Identification of Somatic Genetic Alterations Using Whole-Exome Sequencing of Uterine Leiomyosarcoma Tumors
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...
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Frontiers Media S.A.
2021-06-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.687899/full |
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| author | Lihua Chen Lihua Chen Jiajia Li Jiajia Li Xiaohua Wu Xiaohua Wu Zhong Zheng Zhong Zheng |
| author_facet | Lihua Chen Lihua Chen Jiajia Li Jiajia Li Xiaohua Wu Xiaohua Wu Zhong Zheng Zhong Zheng |
| author_sort | Lihua Chen |
| collection | DOAJ |
| description | 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. |
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| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-14T20:22:28Z |
| publishDate | 2021-06-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Oncology |
| spelling | doaj.art-041eb981ae7c4742a28db1b4d5c4667e2022-12-21T22:48:42ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-06-011110.3389/fonc.2021.687899687899Identification of Somatic Genetic Alterations Using Whole-Exome Sequencing of Uterine Leiomyosarcoma TumorsLihua Chen0Lihua Chen1Jiajia Li2Jiajia Li3Xiaohua Wu4Xiaohua Wu5Zhong Zheng6Zhong Zheng7Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaDepartment of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaDepartment of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaDepartment of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaBackgroundThe 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.https://www.frontiersin.org/articles/10.3389/fonc.2021.687899/fullexome sequencinguterine leiomyosarcomaSHARPINTP53ULMS |
| spellingShingle | Lihua Chen Lihua Chen Jiajia Li Jiajia Li Xiaohua Wu Xiaohua Wu Zhong Zheng Zhong Zheng Identification of Somatic Genetic Alterations Using Whole-Exome Sequencing of Uterine Leiomyosarcoma Tumors Frontiers in Oncology exome sequencing uterine leiomyosarcoma SHARPIN TP53 ULMS |
| title | Identification of Somatic Genetic Alterations Using Whole-Exome Sequencing of Uterine Leiomyosarcoma Tumors |
| title_full | Identification of Somatic Genetic Alterations Using Whole-Exome Sequencing of Uterine Leiomyosarcoma Tumors |
| title_fullStr | Identification of Somatic Genetic Alterations Using Whole-Exome Sequencing of Uterine Leiomyosarcoma Tumors |
| title_full_unstemmed | Identification of Somatic Genetic Alterations Using Whole-Exome Sequencing of Uterine Leiomyosarcoma Tumors |
| title_short | Identification of Somatic Genetic Alterations Using Whole-Exome Sequencing of Uterine Leiomyosarcoma Tumors |
| title_sort | identification of somatic genetic alterations using whole exome sequencing of uterine leiomyosarcoma tumors |
| topic | exome sequencing uterine leiomyosarcoma SHARPIN TP53 ULMS |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.687899/full |
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