Integrated mutational landscape analysis of uterine leiomyosarcomas

被引：86

作者：

Choi, Jungmin ^{[1
,2
]}

Manzano, Aranzazu ^{[3
]}

Dong, Weilai ^{[2
,4
]}

Bellone, Stefania ^{[3
]}

Bonazzoli, Elena ^{[3
]}

Zammataro, Luca ^{[3
]}

Yao, Xiaotong ^{[5
,6
,7
]}

Deshpande, Aditya ^{[5
,6
,7
]}

Zaidi, Samir ^{[8
]}

Guglielmi, Adele ^{[3
]}

Gnutti, Barbara ^{[3
]}

Nagarkatti, Nupur ^{[3
]}

Tymon-Rosario, Joan R. ^{[3
]}

Harold, Justin ^{[3
]}

Mauricio, Dennis ^{[3
]}

Zeybek, Burak ^{[3
]}

Menderes, Gulden ^{[3
]}

Altwerger, Gary ^{[3
]}

Jeong, Kyungjo ^{[1
]}

Zhao, Siming ^{[9
]}

Buza, Natalia ^{[10
]}

Hui, Pei ^{[10
]}

Ravaggi, Antonella ^{[11
]}

Bignotti, Eliana ^{[11
]}

Romani, Chiara ^{[11
]}

Todeschini, Paola ^{[11
]}

Zanotti, Laura ^{[11
]}

Odicino, Franco ^{[11
]}

Pecorelli, Sergio ^{[11
]}

Ardighieri, Laura ^{[12
]}

Bilguvar, Kaya ^{[2
]}

Quick, Charles M. ^{[13
]}

Silasi, Dan-Arin ^{[14
]}

Huang, Gloria S. ^{[3
]}

Andikyan, Vaagn ^{[3
]}

Clark, Mitchell ^{[3
]}

Ratner, Elena ^{[3
]}

Azodi, Masoud ^{[3
]}

Imielinski, Marcin ^{[5
,6
]}

Schwartz, Peter E. ^{[3
]}

Alexandrov, Ludmil B. ^{[15
]}

Lifton, Richard P. ^{[4
]}

Schlessinger, Joseph ^{[16
]}

Santin, Alessandro D. ^{[3
]}

机构：

[1] Korea Univ, Coll Med, Dept Biomed Sci, Seoul 02841, South Korea

[2] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA

[3] Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT 06510 USA

[4] Rockefeller Univ, Lab Human Genet & Genom, New York, NY 10065 USA

[5] Weill Cornell Med, Dept Pathol & Lab Med, New York, NY USA

[6] New York Genome Ctr, New York, NY 10013 USA

[7] Weill Cornell Med, Triinst PhD Program Computat Biol & Med, New York, NY 10021 USA

[8] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[9] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA

[10] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA

[11] Univ Brescia, Angelo Nocivelli Inst Mol Med, Dept Obstet & Gynecol, I-25100 Brescia, Italy

[12] Univ Brescia, Azienda Socio Sanit Terr Spedali Civili Brescia, Dept Pathol, I-25100 Brescia, Italy

[13] Univ Arkansas Med Sci, Dept Pathol, Little Rock, AR 72205 USA

[14] Mercy Clin, Div Gynecol Oncol, St Louis, MO 63141 USA

[15] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA

[16] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2021年 / 118卷 / 15期

关键词：

uterine leiomyosarcomas; whole-exome sequencing; mutational landscape; whole-genome sequencing; ENDOCRINE NEOPLASIA TYPE-1; GENOME ANALYSIS; CANCER; TELOMERES; ATRX; AMPLIFICATION; EXPRESSION; LEIOMYOMA; VARIANTS; EVENTS;

D O I：

10.1073/pnas.2025182118

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 on-cogenes were deetected, with most fusions disrupting RB1, TP53, and ATRX/DAXX, and one fusion (ACTG2-ALK) being po-tentially targetable. WGS results demonstrated that 76% (16 of 21) of the samples harbored chromoplexy and/or chromothrip-sis. 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-62 6510 (C-MYC/BETi; P < 0.000001 and P = 0.0005), and copanlisib (PIK3CAi; P = 0.0001) monotherapy to significantly inhibit uLMS-PDXs harboring de-rangements 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 sug-gest that a subset of uLMS may benefit from existing PARP-, PIK3CA-, and C-MYC/BET-targeted drugs.

引用

页数：9

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