TY - JOUR
T1 - Relationships between highly recurrent tumor suppressor alterations in 489 leiomyosarcomas
AU - Schaefer, Inga Marie
AU - Lundberg, Meijun Z.
AU - Demicco, Elizabeth G.
AU - Przybyl, Joanna
AU - Matusiak, Magdalena
AU - Chibon, Frédéric
AU - Ingram, Davis R.
AU - Hornick, Jason L.
AU - Wang, Wei Lien
AU - Bauer, Sebastian
AU - Baker, Laurence H.
AU - Lazar, Alexander J.
AU - van de Rijn, Matt
AU - Mariño-Enríquez, Adrian
AU - Fletcher, Jonathan A.
N1 - Publisher Copyright:
© 2021 American Cancer Society
PY - 2021/8/1
Y1 - 2021/8/1
N2 - 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.
AB - 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.
KW - DNA damage repair
KW - biomarker
KW - cell cycle
KW - immunohistochemistry
KW - leiomyosarcoma (LMS)
KW - soft tissue
KW - uterine
KW - uterus
UR - http://www.scopus.com/inward/record.url?scp=85103418683&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85103418683&partnerID=8YFLogxK
U2 - 10.1002/cncr.33542
DO - 10.1002/cncr.33542
M3 - Article
C2 - 33788262
AN - SCOPUS:85103418683
SN - 0008-543X
VL - 127
SP - 2666
EP - 2673
JO - Cancer
JF - Cancer
IS - 15
ER -