Integrated mutational landscape analysis of uterine leiomyosarcomas.
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.
['Choi|Jungmin|J|', 'Manzano|Aranzazu|A|', 'Dong|Weilai|W|0000-0002-8376-1758', 'Bellone|Stefania|S|', 'Bonazzoli|Elena|E|', 'Zammataro|Luca|L|0000-0002-4348-6341', 'Yao|Xiaotong|X|0000-0002-5140-6639', 'Deshpande|Aditya|A|0000-0002-4463-2697', 'Zaidi|Samir|S|', 'Guglielmi|Adele|A|', 'Gnutti|Barbara|B|0000-0001-8583-2583', 'Nagarkatti|Nupur|N|0000-0002-5736-4214', 'Tymon-Rosario|Joan R|JR|', 'Harold|Justin|J|', 'Mauricio|Dennis|D|0000-0002-1511-9544', 'Zeybek|Burak|B|', 'Menderes|Gulden|G|', 'Altwerger|Gary|G|', 'Jeong|Kyungjo|K|0000-0001-5210-9962', 'Zhao|Siming|S|', 'Buza|Natalia|N|0000-0002-0008-334X', 'Hui|Pei|P|', 'Ravaggi|Antonella|A|0000-0003-4661-9979', 'Bignotti|Eliana|E|0000-0001-6380-6181', 'Romani|Chiara|C|', 'Todeschini|Paola|P|', 'Zanotti|Laura|L|', 'Odicino|Franco|F|0000-0001-8870-4739', 'Pecorelli|Sergio|S|0000-0002-5126-4300', 'Ardighieri|Laura|L|', 'Bilguvar|Kaya|K|', 'Quick|Charles M|CM|0000-0002-8619-3477', 'Silasi|Dan-Arin|DA|', 'Huang|Gloria S|GS|0000-0002-0001-888X', 'Andikyan|Vaagn|V|0000-0001-9326-0255', 'Clark|Mitchell|M|0000-0003-1118-9585', 'Ratner|Elena|E|', 'Azodi|Masoud|M|', 'Imielinski|Marcin|M|', 'Schwartz|Peter E|PE|0000-0002-0845-3624', 'Alexandrov|Ludmil B|LB|0000-0003-3596-4515', 'Lifton|Richard P|RP|', 'Schlessinger|Joseph|J|0000-0002-5085-5969', 'Santin|Alessandro D|AD|0000-0003-4724-9738']
D000818:Animals D000970:Antineoplastic Agents D005260:Female D005838:Genotype D006801:Humans D007890:Leiomyosarcoma D053858:Metabolic Networks and Pathways D051379:Mice D008810:Mice, Inbred C57BL D058990:Molecular Targeted Therapy D009154:Mutation D050596:Oncogene Fusion D010793:Phthalazines D010879:Piperazines D011743:Pyrimidines D011799:Quinazolines D014594:Uterine Neoplasms
mutational landscape uterine leiomyosarcomas whole-exome sequencing whole-genome sequencing