Abstract
BackgroundThe genomic abnormalities associated with uterine leiomyosarcoma (uLMS) have not been fully elucidated to date.ObjectiveTo understand the pathogenesis of uLMS and to identify driver mutations and potential therapeutic targets in uLMS.MethodsThree matched tumor-constitutional DNA pairs from patients with recurrent uLMS were subjected to whole-exome capture and next-generation sequencing. The role of the selected gene SHARPIN in uLMS was analyzed by the CCK-8 assay and colony formation assay after specific siRNA knockdown.ResultsWe identified four genes with somatic SNVs, namely, SLC39A7, GPR19, ZNF717, and TP53, that could be driver mutations. We observed that 30.7% (4/13) of patients with uLMS had TP53 mutations as analyzed by direct sequencing. Analysis of somatic copy number variants (CNVs) showed regions of chromosomal gain at 1q21-23, 19p13, 17q21, and 17q25, whereas regions of chromosomal loss were observed at 2q35, 2q37, 1p36, 10q26, 6p22, 8q24, 11p15, 11q12, and 9p21. The SHARPIN gene was amplified in two patients and mutated in another (SHARPIN: NM_030974: exon2: c.G264C, p.E88D). Amplification of the SHARPIN gene was associated with shorter PFS and OS in soft tissue sarcoma, as shown by TCGA database analysis. Knockdown of SHARPIN expression was observed to decrease cell growth and colony formation in uterine sarcoma cell lines.ConclusionsExome sequencing revealed mutational heterogeneity of uLMS. The SHARPIN gene was amplified in uLMS and could be a candidate oncogene.
Highlights
Uterine leiomyosarcoma is a rare but aggressive malignancy. uLMS accounts for only 1–3% of all uterine malignancies, exhibiting an annual incidence rate of 0.4–0.9/100,000 women, but it is the most common type of uterine sarcoma [1]. uLMS is a highly malignant disease, with 5-year survival rates averaging approximately 40%
We identified several potential driving mutations, and amplification of the SHARPIN (Shank-associated RH domain-interacting protein) gene may be involved in uLMS progression
The SHARPIN gene was amplified in patients 1 and 3 and mutated
Summary
Uterine leiomyosarcoma (uLMS) is a rare but aggressive malignancy. uLMS accounts for only 1–3% of all uterine malignancies, exhibiting an annual incidence rate of 0.4–0.9/100,000 women, but it is the most common type of uterine sarcoma [1]. uLMS is a highly malignant disease, with 5-year survival rates averaging approximately 40%. Somatic Genetic Alterations of Uterine Leiomyosarcoma disease, the recurrence rate, even among patients with uterine confined disease (FIGO stage I), is greater than 50% [2]. For these cases of recurrent uLMS, no curative treatment has been identified to date. In a randomized phase II study, Olaratumab plus doxorubicin exhibited a response rate of 18.2% and improved PFS and OS compared with those in a control group [6]. The later phase III study ANNOUNCE showed that the combination of Olaratumab and doxorubicin produced no significant difference in median overall survival compared with doxorubicin alone [7]. The genomic abnormalities associated with uterine leiomyosarcoma (uLMS) have not been fully elucidated to date
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