The landscape of genetic aberrations in myxofibrosarcoma

Myxofibrosarcoma (MFS) is a rare subtype of sarcoma, whose genetic basis is poorly understood. We analyzed 69 MFS cases using whole‐genome (WGS), whole‐exome (WES) and/or targeted‐sequencing (TS). Newly sequenced genomic data were combined with additional deposited 116 MFS samples. WGS identified a high number of structural variations (SVs) per tumor most frequently affecting the TP53 and RB1 loci, 40% of tumors showed a BRCAness‐associated mutation signature, and evidence of chromothripsis was found in all cases. Most frequently mutated/copy number altered genes affected known disease drivers such as TP53 (56.2%), CDKN2A/B (29.7%), RB1 (27.0%), ATRX (19.5%) and HDLBP (18.9%). Several previously unappreciated genetic aberrations including MUC17, FLG and ZNF780A were identified in more than 20% of patients. Longitudinal analysis of paired diagnosis and relapse time points revealed a 1.2‐fold mutation number increase accompanied with substantial changes in clonal composition over time. Our study highlights the genetic complexity underlying sarcomagenesis of MFS.

黏液纤维肉瘤（MFS）是一种罕见的肉瘤亚型，其遗传基础了解甚少。我们使用全基因组测序（WGS）、全外显子组测序（WES）和/或靶向测序（TS）分析了69例MFS病例。新测序的基因组数据与另外116例已存档的MFS样本相结合。WGS发现每个肿瘤存在大量结构变异（SVs），最常影响TP53和RB1基因座，40%的肿瘤显示出与BRCAness相关的突变特征，并且在所有病例中都发现了染色体碎裂的证据。最常发生突变/拷贝数改变的基因影响已知的疾病驱动因子，如TP53（56.2%）、CDKN2A/B（29.7%）、RB1（27.0%）、ATRX（19.5%）和HDLBP（18.9%）。在超过20%的患者中发现了几种此前未被重视的基因异常，包括MUC17、FLG和ZNF780A。对成对的诊断和复发时间点进行纵向分析显示，随着时间推移，突变数量增加了1.2倍，同时克隆组成发生了重大变化。我们的研究强调了MFS肉瘤发生的遗传复杂性。