Department of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, Ohio.
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
Clin Cancer Res. 2024 Oct 15;30(20):4780-4790. doi: 10.1158/1078-0432.CCR-24-1160.
Leiomyosarcomas (LMS) are clinically and molecularly heterogeneous, occurring mostly in sporadic but also syndromic settings. The role of pathogenic germline variants (PGV) as LMS drivers and their impact on outcomes remains uncertain.
We performed a comprehensive clinicopathologic and molecular analysis using a tumor-normal DNA next-generation sequencing assay (Memorial Sloan Kettering-Integrated Mutational Profiling of Actionable Cancer Targets) of germline-associated LMS compared with sporadic LMS.
Among 285 LMS [120 soft-tissue LMS (STLMS) and 165 uterine LMS (ULMS)] with germline testing, 78 (27%, 43 STLMS and 35 ULMS) cases harbored PGV, with 35/78 (45%) of PGV carriers showing biallelic inactivation of the corresponding gene in the tumor (26 STLMS and nine ULMS). The most frequent germline predispositions were TP53 (Li-Fraumeni syndrome; 17 patients, 16 in STLMS) and RB1 (retinoblastoma; 13 patients, 11 in STLMS). Germline TP53 and somatic RB1 alterations often co-occurred in the tumor andvice versa. Other biallelically inactivated PGV were enriched in DNA damage repair-related genes: CHEK2, MSH2, MSH6, RAD51D, BRCA2, and FANCA. Monoallelic PGV were mostly in ULMS and associated with co-occurring TP53 and RB1 somatic alterations. Patients with STLMS with biallelic but not monoallelic PGV were significantly younger than patients with sporadic STLMS (median ages 38 vs. 52 vs. 58 years). No differences in disease-specific or progression-free survival were observed in germline-associated versus sporadic LMS regardless of biallelic status.
Although patients with ULMS had a relatively low proportion of PGV, a high percentage of patients with STLMS with PGV had tumor biallelic status, indicating that PGV drive tumorigenesis in these individuals. These findings have significant implications for genetic testing recommendations.
平滑肌肉瘤（LMS）在临床上和分子上具有异质性，主要发生在散发性但也有综合征性环境中。致病性种系变异（PGV）作为 LMS 驱动因素及其对结果的影响仍不确定。
我们使用肿瘤-正常 DNA 下一代测序检测（纪念斯隆凯特琳综合可操作癌症靶点突变分析）对与散发性 LMS 相比的种系相关 LMS 进行了全面的临床病理和分子分析。
在 285 例接受种系检测的 LMS [120 例软组织 LMS（STLMS）和 165 例子宫 LMS（ULMS）]中，78 例（27%，43 例 STLMS 和 35 例 ULMS）存在 PGV，其中 35/78（45%）PGV 携带者在肿瘤中存在相应基因的双等位基因失活（26 例 STLMS 和 9 例 ULMS）。最常见的种系易感性是 TP53（Li-Fraumeni 综合征；17 例患者，16 例在 STLMS 中）和 RB1（视网膜母细胞瘤；13 例患者，11 例在 STLMS 中）。种系 TP53 和体细胞 RB1 改变通常在肿瘤中共同发生，反之亦然。其他双等位基因失活的 PGV 在 DNA 损伤修复相关基因中富集：CHEK2、MSH2、MSH6、RAD51D、BRCA2 和 FANCA。单等位基因 PGV 主要在 ULMS 中，并与同时存在的 TP53 和 RB1 体细胞改变相关。与散发性 STLMS 相比，具有双等位基因而非单等位基因 PGV 的 STLMS 患者明显更年轻（中位年龄分别为 38 岁、52 岁和 58 岁）。无论双等位基因状态如何，与散发性 LMS 相比，种系相关与散发性 LMS 之间在疾病特异性或无进展生存期方面均无差异。
尽管 ULMS 患者的 PGV 比例相对较低，但具有 PGV 的 STLMS 患者中有很高比例的肿瘤具有双等位基因状态，表明 PGV 驱动这些个体的肿瘤发生。这些发现对遗传检测建议具有重要意义。
