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Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germline CHEK2:c.1100delC mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma

We describe a woman with the known pathogenic germline variant CHEK2:c.1100delC and synchronous diagnoses of both pelvic genital type leiomyosarcoma (LMS) and metastatic invasive ductal breast carcinoma. CHEK2 (checkpoint kinase 2) is a tumor-suppressor gene encoding a serine/threonine-protein kinas...

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Autores principales: Thibodeau, My Linh, Reisle, Caralyn, Zhao, Eric, Martin, Lee Ann, Alwelaie, Yazeed, Mungall, Karen L., Ch'ng, Carolyn, Thomas, Ruth, Ng, Tony, Yip, Stephen, J. Lim, Howard, Sun, Sophie, Young, Sean S., Karsan, Aly, Zhao, Yongjun, Mungall, Andrew J., Moore, Richard A., J. Renouf, Daniel, Gelmon, Karen, Ma, Yussanne P., Hayes, Malcolm, Laskin, Janessa, Marra, Marco A., Schrader, Kasmintan A., Jones, Steven J. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593158/
https://www.ncbi.nlm.nih.gov/pubmed/28514723
http://dx.doi.org/10.1101/mcs.a001628
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author Thibodeau, My Linh
Reisle, Caralyn
Zhao, Eric
Martin, Lee Ann
Alwelaie, Yazeed
Mungall, Karen L.
Ch'ng, Carolyn
Thomas, Ruth
Ng, Tony
Yip, Stephen
J. Lim, Howard
Sun, Sophie
Young, Sean S.
Karsan, Aly
Zhao, Yongjun
Mungall, Andrew J.
Moore, Richard A.
J. Renouf, Daniel
Gelmon, Karen
Ma, Yussanne P.
Hayes, Malcolm
Laskin, Janessa
Marra, Marco A.
Schrader, Kasmintan A.
Jones, Steven J. M.
author_facet Thibodeau, My Linh
Reisle, Caralyn
Zhao, Eric
Martin, Lee Ann
Alwelaie, Yazeed
Mungall, Karen L.
Ch'ng, Carolyn
Thomas, Ruth
Ng, Tony
Yip, Stephen
J. Lim, Howard
Sun, Sophie
Young, Sean S.
Karsan, Aly
Zhao, Yongjun
Mungall, Andrew J.
Moore, Richard A.
J. Renouf, Daniel
Gelmon, Karen
Ma, Yussanne P.
Hayes, Malcolm
Laskin, Janessa
Marra, Marco A.
Schrader, Kasmintan A.
Jones, Steven J. M.
author_sort Thibodeau, My Linh
collection PubMed
description We describe a woman with the known pathogenic germline variant CHEK2:c.1100delC and synchronous diagnoses of both pelvic genital type leiomyosarcoma (LMS) and metastatic invasive ductal breast carcinoma. CHEK2 (checkpoint kinase 2) is a tumor-suppressor gene encoding a serine/threonine-protein kinase (CHEK2) involved in double-strand DNA break repair and cell cycle arrest. The CHEK2:c.1100delC variant is a moderate penetrance allele resulting in an approximately twofold increase in breast cancer risk. Whole-genome and whole-transcriptome sequencing were performed on the leiomyosarcoma and matched blood-derived DNA. Despite the presence of several genomic hits within the double-strand DNA damage pathway (CHEK2 germline variant and multiple RAD51B somatic structural variants), tumor profiling did not show an obvious DNA repair deficiency signature. However, even though the LMS displayed clear malignant features, its genomic profiling revealed several characteristics classically associated with leiomyomas including a translocation, t(12;14), with one breakpoint disrupting RAD51B and the other breakpoint upstream of HMGA2 with very high expression of HMGA2 and PLAG1. This is the first report of LMS genomic profiling in a patient with the germline CHEK2:c.1100delC variant and an additional diagnosis of metastatic invasive ductal breast carcinoma. We also describe a possible mechanistic relationship between leiomyoma and LMS based on genomic and transcriptome data. Our findings suggest that RAD51B translocation and HMGA2 overexpression may play an important role in LMS oncogenesis.
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spelling pubmed-55931582017-09-14 Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germline CHEK2:c.1100delC mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma Thibodeau, My Linh Reisle, Caralyn Zhao, Eric Martin, Lee Ann Alwelaie, Yazeed Mungall, Karen L. Ch'ng, Carolyn Thomas, Ruth Ng, Tony Yip, Stephen J. Lim, Howard Sun, Sophie Young, Sean S. Karsan, Aly Zhao, Yongjun Mungall, Andrew J. Moore, Richard A. J. Renouf, Daniel Gelmon, Karen Ma, Yussanne P. Hayes, Malcolm Laskin, Janessa Marra, Marco A. Schrader, Kasmintan A. Jones, Steven J. M. Cold Spring Harb Mol Case Stud Research Report We describe a woman with the known pathogenic germline variant CHEK2:c.1100delC and synchronous diagnoses of both pelvic genital type leiomyosarcoma (LMS) and metastatic invasive ductal breast carcinoma. CHEK2 (checkpoint kinase 2) is a tumor-suppressor gene encoding a serine/threonine-protein kinase (CHEK2) involved in double-strand DNA break repair and cell cycle arrest. The CHEK2:c.1100delC variant is a moderate penetrance allele resulting in an approximately twofold increase in breast cancer risk. Whole-genome and whole-transcriptome sequencing were performed on the leiomyosarcoma and matched blood-derived DNA. Despite the presence of several genomic hits within the double-strand DNA damage pathway (CHEK2 germline variant and multiple RAD51B somatic structural variants), tumor profiling did not show an obvious DNA repair deficiency signature. However, even though the LMS displayed clear malignant features, its genomic profiling revealed several characteristics classically associated with leiomyomas including a translocation, t(12;14), with one breakpoint disrupting RAD51B and the other breakpoint upstream of HMGA2 with very high expression of HMGA2 and PLAG1. This is the first report of LMS genomic profiling in a patient with the germline CHEK2:c.1100delC variant and an additional diagnosis of metastatic invasive ductal breast carcinoma. We also describe a possible mechanistic relationship between leiomyoma and LMS based on genomic and transcriptome data. Our findings suggest that RAD51B translocation and HMGA2 overexpression may play an important role in LMS oncogenesis. Cold Spring Harbor Laboratory Press 2017-09 /pmc/articles/PMC5593158/ /pubmed/28514723 http://dx.doi.org/10.1101/mcs.a001628 Text en © 2017 Thibodeau 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
Thibodeau, My Linh
Reisle, Caralyn
Zhao, Eric
Martin, Lee Ann
Alwelaie, Yazeed
Mungall, Karen L.
Ch'ng, Carolyn
Thomas, Ruth
Ng, Tony
Yip, Stephen
J. Lim, Howard
Sun, Sophie
Young, Sean S.
Karsan, Aly
Zhao, Yongjun
Mungall, Andrew J.
Moore, Richard A.
J. Renouf, Daniel
Gelmon, Karen
Ma, Yussanne P.
Hayes, Malcolm
Laskin, Janessa
Marra, Marco A.
Schrader, Kasmintan A.
Jones, Steven J. M.
Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germline CHEK2:c.1100delC mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma
title Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germline CHEK2:c.1100delC mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma
title_full Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germline CHEK2:c.1100delC mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma
title_fullStr Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germline CHEK2:c.1100delC mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma
title_full_unstemmed Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germline CHEK2:c.1100delC mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma
title_short Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germline CHEK2:c.1100delC mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma
title_sort genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germline chek2:c.1100delc mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma
topic Research Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593158/
https://www.ncbi.nlm.nih.gov/pubmed/28514723
http://dx.doi.org/10.1101/mcs.a001628
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