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A clinico-genomic analysis of soft tissue sarcoma patients reveals CDKN2A deletion as a biomarker for poor prognosis

BACKGROUND: Sarcomas are a rare, heterogeneous group of tumors with variable tendencies for aggressive behavior. Molecular markers for prognosis are needed to risk stratify patients and identify those who might benefit from more intensive therapeutic strategies. PATIENTS AND METHODS: We analyzed som...

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Autores principales: Bui, Nam Q., Przybyl, Joanna, Trabucco, Sally E., Frampton, Garrett, Hastie, Trevor, van de Rijn, Matt, Ganjoo, Kristen N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739971/
https://www.ncbi.nlm.nih.gov/pubmed/31528332
http://dx.doi.org/10.1186/s13569-019-0122-5
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author Bui, Nam Q.
Przybyl, Joanna
Trabucco, Sally E.
Frampton, Garrett
Hastie, Trevor
van de Rijn, Matt
Ganjoo, Kristen N.
author_facet Bui, Nam Q.
Przybyl, Joanna
Trabucco, Sally E.
Frampton, Garrett
Hastie, Trevor
van de Rijn, Matt
Ganjoo, Kristen N.
author_sort Bui, Nam Q.
collection PubMed
description BACKGROUND: Sarcomas are a rare, heterogeneous group of tumors with variable tendencies for aggressive behavior. Molecular markers for prognosis are needed to risk stratify patients and identify those who might benefit from more intensive therapeutic strategies. PATIENTS AND METHODS: We analyzed somatic tumor genomic profiles and clinical outcomes of 152 soft tissue (STS) and bone sarcoma (BS) patients sequenced at Stanford Cancer Institute as well as 206 STS patients from The Cancer Genome Atlas. Genomic profiles of 7733 STS from the Foundation Medicine database were used to assess the frequency of CDKN2A alterations in histological subtypes of sarcoma. RESULTS: Compared to all other tumor types, sarcomas were found to carry the highest relative percentage of gene amplifications/deletions/fusions and the lowest average mutation count. The most commonly altered genes in STS were TP53 (47%), CDKN2A (22%), RB1 (22%), NF1 (11%), and ATRX (11%). When all genomic alterations were tested for prognostic significance in the specific Stanford cohort of localized STS, only CDKN2A alterations correlated significantly with prognosis, with a hazard ratio (HR) of 2.83 for overall survival (p = 0.017). These findings were validated in the TCGA dataset where CDKN2A altered patients had significantly worse overall survival with a HR of 2.7 (p = 0.002). Analysis of 7733 STS patients from Foundation One showed high prevalence of CDKN2A alterations in malignant peripheral nerve sheath tumors, myxofibrosarcomas, and undifferentiated pleomorphic sarcomas. CONCLUSION: Our clinico-genomic profiling of STS shows that CDKN2A deletion was the most prevalent DNA copy number aberration and was associated with poor prognosis.
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spelling pubmed-67399712019-09-16 A clinico-genomic analysis of soft tissue sarcoma patients reveals CDKN2A deletion as a biomarker for poor prognosis Bui, Nam Q. Przybyl, Joanna Trabucco, Sally E. Frampton, Garrett Hastie, Trevor van de Rijn, Matt Ganjoo, Kristen N. Clin Sarcoma Res Research BACKGROUND: Sarcomas are a rare, heterogeneous group of tumors with variable tendencies for aggressive behavior. Molecular markers for prognosis are needed to risk stratify patients and identify those who might benefit from more intensive therapeutic strategies. PATIENTS AND METHODS: We analyzed somatic tumor genomic profiles and clinical outcomes of 152 soft tissue (STS) and bone sarcoma (BS) patients sequenced at Stanford Cancer Institute as well as 206 STS patients from The Cancer Genome Atlas. Genomic profiles of 7733 STS from the Foundation Medicine database were used to assess the frequency of CDKN2A alterations in histological subtypes of sarcoma. RESULTS: Compared to all other tumor types, sarcomas were found to carry the highest relative percentage of gene amplifications/deletions/fusions and the lowest average mutation count. The most commonly altered genes in STS were TP53 (47%), CDKN2A (22%), RB1 (22%), NF1 (11%), and ATRX (11%). When all genomic alterations were tested for prognostic significance in the specific Stanford cohort of localized STS, only CDKN2A alterations correlated significantly with prognosis, with a hazard ratio (HR) of 2.83 for overall survival (p = 0.017). These findings were validated in the TCGA dataset where CDKN2A altered patients had significantly worse overall survival with a HR of 2.7 (p = 0.002). Analysis of 7733 STS patients from Foundation One showed high prevalence of CDKN2A alterations in malignant peripheral nerve sheath tumors, myxofibrosarcomas, and undifferentiated pleomorphic sarcomas. CONCLUSION: Our clinico-genomic profiling of STS shows that CDKN2A deletion was the most prevalent DNA copy number aberration and was associated with poor prognosis. BioMed Central 2019-09-11 /pmc/articles/PMC6739971/ /pubmed/31528332 http://dx.doi.org/10.1186/s13569-019-0122-5 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Bui, Nam Q.
Przybyl, Joanna
Trabucco, Sally E.
Frampton, Garrett
Hastie, Trevor
van de Rijn, Matt
Ganjoo, Kristen N.
A clinico-genomic analysis of soft tissue sarcoma patients reveals CDKN2A deletion as a biomarker for poor prognosis
title A clinico-genomic analysis of soft tissue sarcoma patients reveals CDKN2A deletion as a biomarker for poor prognosis
title_full A clinico-genomic analysis of soft tissue sarcoma patients reveals CDKN2A deletion as a biomarker for poor prognosis
title_fullStr A clinico-genomic analysis of soft tissue sarcoma patients reveals CDKN2A deletion as a biomarker for poor prognosis
title_full_unstemmed A clinico-genomic analysis of soft tissue sarcoma patients reveals CDKN2A deletion as a biomarker for poor prognosis
title_short A clinico-genomic analysis of soft tissue sarcoma patients reveals CDKN2A deletion as a biomarker for poor prognosis
title_sort clinico-genomic analysis of soft tissue sarcoma patients reveals cdkn2a deletion as a biomarker for poor prognosis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739971/
https://www.ncbi.nlm.nih.gov/pubmed/31528332
http://dx.doi.org/10.1186/s13569-019-0122-5
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