The landscape of genetic aberrations in myxofibrosarcoma. Issue 4 (13th May 2022)

• Record Type: Journal Article
• Authors: Takeuchi, Yasuhide; Yoshida, Kenichi; Halik, Adriane; Kunitz, Annegret; Suzuki, Hiromichi; Kakiuchi, Nobuyuki; Shiozawa, Yusuke; Yokoyama, Akira; Inoue, Yoshikage; Hirano, Tomonori; Yoshizato, Tetsuichi; Aoki, Kosuke; Fujii, Yoichi; Nannya, Yasuhito; Makishima, Hideki; Pfitzner, Berit Maria; Bullinger, Lars; Hirata, Masahiro; Jinnouchi, Keita; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Okamoto, Takeshi; Haga, Hironori; Ogawa, Seishi; Damm, Frederik
• Is Part Of: International journal of cancer. Volume 151:Issue 4(2022)
• Page Start: 565
• Page End: 577
• Publication Date: 2022-05-13
• Subjects: druggable alterations -- genetics -- myxofibrosarcoma -- whole genome/exome/targeted‐capture sequence; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.34051
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract: 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. Abstract : What's new? The genetic basis of myxofibrosarcoma, a rare subtype of sarcoma, remains poorly understood. This large‐scale integrated genetic study of 185 myxofibrosarcoma cases reveals ubiquitous genetic complexity, including the common occurrence of chromothripsis accompanied with local hypermutation. The results also highlight mutually exclusive alterations in CDKN2A/B and HDLBP on the one hand, and co‐occurrence of mutations in TP53 and other genes implicated in DNA double‐strand break repair on the other hand. Taken together, the findings offer a strong rational for investigating PARP inhibition and/or restoration of normal p53 function as potential treatment avenues for myxofibrosarcoma.