Integrated genomic and transcriptomic analysis revealed mutation patterns of de-differentiated liposarcoma and leiomyosarcoma
Abstract Background Treating patients with advanced sarcomas is challenging due to great histologic diversity among its subtypes. Leiomyosarcoma (LMS) and de-differentiated liposarcoma (DDLPS) are two common and aggressive subtypes of soft tissue sarcoma (STS). They differ significantly in histology...
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2020-10-01
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Online Access: | http://link.springer.com/article/10.1186/s12885-020-07456-2 |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wenshuai Liu Hanxing Tong Chenlu Zhang Rongyuan Zhuang He Guo Chentao Lv Hua Yang Qiaowei Lin Xi Guo Zhiming Wang Yan Wang Feng Shen Shengzhou Wang Chun Dai Guan Wang Jun Liu Weiqi Lu Yong Zhang Yuhong Zhou |
spellingShingle |
Wenshuai Liu Hanxing Tong Chenlu Zhang Rongyuan Zhuang He Guo Chentao Lv Hua Yang Qiaowei Lin Xi Guo Zhiming Wang Yan Wang Feng Shen Shengzhou Wang Chun Dai Guan Wang Jun Liu Weiqi Lu Yong Zhang Yuhong Zhou Integrated genomic and transcriptomic analysis revealed mutation patterns of de-differentiated liposarcoma and leiomyosarcoma BMC Cancer Soft tissue sarcoma Gene fusion Tumor microenvironment Immune infiltration |
author_facet |
Wenshuai Liu Hanxing Tong Chenlu Zhang Rongyuan Zhuang He Guo Chentao Lv Hua Yang Qiaowei Lin Xi Guo Zhiming Wang Yan Wang Feng Shen Shengzhou Wang Chun Dai Guan Wang Jun Liu Weiqi Lu Yong Zhang Yuhong Zhou |
author_sort |
Wenshuai Liu |
title |
Integrated genomic and transcriptomic analysis revealed mutation patterns of de-differentiated liposarcoma and leiomyosarcoma |
title_short |
Integrated genomic and transcriptomic analysis revealed mutation patterns of de-differentiated liposarcoma and leiomyosarcoma |
title_full |
Integrated genomic and transcriptomic analysis revealed mutation patterns of de-differentiated liposarcoma and leiomyosarcoma |
title_fullStr |
Integrated genomic and transcriptomic analysis revealed mutation patterns of de-differentiated liposarcoma and leiomyosarcoma |
title_full_unstemmed |
Integrated genomic and transcriptomic analysis revealed mutation patterns of de-differentiated liposarcoma and leiomyosarcoma |
title_sort |
integrated genomic and transcriptomic analysis revealed mutation patterns of de-differentiated liposarcoma and leiomyosarcoma |
publisher |
BMC |
series |
BMC Cancer |
issn |
1471-2407 |
publishDate |
2020-10-01 |
description |
Abstract Background Treating patients with advanced sarcomas is challenging due to great histologic diversity among its subtypes. Leiomyosarcoma (LMS) and de-differentiated liposarcoma (DDLPS) are two common and aggressive subtypes of soft tissue sarcoma (STS). They differ significantly in histology and clinical behaviors. However, the molecular driving force behind the difference is unclear. Methods We collected 20 LMS and 12 DDLPS samples and performed whole exome sequencing (WES) to obtain their somatic mutation profiles. We also performed RNA-Seq to analyze the transcriptomes of 8 each of the LMS and DDLPS samples and obtained information about differential gene expression, pathway enrichment, immune cell infiltration in tumor microenvironment, and chromosomal rearrangement including gene fusions. Selected gene fusion events from the RNA-seq prediction were checked by RT-PCR in tandem with Sanger sequencing. Results We detected loss of function mutation and deletion of tumor suppressors mostly in LMS, and oncogene amplification mostly in DDLPS. A focal amplification affecting chromosome 12q13–15 region which encodes MDM2, CDK4 and HMGA2 is notable in DDLPS. Mutations in TP53, ATRX, PTEN, and RB1 are identified in LMS but not DDLPS, while mutation of HERC2 is only identified in DDLPS but not LMS. RNA-seq revealed overexpression of MDM2, CDK4 and HMGA2 in DDLPS and down-regulation of TP53 and RB1 in LMS. It also detected more fusion events in DDLPS than LMS (4.5 vs. 1, p = 0.0195), and the ones involving chromosome 12 in DDLPS stand out. RT-PCR and Sanger sequencing verified the majority of the fusion events in DDLPS but only one event in LMS selected to be tested. The tumor microenvironmental signatures are highly correlated with histologic types. DDLPS has more endothelial cells and fibroblasts content than LMS. Conclusions Our analysis revealed different recurrent genetic variations in LMS and DDLPS including simultaneous upregulation of gene expression and gene copy number amplification of MDM2 and CDK4. Up-regulation of tumor related genes is favored in DDLPS, while loss of suppressor function is favored in LMS. DDLPS harbors more frequent fusion events which can generate neoepitopes and potentially targeted by personalized immune treatment. |
topic |
Soft tissue sarcoma Gene fusion Tumor microenvironment Immune infiltration |
url |
http://link.springer.com/article/10.1186/s12885-020-07456-2 |
work_keys_str_mv |
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1724465823121145856 |
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doaj-dd562453af65400a90cc4e61a7c63a892020-11-25T03:56:17ZengBMCBMC Cancer1471-24072020-10-0120111410.1186/s12885-020-07456-2Integrated genomic and transcriptomic analysis revealed mutation patterns of de-differentiated liposarcoma and leiomyosarcomaWenshuai Liu0Hanxing Tong1Chenlu Zhang2Rongyuan Zhuang3He Guo4Chentao Lv5Hua Yang6Qiaowei Lin7Xi Guo8Zhiming Wang9Yan Wang10Feng Shen11Shengzhou Wang12Chun Dai13Guan Wang14Jun Liu15Weiqi Lu16Yong Zhang17Yuhong Zhou18Department of General Surgery, Shanghai Public Health Clinical Center, Fudan UniversityDepartment of General Surgery, Zhongshan Hospital, Fudan UniversityDepartment of Medical Oncology, Zhongshan Hospital, Fudan UniversityDepartment of Medical Oncology, Zhongshan Hospital, Fudan UniversityGenomiCare Biotechnology (Shanghai) Co. Ltd.Department of General Surgery, Shanghai Public Health Clinical Center, Fudan UniversityDepartment of General Surgery, Shanghai Public Health Clinical Center, Fudan UniversityDepartment of General Surgery, Zhongshan Hospital, Fudan UniversityDepartment of Medical Oncology, Zhongshan Hospital, Fudan UniversityDepartment of Medical Oncology, Zhongshan Hospital, Fudan UniversityDepartment of Medical Oncology, Zhongshan Hospital, Fudan UniversityDepartment of Medical Oncology, Zhongshan Hospital, Fudan UniversityGenomiCare Biotechnology (Shanghai) Co. Ltd.GenomiCare Biotechnology (Shanghai) Co. Ltd.GenomiCare Biotechnology (Shanghai) Co. Ltd.GenomiCare Biotechnology (Shanghai) Co. Ltd.Department of General Surgery, Zhongshan Hospital, Fudan UniversityDepartment of General Surgery, Zhongshan Hospital, Fudan UniversityDepartment of Medical Oncology, Zhongshan Hospital, Fudan UniversityAbstract Background Treating patients with advanced sarcomas is challenging due to great histologic diversity among its subtypes. Leiomyosarcoma (LMS) and de-differentiated liposarcoma (DDLPS) are two common and aggressive subtypes of soft tissue sarcoma (STS). They differ significantly in histology and clinical behaviors. However, the molecular driving force behind the difference is unclear. Methods We collected 20 LMS and 12 DDLPS samples and performed whole exome sequencing (WES) to obtain their somatic mutation profiles. We also performed RNA-Seq to analyze the transcriptomes of 8 each of the LMS and DDLPS samples and obtained information about differential gene expression, pathway enrichment, immune cell infiltration in tumor microenvironment, and chromosomal rearrangement including gene fusions. Selected gene fusion events from the RNA-seq prediction were checked by RT-PCR in tandem with Sanger sequencing. Results We detected loss of function mutation and deletion of tumor suppressors mostly in LMS, and oncogene amplification mostly in DDLPS. A focal amplification affecting chromosome 12q13–15 region which encodes MDM2, CDK4 and HMGA2 is notable in DDLPS. Mutations in TP53, ATRX, PTEN, and RB1 are identified in LMS but not DDLPS, while mutation of HERC2 is only identified in DDLPS but not LMS. RNA-seq revealed overexpression of MDM2, CDK4 and HMGA2 in DDLPS and down-regulation of TP53 and RB1 in LMS. It also detected more fusion events in DDLPS than LMS (4.5 vs. 1, p = 0.0195), and the ones involving chromosome 12 in DDLPS stand out. RT-PCR and Sanger sequencing verified the majority of the fusion events in DDLPS but only one event in LMS selected to be tested. The tumor microenvironmental signatures are highly correlated with histologic types. DDLPS has more endothelial cells and fibroblasts content than LMS. Conclusions Our analysis revealed different recurrent genetic variations in LMS and DDLPS including simultaneous upregulation of gene expression and gene copy number amplification of MDM2 and CDK4. Up-regulation of tumor related genes is favored in DDLPS, while loss of suppressor function is favored in LMS. DDLPS harbors more frequent fusion events which can generate neoepitopes and potentially targeted by personalized immune treatment.http://link.springer.com/article/10.1186/s12885-020-07456-2Soft tissue sarcomaGene fusionTumor microenvironmentImmune infiltration |