bims-myxlip 2021-03-28 papers

Issue of 2021–03–28
two papers selected by
Laura Mannarino, Humanitas Research

Oncol Lett. 2021 May;21(5): 353

Potential application of genomic profiling for the diagnosis and treatment of patients with sarcoma.

Libin Xu, Xianbiao Xie, Xiaoliang Shi, Peng Zhang, Angen Liu, Jian Wang, Bo Zhang.

Sarcomas represent a heterogeneous group of mesenchymal malignancies arising at various locations in the soft tissue and bone. Though a rare disease, sarcoma affects ~200,000 patients worldwide every year. The prognosis of patients with sarcoma is poor, and targeted therapy options are limited; therefore, accurate diagnosis and classification are essential for effective treatment. Sarcoma samples were acquired from 199 patients, in which TP53 (39.70%, 79/199), CDKN2A (19.10%, 38/199), CDKN2B (15.08%, 30/199), KIT (14.07%, 28/199), ATRX (10.05%, 20/199) and RB1 (10.05%, 20/199) were identified as the most commonly mutated genes (>10% incidence). Among 64 soft-tissue sarcomas that were unclassified by immunohistochemistry, 15 (23.44%, 15/64) were subsequently classified using next-generation sequencing (NGS). For the most part, the sarcoma subtypes were evenly distributed between male and female patients, while a significant association with sex was detected in leiomyosarcomas. Statistical analysis showed that osteosarcoma, Ewing's sarcoma, gastrointestinal stromal tumors and liposarcoma were all significantly associated with the patient age, and that angiosarcoma was significantly associated with high tumor mutational burden. Furthermore, serially mutated genes associated with myxofibrosarcoma, gastrointestinal stromal tumor, osteosarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma and Ewing's sarcoma were identified, as well as neurotrophic tropomyosin-related kinase (NTRK) fusions of IRF2BP2-NTRK1, MEF2A-NTRK3 and ITFG1-NTRK3. Collectively, the results of the present study suggest that NGS-targeting provides potential new biomarkers for sarcoma diagnosis, and may guide more precise therapeutic strategies for patients with bone and soft-tissue sarcomas.

Keywords: biomarker; diagnosis; genomic profiling; next-generation sequencing; sarcoma; tumor mutational burden

DOI: https://doi.org/10.3892/ol.2021.12614

Genes Dev. 2021 Mar 25.

RAD21 is a driver of chromosome 8 gain in Ewing sarcoma to mitigate replication stress.

Xiaofeng A Su, Duanduan Ma, James V Parsons, John M Replogle, James F Amatruda, Charles A Whittaker, Kimberly Stegmaier, Angelika Amon.

Aneuploidy, defined as whole-chromosome gain or loss, causes cellular stress but, paradoxically, is a frequent occurrence in cancers. Here, we investigate why ∼50% of Ewing sarcomas, driven by the EWS-FLI1 fusion oncogene, harbor chromosome 8 gains. Expression of the EWS-FLI1 fusion in primary cells causes replication stress that can result in cellular senescence. Using an evolution approach, we show that trisomy 8 mitigates EWS-FLI1-induced replication stress through gain of a copy of RAD21. Low-level ectopic expression of RAD21 is sufficient to dampen replication stress and improve proliferation in EWS-FLI1-expressing cells. Conversely, deleting one copy in trisomy 8 cells largely neutralizes the fitness benefit of chromosome 8 gain and reduces tumorgenicity of a Ewing sarcoma cancer cell line in soft agar assays. We propose that RAD21 promotes tumorigenesis through single gene copy gain. Such genes may explain some recurrent aneuploidies in cancer.

Keywords: DNA damage; Ewing sarcoma; RAD21; aneuploidy; cohesin; replication stress; trisomy 8

DOI: https://doi.org/10.1101/gad.345454.120