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- Title
Relationships between highly recurrent tumor suppressor alterations in 489 leiomyosarcomas.
- Authors
Schaefer, Inga‐Marie; Lundberg, Meijun Z.; Demicco, Elizabeth G.; Przybyl, Joanna; Matusiak, Magdalena; Chibon, Frédéric; Ingram, Davis R.; Hornick, Jason L.; Wang, Wei‐Lien; Bauer, Sebastian; Baker, Laurence H.; Lazar, Alexander J.; Rijn, Matt; Mariño‐Enríquez, Adrian; Fletcher, Jonathan A.
- Abstract
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. Aberrations of TP53, p16/RB1, and PTEN are found in 90%, 95%, and 41% of metastatic soft tissue and uterine leiomyosarcomas, respectively, with PTEN inactivation being more common in soft tissue cases. These key aberrations are generally conserved between primary and metastatic disease in a given patient.
- Subjects
LEIOMYOSARCOMA; FLUORESCENCE in situ hybridization; SARCOMA; PROGESTERONE receptors; ESTROGEN receptors; DNA damage
- Publication
Cancer (0008543X), 2021, Vol 127, Issue 15, p2666
- ISSN
0008-543X
- Publication type
Article
- DOI
10.1002/cncr.33542