Purpose: Leiomyosarcomas (LMS) are clinically and molecularly heterogeneous tumors. Despite genomic studies, current LMS risk stratification is not informed by molecular alterations. We propose a clinically applicable genomic risk stratification model. Experimental Design: We performed comprehensive genomic profiling in a cohort of 195 soft tissue LMS (STLMS), 151 primary at presentation, and a control group of 238 uterine LMS (ULMS), 177 primary at presentation, with at least one-year follow up. Results: In STLMS, FNCLCC grade but not tumor size predicted progression-free survival (PFS) or disease-specific survival (DSS). In contrast, in ULMS, tumor size, mitotic rate and necrosis were associated with inferior PFS and DSS. In STLMS, a 3-tier genomic risk stratification performed well for DSS: high risk – co-occurrence of RB1 mutation and chr12q deletion (del12q)/ATRX mutation; intermediate risk – presence of RB1 mutation, ATRX mutation or del12q; low risk – lack of any of these three alterations. The ability of RB1 and ATRX alterations to stratify STLMS was validated in an external AACR GENIE cohort. In ULMS, a 3-tier genomic risk stratification was significant for both PFS and DSS: high risk – concurrent TP53 mutation and chr20q amplification/ATRX mutations; intermediate risk – presence of TP53 mutation, ATRX mutation or amp20q; low risk – lack of any of these three alterations. Longitudinal sequencing showed that most molecular alterations were early clonal events that persisted during disease progression. Conclusions: Compared to traditional clinicopathologic models, genomic risk stratification demonstrates superior prediction of clinical outcome in STLMS and is comparable in ULMS.

中文翻译：

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开发软组织和子宫平滑肌肉瘤的新型基因组风险分层模型

目的：平滑肌肉瘤（LMS）是临床和分子异质性肿瘤。尽管进行了基因组研究，但目前的 LMS 风险分层并未通过分子改变来确定。我们提出了一种临床适用的基因组风险分层模型。实验设计：我们对 195 例软组织 LMS (STLMS)、151 例就诊时原发性的队列和由 238 例子宫 LMS (ULMS)、177 例就诊时原发性的对照组进行了全面的基因组分析，并进行了至少一年的随访。结果：在 STLMS 中，FNCCLCC 分级而非肿瘤大小可预测无进展生存期 (PFS) 或疾病特异性生存期 (DSS)。相反，在 ULMS 中，肿瘤大小、有丝分裂率和坏死与较差的 PFS 和 DSS 相关。在 STLMS 中，3 层基因组风险分层对于 DSS 表现良好：高风险 – RB1 突变和 chr12q 缺失 (del12q)/ATRX 突变同时出现；中等风险 – 存在 RB1 突变、ATRX 突变或 del12q；低风险——缺乏这三种改变中的任何一种。RB1 和 ATRX 改变对 STLMS 进行分层的能力在外部 AACR GENIE 队列中得到了验证。在 ULMS 中，3 级基因组风险分层对于 PFS 和 DSS 都很重要：高风险 – 并发 TP53 突变和 chr20q 扩增/ATRX 突变；中等风险 – 存在 TP53 突变、ATRX 突变或 amp20q；低风险——缺乏这三种改变中的任何一种。纵向测序表明，大多数分子改变是早期克隆事件，在疾病进展过程中持续存在。结论：与传统的临床病理模型相比，基因组风险分层在 STLMS 中对临床结果的预测效果更好，并且在 ULMS 中具有可比性。