TY - JOUR
T1 - Chromosome 8 gain is associated with high-grade transformation in MPNST
AU - Dehner, Carina
AU - Moon, Chang In
AU - Zhang, Xiyuan
AU - Zhou, Zhaohe
AU - Miller, Chris
AU - Xu, Hua
AU - Wan, Xiaodan
AU - Yang, Kuangying
AU - Mashl, Jay
AU - Gosline, Sara J.C.
AU - Wang, Yuxi
AU - Zhang, Xiaochun
AU - Godec, Abigail
AU - Jones, Paul A.
AU - Dahiya, Sonika
AU - Bhatia, Himanshi
AU - Primeau, Tina
AU - Li, Shunqiang
AU - Pollard, Kai
AU - Rodriguez, Fausto J.
AU - Ding, Li
AU - Pratilas, Christine A.
AU - Shern, Jack F.
AU - Hirbe, Angela C.
N1 - Publisher Copyright:
Copyright: © 2021, Dehner et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2021/3/22
Y1 - 2021/3/22
N2 - One of the most common malignancies affecting adults with Neurofibromatosis type 1 (NF1) is the malignant peripheral nerve sheath tumor (MPNST), an aggressive and often fatal sarcoma that commonly arises from benign plexiform neurofibromas. Despite advances in our understanding of MPNST pathobiology, there are few effective therapeutic options, and no investigational agents have proven successful in clinical trials. To further understand the genomic heterogeneity of MPNST, and to generate a preclinical platform that encompasses this heterogeneity, we developed a collection of NF1-MPNST patient-derived xenografts (PDX). These PDX were compared with the primary tumors from which they were derived using copy number analysis, whole exome sequencing, and RNA sequencing. We identified chromosome 8 gain as a recurrent genomic event in MPNST and validated its occurrence by FISH in the PDX and parental tumors, in a validation cohort, and by single-cell sequencing in the PDX. Finally, we show that chromosome 8 gain is associated with inferior overall survival in soft-tissue sarcomas. These data suggest that chromosome 8 gain is a critical event in MPNST pathogenesis and may account for the aggressive nature and poor outcomes in this sarcoma subtype.
AB - One of the most common malignancies affecting adults with Neurofibromatosis type 1 (NF1) is the malignant peripheral nerve sheath tumor (MPNST), an aggressive and often fatal sarcoma that commonly arises from benign plexiform neurofibromas. Despite advances in our understanding of MPNST pathobiology, there are few effective therapeutic options, and no investigational agents have proven successful in clinical trials. To further understand the genomic heterogeneity of MPNST, and to generate a preclinical platform that encompasses this heterogeneity, we developed a collection of NF1-MPNST patient-derived xenografts (PDX). These PDX were compared with the primary tumors from which they were derived using copy number analysis, whole exome sequencing, and RNA sequencing. We identified chromosome 8 gain as a recurrent genomic event in MPNST and validated its occurrence by FISH in the PDX and parental tumors, in a validation cohort, and by single-cell sequencing in the PDX. Finally, we show that chromosome 8 gain is associated with inferior overall survival in soft-tissue sarcomas. These data suggest that chromosome 8 gain is a critical event in MPNST pathogenesis and may account for the aggressive nature and poor outcomes in this sarcoma subtype.
UR - http://www.scopus.com/inward/record.url?scp=85103265102&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.146351
DO - 10.1172/jci.insight.146351
M3 - Article
C2 - 33591953
AN - SCOPUS:85103265102
SN - 2379-3708
VL - 6
JO - JCI Insight
JF - JCI Insight
IS - 6
M1 - e146351
ER -