Abstract 3384: Comprehensive genetic analysis of myxofibrosarcoma and comparison with other soft tissue sarcomas
Authors: Takeuchi Yasuhide , Kunitz Annegret , Suzuki Hiromichi , Yoshida Kenichi , Shiraishi Yuichi , Shimamura Teppei , Chiba Kenichi , Tanaka Hiroko , Kakiuchi Nobuyuki , Shiozawa Yusuke , Yokoyama Akira , Yoshizato Tetsuichi , Aoki Kosuke , Fujii Yoichi , Makishima Hideki , Haga Hironori , Miyano Satoru , Damm Frederik , Ogawa Seishi 
Published: July 2017

Abstract
Background:
Myxofibrosarcoma (MFS) is a relatively common subtype of soft tissue sarcomas (STSs) in the elderly, which is characterized by the proliferation of pleomorphic spindle cells with varying degrees of the myxoid component and on the basis of this unique histological picture, together with other clinical characteristics, is separated from other STSs. However, the genetic basis of MFS is poorly understood.
Aims and Methods:
The purpose of this study is to clarify the comprehensive registry of genetic alterations in MFS and other STSs using whole exome/genome sequencing (WES/WGS) of paired tumor/normal DNA from 41 samples with MFS, combined with the WES data of 25 samples with MFS and 234 with STS, which were available from The Cancer Genome Atlas (TCGA) database. WGS was performed in 2 cases. Data for DNA methylation and gene expression from the TCGA registry were also analyzed. Moreover, the genetic basis of mixed histological components characteristic of MFS and its chronological changes was interrogated using multi-regional and/or multi-time points sampling.
Results:
A total of 8,661 mutations were identified in WES of 66 primary MFS samples with a median of 131.2 mutations/sample, which were dominated by age-related C to T transitions at CpG sites. WGS (n = 2) detected 491 and 198 somatic structural variations in each case, which suggested MFSs have undergone complex chromosomal rearrangements. Most frequently mutated genes included TP53 (n = 19, 28.8%), ATRX (n = 10, 15.5%), and RB1 (n = 8, 12.1%), which were also detected in several types of STSs (n = 234) at similar frequencies with no mutations being specifically associated with MFS compared to other STSs. However, interestingly, STSs were reproducibly clustered into four distinct subtypes based on DNA methylation and gene expression (Cramér's V = 0.73), regardless of the histological classification. These subtypes based on DNA methylation and gene expression showed stronger correlations with the prognosis (p-value: 0.025, 0.028, respectively) than the histological classification (p-value = 0.528). Paired multi-regional sampling (n = 4) analysis disclosed high degrees of intratumor heterogeneity with less than 27% (range 9.5-26.6%) mutations being shared by different sampling. Multi-time points sampling analysis (n = 6) showed that the number of mutations did not significantly differ between primary and relapsed tumors (p-value = 0.35). There were no recurrent morphological feature-associated or relapse-specific mutational/copy number alterations.
Conclusions:
MFS is characterized by frequent mutations in TP53, ATRX, and RB1. STSs, including MFS, are classified into 4 distinct subgroups based on DNA methylation and gene expression, which correlated well with clinical outcomes. There were high degrees of intratumor heterogeneity in terms of mutations, which however, showed no clear correlation with morphological features.
Citation Format: Yasuhide Takeuchi, Annegret Kunitz, Hiromichi Suzuki, Kenichi Yoshida, Yuichi Shiraishi, Teppei Shimamura, Kenichi Chiba, Hiroko Tanaka, Nobuyuki Kakiuchi, Yusuke Shiozawa, Akira Yokoyama, Tetsuichi Yoshizato, Kosuke Aoki, Yoichi Fujii, Hideki Makishima, Hironori Haga, Satoru Miyano, Frederik Damm, Seishi Ogawa. Comprehensive genetic analysis of myxofibrosarcoma and comparison with other soft tissue sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3384. doi:10.1158/1538-7445.AM2017-3384