Cargando…

Correlation of Immunological and Molecular Profiles with Response to Crizotinib in Alveolar Soft Part Sarcoma: An Exploratory Study Related to the EORTC 90101 “CREATE” Trial

Alveolar soft part sarcoma (ASPS) is a rare subtype of soft tissue sarcoma characterized by an unbalanced translocation, resulting in ASPSCR1-TFE3 fusion that transcriptionally upregulates MET expression. The European Organization for Research and Treatment of Cancer (EORTC) 90101 “CREATE” phase II...

Descripción completa

Detalles Bibliográficos
Autores principales: Lee, Che-Jui, Modave, Elodie, Boeckx, Bram, Kasper, Bernd, Aamdal, Steinar, Leahy, Michael G., Rutkowski, Piotr, Bauer, Sebastian, Debiec-Rychter, Maria, Sciot, Raf, Lambrechts, Diether, Wozniak, Agnieszka, Schöffski, Patrick
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9145625/
https://www.ncbi.nlm.nih.gov/pubmed/35628499
http://dx.doi.org/10.3390/ijms23105689
_version_ 1784716359934935040
author Lee, Che-Jui
Modave, Elodie
Boeckx, Bram
Kasper, Bernd
Aamdal, Steinar
Leahy, Michael G.
Rutkowski, Piotr
Bauer, Sebastian
Debiec-Rychter, Maria
Sciot, Raf
Lambrechts, Diether
Wozniak, Agnieszka
Schöffski, Patrick
author_facet Lee, Che-Jui
Modave, Elodie
Boeckx, Bram
Kasper, Bernd
Aamdal, Steinar
Leahy, Michael G.
Rutkowski, Piotr
Bauer, Sebastian
Debiec-Rychter, Maria
Sciot, Raf
Lambrechts, Diether
Wozniak, Agnieszka
Schöffski, Patrick
author_sort Lee, Che-Jui
collection PubMed
description Alveolar soft part sarcoma (ASPS) is a rare subtype of soft tissue sarcoma characterized by an unbalanced translocation, resulting in ASPSCR1-TFE3 fusion that transcriptionally upregulates MET expression. The European Organization for Research and Treatment of Cancer (EORTC) 90101 “CREATE” phase II trial evaluated the MET inhibitor crizotinib in ASPS patients, achieving only limited antitumor activity. We performed a comprehensive molecular analysis of ASPS tissue samples collected in this trial to identify potential biomarkers correlating with treatment outcome. A tissue microarray containing 47 ASPS cases was used for the characterization of the tumor microenvironment using multiplex immunofluorescence. DNA isolated from 34 available tumor samples was analyzed to detect recurrent gene copy number alterations (CNAs) and mutations by low-coverage whole-genome sequencing and whole-exome sequencing. Pathway enrichment analysis was used to identify diseased-associated pathways in ASPS sarcomagenesis. Kaplan–Meier estimates, Cox regression, and the Fisher’s exact test were used to correlate histopathological and molecular findings with clinical data related to crizotinib treatment, aiming to identify potential factors associated with patient outcome. Tumor microenvironment characterization showed the presence of PD-L1 and CTLA-4 in 10 and 2 tumors, respectively, and the absence of PD-1 in all specimens. Apart from CD68, other immunological markers were rarely expressed, suggesting a low level of tumor-infiltrating lymphocytes in ASPS. By CNA analysis, we detected a number of broad and focal alterations. The most common alteration was the loss of chromosomal region 1p36.32 in 44% of cases. The loss of chromosomal regions 1p36.32, 1p33, 1p22.2, and 8p was associated with shorter progression-free survival. Using whole-exome sequencing, 13 cancer-associated genes were found to be mutated in at least three cases. Pathway enrichment analysis identified genetic alterations in NOTCH signaling, chromatin organization, and SUMOylation pathways. NOTCH4 intracellular domain dysregulation was associated with poor outcome, while inactivation of the beta-catenin/TCF complex correlated with improved outcome in patients receiving crizotinib. ASPS is characterized by molecular heterogeneity. We identify genetic aberrations potentially predictive of treatment outcome during crizotinib therapy and provide additional insights into the biology of ASPS, paving the way to improve treatment approaches for this extremely rare malignancy.
format Online
Article
Text
id pubmed-9145625
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-91456252022-05-29 Correlation of Immunological and Molecular Profiles with Response to Crizotinib in Alveolar Soft Part Sarcoma: An Exploratory Study Related to the EORTC 90101 “CREATE” Trial Lee, Che-Jui Modave, Elodie Boeckx, Bram Kasper, Bernd Aamdal, Steinar Leahy, Michael G. Rutkowski, Piotr Bauer, Sebastian Debiec-Rychter, Maria Sciot, Raf Lambrechts, Diether Wozniak, Agnieszka Schöffski, Patrick Int J Mol Sci Article Alveolar soft part sarcoma (ASPS) is a rare subtype of soft tissue sarcoma characterized by an unbalanced translocation, resulting in ASPSCR1-TFE3 fusion that transcriptionally upregulates MET expression. The European Organization for Research and Treatment of Cancer (EORTC) 90101 “CREATE” phase II trial evaluated the MET inhibitor crizotinib in ASPS patients, achieving only limited antitumor activity. We performed a comprehensive molecular analysis of ASPS tissue samples collected in this trial to identify potential biomarkers correlating with treatment outcome. A tissue microarray containing 47 ASPS cases was used for the characterization of the tumor microenvironment using multiplex immunofluorescence. DNA isolated from 34 available tumor samples was analyzed to detect recurrent gene copy number alterations (CNAs) and mutations by low-coverage whole-genome sequencing and whole-exome sequencing. Pathway enrichment analysis was used to identify diseased-associated pathways in ASPS sarcomagenesis. Kaplan–Meier estimates, Cox regression, and the Fisher’s exact test were used to correlate histopathological and molecular findings with clinical data related to crizotinib treatment, aiming to identify potential factors associated with patient outcome. Tumor microenvironment characterization showed the presence of PD-L1 and CTLA-4 in 10 and 2 tumors, respectively, and the absence of PD-1 in all specimens. Apart from CD68, other immunological markers were rarely expressed, suggesting a low level of tumor-infiltrating lymphocytes in ASPS. By CNA analysis, we detected a number of broad and focal alterations. The most common alteration was the loss of chromosomal region 1p36.32 in 44% of cases. The loss of chromosomal regions 1p36.32, 1p33, 1p22.2, and 8p was associated with shorter progression-free survival. Using whole-exome sequencing, 13 cancer-associated genes were found to be mutated in at least three cases. Pathway enrichment analysis identified genetic alterations in NOTCH signaling, chromatin organization, and SUMOylation pathways. NOTCH4 intracellular domain dysregulation was associated with poor outcome, while inactivation of the beta-catenin/TCF complex correlated with improved outcome in patients receiving crizotinib. ASPS is characterized by molecular heterogeneity. We identify genetic aberrations potentially predictive of treatment outcome during crizotinib therapy and provide additional insights into the biology of ASPS, paving the way to improve treatment approaches for this extremely rare malignancy. MDPI 2022-05-19 /pmc/articles/PMC9145625/ /pubmed/35628499 http://dx.doi.org/10.3390/ijms23105689 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lee, Che-Jui
Modave, Elodie
Boeckx, Bram
Kasper, Bernd
Aamdal, Steinar
Leahy, Michael G.
Rutkowski, Piotr
Bauer, Sebastian
Debiec-Rychter, Maria
Sciot, Raf
Lambrechts, Diether
Wozniak, Agnieszka
Schöffski, Patrick
Correlation of Immunological and Molecular Profiles with Response to Crizotinib in Alveolar Soft Part Sarcoma: An Exploratory Study Related to the EORTC 90101 “CREATE” Trial
title Correlation of Immunological and Molecular Profiles with Response to Crizotinib in Alveolar Soft Part Sarcoma: An Exploratory Study Related to the EORTC 90101 “CREATE” Trial
title_full Correlation of Immunological and Molecular Profiles with Response to Crizotinib in Alveolar Soft Part Sarcoma: An Exploratory Study Related to the EORTC 90101 “CREATE” Trial
title_fullStr Correlation of Immunological and Molecular Profiles with Response to Crizotinib in Alveolar Soft Part Sarcoma: An Exploratory Study Related to the EORTC 90101 “CREATE” Trial
title_full_unstemmed Correlation of Immunological and Molecular Profiles with Response to Crizotinib in Alveolar Soft Part Sarcoma: An Exploratory Study Related to the EORTC 90101 “CREATE” Trial
title_short Correlation of Immunological and Molecular Profiles with Response to Crizotinib in Alveolar Soft Part Sarcoma: An Exploratory Study Related to the EORTC 90101 “CREATE” Trial
title_sort correlation of immunological and molecular profiles with response to crizotinib in alveolar soft part sarcoma: an exploratory study related to the eortc 90101 “create” trial
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9145625/
https://www.ncbi.nlm.nih.gov/pubmed/35628499
http://dx.doi.org/10.3390/ijms23105689
work_keys_str_mv AT leechejui correlationofimmunologicalandmolecularprofileswithresponsetocrizotinibinalveolarsoftpartsarcomaanexploratorystudyrelatedtotheeortc90101createtrial
AT modaveelodie correlationofimmunologicalandmolecularprofileswithresponsetocrizotinibinalveolarsoftpartsarcomaanexploratorystudyrelatedtotheeortc90101createtrial
AT boeckxbram correlationofimmunologicalandmolecularprofileswithresponsetocrizotinibinalveolarsoftpartsarcomaanexploratorystudyrelatedtotheeortc90101createtrial
AT kasperbernd correlationofimmunologicalandmolecularprofileswithresponsetocrizotinibinalveolarsoftpartsarcomaanexploratorystudyrelatedtotheeortc90101createtrial
AT aamdalsteinar correlationofimmunologicalandmolecularprofileswithresponsetocrizotinibinalveolarsoftpartsarcomaanexploratorystudyrelatedtotheeortc90101createtrial
AT leahymichaelg correlationofimmunologicalandmolecularprofileswithresponsetocrizotinibinalveolarsoftpartsarcomaanexploratorystudyrelatedtotheeortc90101createtrial
AT rutkowskipiotr correlationofimmunologicalandmolecularprofileswithresponsetocrizotinibinalveolarsoftpartsarcomaanexploratorystudyrelatedtotheeortc90101createtrial
AT bauersebastian correlationofimmunologicalandmolecularprofileswithresponsetocrizotinibinalveolarsoftpartsarcomaanexploratorystudyrelatedtotheeortc90101createtrial
AT debiecrychtermaria correlationofimmunologicalandmolecularprofileswithresponsetocrizotinibinalveolarsoftpartsarcomaanexploratorystudyrelatedtotheeortc90101createtrial
AT sciotraf correlationofimmunologicalandmolecularprofileswithresponsetocrizotinibinalveolarsoftpartsarcomaanexploratorystudyrelatedtotheeortc90101createtrial
AT lambrechtsdiether correlationofimmunologicalandmolecularprofileswithresponsetocrizotinibinalveolarsoftpartsarcomaanexploratorystudyrelatedtotheeortc90101createtrial
AT wozniakagnieszka correlationofimmunologicalandmolecularprofileswithresponsetocrizotinibinalveolarsoftpartsarcomaanexploratorystudyrelatedtotheeortc90101createtrial
AT schoffskipatrick correlationofimmunologicalandmolecularprofileswithresponsetocrizotinibinalveolarsoftpartsarcomaanexploratorystudyrelatedtotheeortc90101createtrial