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. 2021 Apr 13;118(15):e2025182118.
doi: 10.1073/pnas.2025182118.

Integrated mutational landscape analysis of uterine leiomyosarcomas

Jungmin Choi  1   2 , Aranzazu Manzano  3 , Weilai Dong  2   4 , Stefania Bellone  3 , Elena Bonazzoli  3 , Luca Zammataro  3 , Xiaotong Yao  5   6   7 , Aditya Deshpande  5   6   7 , Samir Zaidi  8 , Adele Guglielmi  3 , Barbara Gnutti  3 , Nupur Nagarkatti  3 , Joan R Tymon-Rosario  3 , Justin Harold  3 , Dennis Mauricio  3 , Burak Zeybek  3 , Gulden Menderes  3 , Gary Altwerger  3 , Kyungjo Jeong  1 , Siming Zhao  9 , Natalia Buza  10 , Pei Hui  10 , Antonella Ravaggi  11 , Eliana Bignotti  11 , Chiara Romani  11 , Paola Todeschini  11 , Laura Zanotti  11 , Franco Odicino  11 , Sergio Pecorelli  11 , Laura Ardighieri  12 , Kaya Bilguvar  2 , Charles M Quick  13 , Dan-Arin Silasi  14 , Gloria S Huang  3 , Vaagn Andikyan  3 , Mitchell Clark  3 , Elena Ratner  3 , Masoud Azodi  3 , Marcin Imielinski  5   6 , Peter E Schwartz  3 , Ludmil B Alexandrov  15 , Richard P Lifton  4 , Joseph Schlessinger  16 , Alessandro D Santin  3
Affiliations

Integrated mutational landscape analysis of uterine leiomyosarcomas

Jungmin Choi et al. Proc Natl Acad Sci U S A. .

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.

Keywords: mutational landscape; uterine leiomyosarcomas; whole-exome sequencing; whole-genome sequencing.

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Conflict of interest statement

The authors declare no competing interest.

Figures

Fig. 1.
Fig. 1.
Somatic mutation landscape underlying uLMS. (A) Venn diagram of Yale and TCGA genomic and transcriptomic data composition. Distribution of somatic mutation in 83 uLMS samples. (B) Frequency and type of somatic mutations. Rows represent genes affected by at least two somatic SNVs or small INDELs, and columns represent individual uLMS. Source: Yale (purple), TCGA (yellow). CNV availability: CNV data available (light green), CNV data not available (dark green). (C) Recurrent CNV pattern. Significant amplifications (Left) and deletions (Right). The green line indicates the cutoff for significance (q = 0.25).
Fig. 2.
Fig. 2.
Mutational gene burden in uLMS. (A) Q–Q plot of significantly mutated genes according to MutSigCV. (B) Schematic representation of SNVs and INDELs in significantly mutated genes MEN1, TP53, ATRX, and PTEN using Lollipops tool (https://github.com/joiningdata/lollipops). (C) Kaplan–Meier curves comparing overall survival according to TP53 (77 mo vs. 31 mo, P = 0.051) mutation and ATRX status (median not reached vs. 29 mo, P = 0.001).
Fig. 3.
Fig. 3.
Fusions and translocations in uLMS. (A) ACTG2-ALK and KAT6B-KANSL1 fusions detected in TCGA-IW-A3M6 and TCGA-HS-A5N8, respectively. (B) Fusions detected in RB1 in 10 uLMS samples. (Upper) Protein domains of RB1. Triangle arrows indicate the break points. (Bottom) Exon distributions of RB1. Curved arrows indicate different types of fusion events.
Fig. 4.
Fig. 4.
Complex structural variations in 21 μLMS samples with WGS. (A) Heat map of different types of complex structural variation events across 21 samples. The color bar indicates the number of junctions. (B) An example of a chromoplexy event found in LEY1. (C) Chromoplexy/chromothripsis events that potentially lead to RB1 copy loss in four μLMS samples.
Fig. 5.
Fig. 5.
Copanlisib, Olaparib, and GS-626510 inhibited cell proliferation in uLMS PDXs in vivo. (A) Copanlisib and GS-626510 tumor growth inhibition in LEY11. (B and C) Olaparib and GS-626510 tumor growth inhibition in LEY16.
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