly always conserved in p-LMS and np-LMS from the same patients.
Conclusions:
These studies show that nearly all np-LMS have TP53 and/or RB1 aberrations. Therefore, therapies targeting cell cycle and DNA damage checkpoint vulnerabilities should be prioritized for evaluations in LMS.
Insights
Nearly all non-primary leiomyosarcomas (np-LMS) show TP53 and/or RB1 pathway alterations. These findings suggest prioritizing therapies targeting cell cycle and DNA damage checkpoints for leiomyosarcoma (LMS) treatment.
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.
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