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A novel TP53-KPNA3 translocation defines a de novo treatment-resistant clone in osteosarcoma

Osteosarcoma is the most common primary bone cancer. It can be cured by aggressive surgery and chemotherapy, but outcomes for metastatic or chemoresistant disease remain dismal. Cancer sequencing studies have shown that the p53 pathway is dysregulated in nearly every case, often by translocation; ho...

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Autores principales: Chen, Kenneth S., Kwon, Woo Sun, Kim, Jiwoong, Heo, Su Jin, Kim, Hyo Song, Kim, Hyo Ki, Kim, Soo Hee, Lee, Won Suk, Chung, Hyun Cheol, Rha, Sun Young, Hwang, Tae Hyun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002927/
https://www.ncbi.nlm.nih.gov/pubmed/27626065
http://dx.doi.org/10.1101/mcs.a000992
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author Chen, Kenneth S.
Kwon, Woo Sun
Kim, Jiwoong
Heo, Su Jin
Kim, Hyo Song
Kim, Hyo Ki
Kim, Soo Hee
Lee, Won Suk
Chung, Hyun Cheol
Rha, Sun Young
Hwang, Tae Hyun
author_facet Chen, Kenneth S.
Kwon, Woo Sun
Kim, Jiwoong
Heo, Su Jin
Kim, Hyo Song
Kim, Hyo Ki
Kim, Soo Hee
Lee, Won Suk
Chung, Hyun Cheol
Rha, Sun Young
Hwang, Tae Hyun
author_sort Chen, Kenneth S.
collection PubMed
description Osteosarcoma is the most common primary bone cancer. It can be cured by aggressive surgery and chemotherapy, but outcomes for metastatic or chemoresistant disease remain dismal. Cancer sequencing studies have shown that the p53 pathway is dysregulated in nearly every case, often by translocation; however, no studies of osteosarcoma evolution or intratumor heterogeneity have been done to date. We studied a patient with chemoresistant, metastatic disease over the course of 3 years. We performed exome sequencing on germline DNA and DNA collected from tumor at three separate time points. We compared variant calls and variant allele frequencies between different samples. We identified subclonal mutations in several different genes in the primary tumor sample and found that one particular subclone dominated subsequent tumor samples at relapse. This clone was marked by a novel TP53-KPNA3 translocation and loss of the opposite-strand wild-type TP53 allele. Future research must focus on the functional significance of such clones and strategies to eliminate them.
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spelling pubmed-50029272016-09-13 A novel TP53-KPNA3 translocation defines a de novo treatment-resistant clone in osteosarcoma Chen, Kenneth S. Kwon, Woo Sun Kim, Jiwoong Heo, Su Jin Kim, Hyo Song Kim, Hyo Ki Kim, Soo Hee Lee, Won Suk Chung, Hyun Cheol Rha, Sun Young Hwang, Tae Hyun Cold Spring Harb Mol Case Stud Research Report Osteosarcoma is the most common primary bone cancer. It can be cured by aggressive surgery and chemotherapy, but outcomes for metastatic or chemoresistant disease remain dismal. Cancer sequencing studies have shown that the p53 pathway is dysregulated in nearly every case, often by translocation; however, no studies of osteosarcoma evolution or intratumor heterogeneity have been done to date. We studied a patient with chemoresistant, metastatic disease over the course of 3 years. We performed exome sequencing on germline DNA and DNA collected from tumor at three separate time points. We compared variant calls and variant allele frequencies between different samples. We identified subclonal mutations in several different genes in the primary tumor sample and found that one particular subclone dominated subsequent tumor samples at relapse. This clone was marked by a novel TP53-KPNA3 translocation and loss of the opposite-strand wild-type TP53 allele. Future research must focus on the functional significance of such clones and strategies to eliminate them. Cold Spring Harbor Laboratory Press 2016-09 /pmc/articles/PMC5002927/ /pubmed/27626065 http://dx.doi.org/10.1101/mcs.a000992 Text en © 2016 Chen et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.
spellingShingle Research Report
Chen, Kenneth S.
Kwon, Woo Sun
Kim, Jiwoong
Heo, Su Jin
Kim, Hyo Song
Kim, Hyo Ki
Kim, Soo Hee
Lee, Won Suk
Chung, Hyun Cheol
Rha, Sun Young
Hwang, Tae Hyun
A novel TP53-KPNA3 translocation defines a de novo treatment-resistant clone in osteosarcoma
title A novel TP53-KPNA3 translocation defines a de novo treatment-resistant clone in osteosarcoma
title_full A novel TP53-KPNA3 translocation defines a de novo treatment-resistant clone in osteosarcoma
title_fullStr A novel TP53-KPNA3 translocation defines a de novo treatment-resistant clone in osteosarcoma
title_full_unstemmed A novel TP53-KPNA3 translocation defines a de novo treatment-resistant clone in osteosarcoma
title_short A novel TP53-KPNA3 translocation defines a de novo treatment-resistant clone in osteosarcoma
title_sort novel tp53-kpna3 translocation defines a de novo treatment-resistant clone in osteosarcoma
topic Research Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002927/
https://www.ncbi.nlm.nih.gov/pubmed/27626065
http://dx.doi.org/10.1101/mcs.a000992
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