Williams Erik A, Sharaf Radwa, Decker Brennan, Werth Adrienne J, Toma Helen, Montesion Meagan, Sokol Ethan S, Pavlick Dean C, Shah Nikunj, Williams Kevin Jon, Venstrom Jeffrey M, Alexander Brian M, Ross Jeffrey S, Albacker Lee A, Lin Douglas I, Ramkissoon Shakti H, Elvin Julia A
Foundation Medicine, Cambridge, MA.
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
JCO Precis Oncol. 2020 Sep 1;4. doi: 10.1200/PO.20.00040. eCollection 2020.
Leiomyosarcoma (LMS) harbors frequent mutations in and but few actionable genomic alterations. Here, we searched for recurrent actionable genomic alterations in LMS that occur in the absence of common untreatable oncogenic drivers.
Tissues from 276,645 unique advanced cancers, including 2,570 uterine and soft tissue LMS, were sequenced by hybrid-capture-based next-generation DNA and RNA sequencing/comprehensive genomic profiling of up to 406 genes. We characterized clinicopathologic features of relevant patient cases.
Overall, 77 LMS exhibited homozygous copy loss of at chromosome 1p32.3 (3.0% of LMS). Genomic alterations (GAs) in , , and were rare compared with the remainder of the LMS cohort (11.7% 73.4%, 0% 54.5%, 2.6% 24.5%, respectively; all < .0001). -null LMS patient cases were significantly enriched for GAs in (40.3% 1.4%) at 19q13.2, (46.8% 7.0%), and (16.9% 1.7%; all < .0001). Chromosome arm-level aneuploidy analysis of available LMS patient cases (n = 1,284) found that 81% (58 of 72) of -null LMS exhibited 1p/19q-codeletion, a significant enrichment compared with 5.1% in the remainder of the LMS cohort ( < .0001). In total, 99% of -null LMS were in women; the median age was 61 years at surgery (range, 36-81 years). Fifty-five patient cases were uterine primary, four were nonuterine, and the remaining 18 were of uncertain primary site. Sixty percent of cases showed at least focal epithelioid variant histology. Most patients had advanced-stage disease, with 62% of confirmed uterine primary LMS at International Federation of Gynecology and Obstetrics stage IVB. We further validated our findings in two publicly available datasets: The Cancer Genome Atlas and the Project GENIE initiative.
-null LMS defines a genomically distinct tumor that may have prognostic and/or therapeutic clinical implications, including possible use of specific cyclin-dependent kinase inhibitors.
平滑肌肉瘤（LMS）在[基因名称1]和[基因名称2]中频繁发生突变，但可采取行动的基因组改变较少。在此，我们在不存在常见不可治疗致癌驱动因素的情况下，寻找LMS中复发性可采取行动的基因组改变。
对276,645例独特的晚期癌症组织进行测序，包括2570例子宫和软组织LMS，采用基于杂交捕获的下一代DNA和RNA测序/对多达406个基因进行综合基因组分析。我们对相关患者病例的临床病理特征进行了描述。
总体而言，77例LMS在染色体1p32.3处表现出[基因名称3]的纯合缺失（占LMS的3.0%）。与其余LMS队列相比，[基因名称4]、[基因名称5]和[基因名称6]中的基因组改变（GAs）较少（分别为11.7%对73.4%、0%对54.5%、2.6%对24.5%；P均<0.0001）。[基因名称3]缺失的LMS患者病例在19q13.2处的[基因名称7]（40.3%对1.4%）、[基因名称8]（46.8%对7.0%）和[基因名称9]（16.9%对1.7%；P均<0.0001）的GAs中显著富集。对现有LMS患者病例（n = 1284）进行染色体臂水平非整倍体分析发现，81%（72例中的58例）的[基因名称3]缺失LMS表现出1p/19q共缺失，与其余LMS队列中的5.1%相比有显著富集（P<0.0001）。总共有99%的[基因名称3]缺失LMS发生在女性中；手术时的中位年龄为61岁（范围36 - 81岁）。55例患者病例为子宫原发性，4例为非子宫性，其余18例原发部位不确定。60%的病例至少表现出局灶性上皮样变异组织学。大多数患者患有晚期疾病，国际妇产科联合会IVB期确诊的子宫原发性LMS中有62%。我们在两个公开可用的数据集中进一步验证了我们的发现：癌症基因组图谱和GENIE计划。
[基因名称3]缺失的LMS定义了一种基因组上不同的肿瘤，可能具有预后和/或治疗方面的临床意义，包括可能使用特定的细胞周期蛋白依赖性激酶抑制剂。
