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 Article Swipe
Che‐Jui Lee
,
Elodie Modave
,
Bram Boeckx
,
Bernd Kasper
,
Steinar Aamdal
,
Michael Leahy
,
Piotr Rutkowski
,
Sebastian Bauer
,
Maria Dêbiec‐Rychter
,
Raf Sciot
,
Diether Lambrechts
,
Agnieszka Woźniak
,
Patrick Schöffski
·
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.3390/ijms23105689
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.3390/ijms23105689
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.
Related Topics
Concepts
Crizotinib
Alveolar soft part sarcoma
Tissue microarray
Biology
Soft tissue sarcoma
Fluorescence in situ hybridization
Cancer research
Sarcoma
Cancer
Pathology
Tumor microenvironment
Lung cancer
Medicine
Genetics
Gene
Chromosome
Malignant pleural effusion
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.3390/ijms23105689
- https://www.mdpi.com/1422-0067/23/10/5689/pdf?version=1653026311
- OA Status
- gold
- Cited By
- 6
- References
- 62
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4280612056
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4280612056Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.3390/ijms23105689Digital Object Identifier
- 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” TrialWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2022Year of publication
- Publication date
-
2022-05-19Full publication date if available
- Authors
-
Che‐Jui Lee, Elodie Modave, Bram Boeckx, Bernd Kasper, Steinar Aamdal, Michael Leahy, Piotr Rutkowski, Sebastian Bauer, Maria Dêbiec‐Rychter, Raf Sciot, Diether Lambrechts, Agnieszka Woźniak, Patrick SchöffskiList of authors in order
- Landing page
-
https://doi.org/10.3390/ijms23105689Publisher landing page
- PDF URL
-
https://www.mdpi.com/1422-0067/23/10/5689/pdf?version=1653026311Direct link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://www.mdpi.com/1422-0067/23/10/5689/pdf?version=1653026311Direct OA link when available
- Concepts
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Crizotinib, Alveolar soft part sarcoma, Tissue microarray, Biology, Soft tissue sarcoma, Fluorescence in situ hybridization, Cancer research, Sarcoma, Cancer, Pathology, Tumor microenvironment, Lung cancer, Medicine, Genetics, Gene, Chromosome, Malignant pleural effusionTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
6Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 2, 2024: 1, 2023: 3Per-year citation counts (last 5 years)
- References (count)
-
62Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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| primary_location.is_published | True |
| primary_location.raw_source_name | International Journal of Molecular Sciences |
| primary_location.landing_page_url | https://doi.org/10.3390/ijms23105689 |
| publication_date | 2022-05-19 |
| publication_year | 2022 |
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