Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland.
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
J Thorac Oncol. 2022 Jan;17(1):141-153. doi: 10.1016/j.jtho.2021.08.763. Epub 2021 Sep 15.
A new molecular subtype classification was recently proposed for SCLC. It is necessary to validate it in primary SCLC tumors by immunohistochemical (IHC) staining and define its clinical relevance.
We used IHC to assess four subtype markers (ASCL1, NEUROD1, POU2F3, and YAP1) in 194 cores from 146 primary SCLC tumors. The profiles of tumor-associated CD3 and CD8 T-cells, MYC paralogs, SLFN11, and SYP were compared among different subtypes. Validation was performed using publicly available RNA sequencing data of SCLC.
ASCL1, NEUROD1, POU2F3, and YAP1 were the dominant molecular subtypes in 78.2%, 5.6%, 7%, and 2.8% of the tumors, respectively; 6.3% of the tumors were negative for all four subtype markers. Notably, three cases were uniquely positive for YAP1. Substantial intratumoral heterogeneity was observed, with 17.6% and 2.8% of the tumors being positive for two and three subtype markers, respectively. The non-ASCL1/NEUROD1 tumors had more CD8 T-cells and manifested more frequently an "inflamed" immunophenotype. L-MYC and MYC were more often associated with ASCL1/NEUROD1 subtypes and non-ASCL1/NEUROD1 subtypes, respectively. SLFN11 expression was absent in 40% of the tumors, especially those negative for the four subtype markers. SYP was often expressed in the ASCL1 and NEUROD1 subtypes and was associated with less tumor-associated CD8 T-cells and a "desert" immunophenotype.
We validated the new molecular subtype classification in primary SCLC tumors by IHC and identified several intriguing associations between subtypes and therapeutic markers. The new subtype classification may potentially assist treatment decisions in SCLC.
最近提出了一种小细胞肺癌（SCLC）的新分子亚型分类。通过免疫组织化学（IHC）染色在原发性 SCLC 肿瘤中验证该分类并定义其临床相关性是必要的。
我们使用 IHC 评估了 146 例原发性 SCLC 肿瘤的 194 个核心中的四个亚型标志物（ASCL1、NEUROD1、POU2F3 和 YAP1）。比较了不同亚型之间肿瘤相关的 CD3 和 CD8 T 细胞、MYC 基因家族成员、SLFN11 和 SYP 的表达谱。使用 SCLC 的公开 RNA 测序数据进行验证。
ASCL1、NEUROD1、POU2F3 和 YAP1 分别是 78.2%、5.6%、7%和 2.8%的肿瘤中的主要分子亚型；4%的肿瘤四种亚型标志物均为阴性。值得注意的是，有三个病例为 YAP1 阳性。观察到明显的肿瘤内异质性，17.6%和 2.8%的肿瘤分别为两种和三种亚型标志物阳性。非 ASCL1/NEUROD1 肿瘤具有更多的 CD8 T 细胞，并表现出更频繁的“炎症”免疫表型。L-MYC 和 MYC 分别与 ASCL1/NEUROD1 亚型和非 ASCL1/NEUROD1 亚型更为相关。SLFN11 表达缺失见于 40%的肿瘤，尤其是四种亚型标志物均为阴性的肿瘤。SYP 常表达于 ASCL1 和 NEUROD1 亚型，与较少的肿瘤相关 CD8 T 细胞和“荒漠”免疫表型相关。
我们通过 IHC 验证了原发性 SCLC 肿瘤的新分子亚型分类，并确定了亚型与治疗标志物之间的一些有趣关联。新的亚型分类可能有助于 SCLC 的治疗决策。
