INSERM UMR-S1147, Université Sorbonne Paris Cité, Université Paris Descartes, Paris.
Department of Medical Oncology, AP-HP, Hôpital Européen Georges Pompidou, Paris.
Ann Oncol. 2017 Jul 1;28(7):1597-1604. doi: 10.1093/annonc/mdx162.
Pulmonary sarcomatoid carcinoma (SC) is a rare disease with poor prognosis and with strong inter- and intratumor heterogeneity. However, molecular classification is currently focused on activating MET mutations. We sought to better characterize the molecular diversity of SC using mutational signatures that reflect different mutational processes, such as tobacco-associated adducts (signature 4), BRCA1/BRCA2 deficiency (signature 3), or APOBEC enzyme deamination (signatures 2 and 13).
Whole-exome sequencing was carried out in 15 SC patients and on data from 10 previously published cases. Hierarchical clustering and consensus non-negative matrix factorization were carried out for samples classification based on mutational signatures.
In the two series, SC distributed between two clusters (C): Csig4 (characterized by signature 4) and Csig2-3-13 (signatures 2, 3, and 13). Csig4 exhibited more frequent MAPK pathway mutations than Csig2-3-13 (pooled series: n = 10/14 versus 2/11, P < 0.05, respectively) and stronger PD-L1 expression (our series: n = 6/9 versus 1/6, P = 0.12). MET alterations were only found in Csig2-3-13 (pooled series: n = 5/11 versus 0/14, P = 0.009), as well as BRCA1/BRCA2 (n = 3/11 versus 0/15), EGFR (n = 1), and IDH1 (n = 1) mutations. Csig2-3-13 patients had better overall survival than Csig4 patients (median: >45 versus 7 months, respectively, P = 0.001).
Our study suggests that SC presents at least two clusters comprising different mutational processes, gene alterations, and PD-L1 expression. New potential treatment possibilities are immune checkpoint inhibitors in Csig4 and specific targeted agents in Csig2-3-13. These findings should encourage clinicians to conduct broad molecular and immunological testing in SC patients beyond MET exon 14 alterations.
肺肉瘤样癌（SC）是一种预后较差且具有强烈的肿瘤内和肿瘤间异质性的罕见疾病。然而，目前的分子分类主要集中在激活 MET 突变上。我们试图使用反映不同突变过程的突变特征来更好地描述 SC 的分子多样性，例如与烟草相关的加合物（特征 4）、BRCA1/BRCA2 缺陷（特征 3）或 APOBEC 酶脱氨酶（特征 2 和 13）。
对 15 例 SC 患者和 10 例先前发表的病例进行了全外显子组测序。基于突变特征对样本进行层次聚类和共识非负矩阵分解分类。
在这两个系列中，SC 分布在两个聚类（C）之间：Csig4（以特征 4 为特征）和 Csig2-3-13（特征 2、3 和 13）。与 Csig2-3-13 相比，Csig4 表现出更频繁的 MAPK 通路突变（两组汇总：n=10/14 与 2/11，P<0.05）和更强的 PD-L1 表达（我们的系列：n=6/9 与 1/6，P=0.12）。仅在 Csig2-3-13 中发现 MET 改变（两组汇总：n=5/11 与 0/14，P=0.009），以及 BRCA1/BRCA2（n=3/11 与 0/15）、EGFR（n=1）和 IDH1（n=1）突变。与 Csig4 患者相比，Csig2-3-13 患者的总生存期更好（中位：>45 与 7 个月，分别为 P=0.001）。
我们的研究表明，SC 至少存在两个聚类，包括不同的突变过程、基因改变和 PD-L1 表达。新的潜在治疗可能性是 Csig4 中的免疫检查点抑制剂和 Csig2-3-13 中的特定靶向药物。这些发现应鼓励临床医生在 SC 患者中进行广泛的分子和免疫检测，而不仅仅是 MET 外显子 14 改变。
