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Integrated multi-omic analysis of low-grade ovarian serous carcinoma collected from short and long-term survivors

BACKGROUND: Low-grade serous ovarian cancer (LGSOC) is a rare disease that occurs more frequently in younger women than those with high-grade disease. The current treatment is suboptimal and a better understanding of the molecular pathogenesis of this disease is required. In this study, we compared...

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Autores principales: Wong, Kwong-Kwok, Bateman, Nicholas W., Ng, Chun Wai, Tsang, Yvonne T. M., Sun, Charlotte S., Celestino, Joseph, Nguyen, Tri V., Malpica, Anais, Hillman, R. Tyler, Zhang, Jianhua, Futreal, P. Andrew, Rojas, Christine, Conrads, Kelly A., Hood, Brian L., Dalgard, Clifton L., Wilkerson, Matthew D., Phippen, Neil T., Conrads, Thomas P., Maxwell, George L., Sood, Anil K., Gershenson, David M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9758924/
https://www.ncbi.nlm.nih.gov/pubmed/36528667
http://dx.doi.org/10.1186/s12967-022-03820-x
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author Wong, Kwong-Kwok
Bateman, Nicholas W.
Ng, Chun Wai
Tsang, Yvonne T. M.
Sun, Charlotte S.
Celestino, Joseph
Nguyen, Tri V.
Malpica, Anais
Hillman, R. Tyler
Zhang, Jianhua
Futreal, P. Andrew
Rojas, Christine
Conrads, Kelly A.
Hood, Brian L.
Dalgard, Clifton L.
Wilkerson, Matthew D.
Phippen, Neil T.
Conrads, Thomas P.
Maxwell, George L.
Sood, Anil K.
Gershenson, David M.
author_facet Wong, Kwong-Kwok
Bateman, Nicholas W.
Ng, Chun Wai
Tsang, Yvonne T. M.
Sun, Charlotte S.
Celestino, Joseph
Nguyen, Tri V.
Malpica, Anais
Hillman, R. Tyler
Zhang, Jianhua
Futreal, P. Andrew
Rojas, Christine
Conrads, Kelly A.
Hood, Brian L.
Dalgard, Clifton L.
Wilkerson, Matthew D.
Phippen, Neil T.
Conrads, Thomas P.
Maxwell, George L.
Sood, Anil K.
Gershenson, David M.
author_sort Wong, Kwong-Kwok
collection PubMed
description BACKGROUND: Low-grade serous ovarian cancer (LGSOC) is a rare disease that occurs more frequently in younger women than those with high-grade disease. The current treatment is suboptimal and a better understanding of the molecular pathogenesis of this disease is required. In this study, we compared the proteogenomic analyses of LGSOCs from short- and long-term survivors (defined as < 40 and > 60 months, respectively). Our goal was to identify novel mutations, proteins, and mRNA transcripts that are dysregulated in LGSOC, particularly in short-term survivors. METHODS: Initially, targeted sequencing of 409 cancer-related genes was performed on 22 LGSOC and 6 serous borderline ovarian tumor samples. Subsequently, whole-genome sequencing analysis was performed on 14 LGSOC samples (7 long-term survivors and 7 short-term survivors) with matched normal tissue samples. RNA sequencing (RNA-seq), quantitative proteomics, and phosphoproteomic analyses were also performed. RESULTS: We identified single-nucleotide variants (SNVs) (range: 5688–14,833 per sample), insertion and deletion variants (indels) (range: 880–1065), and regions with copy number variants (CNVs) (range: 62–335) among the 14 LGSOC samples. Among all SNVs and indels, 2637 mutation sites were found in the exonic regions. The allele frequencies of the detected variants were low (median12%). The identified recurrent nonsynonymous missense mutations included KRAS, NRAS, EIF1AX, UBR5, and DNM3 mutations. Mutations in DNM3 and UBR5 have not previously been reported in LGSOC. For the two samples, somatic DNM3 nonsynonymous missense mutations in the exonic region were validated using Sanger sequencing. The third sample contained two missense mutations in the intronic region of DNM3, leading to a frameshift mutation detected in RNA transcripts in the RNA-seq data. Among the 14 LGSOC samples, 7754 proteins and 9733 phosphosites were detected by global proteomic analysis. Some of these proteins and signaling pathways, such as BST1, TBXAS1, MPEG1, HBA1, and phosphorylated ASAP1, are potential therapeutic targets. CONCLUSIONS: This is the first study to use whole-genome sequencing to detect somatic mutations in LGSOCs with matched normal tissues. We detected and validated novel mutations in DNM3, which were present in 3 of the 14 samples analyzed. Additionally, we identified novel indels, regions with CNVs, dysregulated mRNA, dysregulated proteins, and phosphosites that are more prevalent in short-term survivors. This integrated proteogenomic analysis can guide research into the pathogenesis and treatment of LGSOC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-022-03820-x.
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spelling pubmed-97589242022-12-18 Integrated multi-omic analysis of low-grade ovarian serous carcinoma collected from short and long-term survivors Wong, Kwong-Kwok Bateman, Nicholas W. Ng, Chun Wai Tsang, Yvonne T. M. Sun, Charlotte S. Celestino, Joseph Nguyen, Tri V. Malpica, Anais Hillman, R. Tyler Zhang, Jianhua Futreal, P. Andrew Rojas, Christine Conrads, Kelly A. Hood, Brian L. Dalgard, Clifton L. Wilkerson, Matthew D. Phippen, Neil T. Conrads, Thomas P. Maxwell, George L. Sood, Anil K. Gershenson, David M. J Transl Med Research BACKGROUND: Low-grade serous ovarian cancer (LGSOC) is a rare disease that occurs more frequently in younger women than those with high-grade disease. The current treatment is suboptimal and a better understanding of the molecular pathogenesis of this disease is required. In this study, we compared the proteogenomic analyses of LGSOCs from short- and long-term survivors (defined as < 40 and > 60 months, respectively). Our goal was to identify novel mutations, proteins, and mRNA transcripts that are dysregulated in LGSOC, particularly in short-term survivors. METHODS: Initially, targeted sequencing of 409 cancer-related genes was performed on 22 LGSOC and 6 serous borderline ovarian tumor samples. Subsequently, whole-genome sequencing analysis was performed on 14 LGSOC samples (7 long-term survivors and 7 short-term survivors) with matched normal tissue samples. RNA sequencing (RNA-seq), quantitative proteomics, and phosphoproteomic analyses were also performed. RESULTS: We identified single-nucleotide variants (SNVs) (range: 5688–14,833 per sample), insertion and deletion variants (indels) (range: 880–1065), and regions with copy number variants (CNVs) (range: 62–335) among the 14 LGSOC samples. Among all SNVs and indels, 2637 mutation sites were found in the exonic regions. The allele frequencies of the detected variants were low (median12%). The identified recurrent nonsynonymous missense mutations included KRAS, NRAS, EIF1AX, UBR5, and DNM3 mutations. Mutations in DNM3 and UBR5 have not previously been reported in LGSOC. For the two samples, somatic DNM3 nonsynonymous missense mutations in the exonic region were validated using Sanger sequencing. The third sample contained two missense mutations in the intronic region of DNM3, leading to a frameshift mutation detected in RNA transcripts in the RNA-seq data. Among the 14 LGSOC samples, 7754 proteins and 9733 phosphosites were detected by global proteomic analysis. Some of these proteins and signaling pathways, such as BST1, TBXAS1, MPEG1, HBA1, and phosphorylated ASAP1, are potential therapeutic targets. CONCLUSIONS: This is the first study to use whole-genome sequencing to detect somatic mutations in LGSOCs with matched normal tissues. We detected and validated novel mutations in DNM3, which were present in 3 of the 14 samples analyzed. Additionally, we identified novel indels, regions with CNVs, dysregulated mRNA, dysregulated proteins, and phosphosites that are more prevalent in short-term survivors. This integrated proteogenomic analysis can guide research into the pathogenesis and treatment of LGSOC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-022-03820-x. BioMed Central 2022-12-17 /pmc/articles/PMC9758924/ /pubmed/36528667 http://dx.doi.org/10.1186/s12967-022-03820-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Wong, Kwong-Kwok
Bateman, Nicholas W.
Ng, Chun Wai
Tsang, Yvonne T. M.
Sun, Charlotte S.
Celestino, Joseph
Nguyen, Tri V.
Malpica, Anais
Hillman, R. Tyler
Zhang, Jianhua
Futreal, P. Andrew
Rojas, Christine
Conrads, Kelly A.
Hood, Brian L.
Dalgard, Clifton L.
Wilkerson, Matthew D.
Phippen, Neil T.
Conrads, Thomas P.
Maxwell, George L.
Sood, Anil K.
Gershenson, David M.
Integrated multi-omic analysis of low-grade ovarian serous carcinoma collected from short and long-term survivors
title Integrated multi-omic analysis of low-grade ovarian serous carcinoma collected from short and long-term survivors
title_full Integrated multi-omic analysis of low-grade ovarian serous carcinoma collected from short and long-term survivors
title_fullStr Integrated multi-omic analysis of low-grade ovarian serous carcinoma collected from short and long-term survivors
title_full_unstemmed Integrated multi-omic analysis of low-grade ovarian serous carcinoma collected from short and long-term survivors
title_short Integrated multi-omic analysis of low-grade ovarian serous carcinoma collected from short and long-term survivors
title_sort integrated multi-omic analysis of low-grade ovarian serous carcinoma collected from short and long-term survivors
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9758924/
https://www.ncbi.nlm.nih.gov/pubmed/36528667
http://dx.doi.org/10.1186/s12967-022-03820-x
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