Integrated mutational landscape analysis of uterine leiomyosarcomas

Abstract

Uterine leiomyosarcomas (uLMS) are aggressive tumors arising from the smooth muscle layer of the uterus. We analyzed 83 uLMS sample genetics, including 56 from Yale and 27 from The Cancer Genome Atlas (TCGA). Among them, a total of 55 Yale samples including two patient-derived xenografts (PDXs) and 27 TCGA samples have whole-exome sequencing (WES) data; 10 Yale and 27 TCGA samples have RNA-sequencing (RNA-Seq) data; and 11 Yale and 10 TCGA samples have whole-genome sequencing (WGS) data. We found recurrent somatic mutations in TP53, MED12, and PTEN genes. Top somatic mutated genes included TP53, ATRX, PTEN, and MEN1 genes. Somatic copy number variation (CNV) analysis identified 8 copy-number gains, including 5p15.33 (TERT), 8q24.21 (C-MYC), and 17p11.2 (MYOCD, MAP2K4) amplifications and 29 copy-number losses. Fusions involving tumor suppressors or oncogenes were deetected, with most fusions disrupting RB1, TP53, and ATRX/DAXX, and one fusion (ACTG2-ALK) being potentially targetable. WGS results demonstrated that 76% (16 of 21) of the samples harbored chromoplexy and/or chromothripsis. Clinically actionable mutational signatures of homologous-recombination DNA-repair deficiency (HRD) and microsatellite instability (MSI) were identified in 25% (12 of 48) and 2% (1 of 48) of fresh frozen uLMS, respectively. Finally, we found olaparib (PARPi; P = 0.002), GS-626510 (C-MYC/BETi; P < 0.000001 and P = 0.0005), and copanlisib (PIK3CAi; P = 0.0001) monotherapy to significantly inhibit uLMS-PDXs harboring derangements in C-MYC and PTEN/PIK3CA/AKT genes (LEY11) and/or HRD signatures (LEY16) compared to vehicle-treated mice. These findings define the genetic landscape of uLMS and suggest that a subset of uLMS may benefit from existing PARP-, PIK3CA-, and C-MYC/BET-targeted drugs.

PLAG1‐rearrangement in a uterine leiomyosarcoma with myxoid stroma and heterologous differentiation

“…Many tumors, including those arising in the uterus, are frequently characterized by alterations involving TP53 and RB1; other genes are less frequently involved, including: ATRX, MED12, PTEN, RBL2, and SP100. [1][2][3][4][5] Recently a subset of myxoid leiomyosarcoma has been reported to harbor genetic fusions involving PLAG1, a finding that can be used to differentiate these tumors from potential mimics. 6 Myxoid leiomyosarcoma is a rare subtype of uterine leiomyosarcoma that can be diagnostically challenging, particularly on limited sampling.…”

“…Most tumors are genetically complex—characterized by significant mutational heterogeneity, without a recurrent alteration. Many tumors, including those arising in the uterus, are frequently characterized by alterations involving TP53 and RB1 ; other genes are less frequently involved, including: ATRX , MED12 , PTEN , RBL2 , and SP100 1‐5 . Recently a subset of myxoid leiomyosarcoma has been reported to harbor genetic fusions involving PLAG1 , a finding that can be used to differentiate these tumors from potential mimics 6 .…”

Protracted clinical course of an AFF1 fusion positive uterine smooth muscle tumor causing diagnostic confusion over a course of 15 years

“…However, a small number of cases reporting LMS arising in a pre-existing leiomyoma have been reported, supported by the finding that MED12 exon 2 more commonly found in uterine leiomyomas is also found in a small subset of uterine LMS as well as STUMP ( Markowski et al, 2014 ). In addition to MED12 mutation, a subset of uterine LMS was recently reported to harbor PLAG1 fusion ( Arias-Stella et al, 2019 ) and KAT6B-KANSL1 fusion ( Choi et al, 2021 ), also seen in a subset of uterine leiomyoma ( Moore et al, 2004 , Ainsworth et al, 2019 ) ( Table 2 ). We identified a novel PTP4A2-AFF1 fusion, which to our knowledge has not been reported previously ( Fig.…”

Epigenetic signatures differentiate uterine and soft tissue leiomyosarcoma

“…Prior studies have made limited attempts to subtype LMS using exome-based, gene expression microarraybased, or RNA-seq-based profiling approaches [13][14][15][16][17][18][19]. However, only few studies have focused on characterizing the epigenetic profiles of LMS and investigating the role of epigenetic changes in LMS subtype progression [18,20,21].…”