Background

Recently, expression of YAP1, a nuclear effector of an inactivated HIPPO pathway, has been identified as one of four molecular subtypes of SCLC. However, the clinicopathological relevance and prognostic significance of YAP1 expression in SCLC stratified by histological subtypes has not been systematically reported to date.

Methods

Tumor sections and corresponding formalin-fixed paraffin-embedded (FFPE) samples of 297 SCLC patients were retrieved from the pathological specimen repository and were subsequently reviewed by pathologists. Forty-six C-SCLCs (combined SCLCs) (15.5%) and 251 P-SCLCs (pure SCLCs) (84.5%) were identified respectively. YAP1 expression was examined by immunohistochemistry (IHC) and assessed semi-quantitatively on tumor tissue array (TMA). Propensity score was used to match C-SCLCs and P-SCLCs in a ratio of 1 to 2 to balance age, gender, tumor stage and treatment methods. Finally, 46 C-SCLCs and 92 P-SCLCs were included for prognostic analysis.

Results

The positive rate of YAP1 expression was significantly higher in C-SCLCs than P-SCLCs before matching (52.2% vs 29.1%, P = 0.004). After matching by propensity score, the prescribed clinical parameters were well balanced between P-SCLCs and C-SCLCs. Expression of YAP1 was associated worse overall survival (OS) (5- year OS%, 39.0% vs. 74.9%, P = 0.013) and was an independent risk factor for OS (HR = 2.93, 95% CI: 1.01-8.51; P=0.048) exclusively in C-SCLC. Univariate survival analysis in subgroups of different clinical variables also confirmed the prognostic impact of YAP1 was most significant in C-SCLC. But for P-SCLCs, expression of YAP1 showed no prognostic impact.

Conclusions

Expression of YAP1 in small cell components of C-SCLC was significantly higher than that in P-SCLC. Besides, it served as an unfavorable predictor for OS in C-SCLC but not in P-SCLC, which suggested different entities of small cell components with variant YAP1 expression and potential different targetable oncogenic pathway between C-SCLC and P-SCLC.

中文翻译：

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YAP1 蛋白表达在按组织学亚型分层的小细胞肺癌 (SCLC) 中具有不同的预后意义

背景

最近，失活的 HIPPO 通路的核效应子 YAP1 的表达已被确定为 SCLC 的四种分子亚型之一。然而，迄今为止，尚未系统地报道 YAP1 在按组织学亚型分层的 SCLC 中表达的临床病理学相关性和预后意义。

方法

从病理标本库中检索了 297 名 SCLC 患者的肿瘤切片和相应的福尔马林固定石蜡包埋 (FFPE) 样本，随后由病理学家进行审查。分别鉴定了 46 个 C-SCLC（合并 SCLC）（15.5%）和 251 个 P-SCLC（纯 SCLC）（84.5%）。通过免疫组织化学 (IHC) 检查 YAP1 表达并在肿瘤组织阵列 (TMA) 上进行半定量评估。倾向评分用于以 1 比 2 的比例匹配 C-SCLC 和 P-SCLC，以平衡年龄、性别、肿瘤分期和治疗方法。最后，包括 46 个 C-SCLC 和 92 个 P-SCLC 用于预后分析。

结果

匹配前，C-SCLCs 中 YAP1 表达的阳性率显着高于 P-SCLCs（52.2% vs 29.1%，P = 0.004）。通过倾向评分匹配后，规定的临床参数在 P-SCLC 和 C-SCLC 之间得到了很好的平衡。YAP1 的表达与较差的总生存期 (OS) 相关（5 年 OS%，39.0% 与 74.9%，P = 0.013）并且是 OS 的独立危险因素（HR = 2.93，95% CI：1.01-8.51；P= 0.048) 仅在 C-SCLC 中。不同临床变量亚组的单变量生存分析也证实了 YAP1 的预后影响在 C-SCLC 中最为显着。但对于 P-SCLC，YAP1 的表达没有显示预后影响。

结论

YAP1在C-SCLC小细胞成分中的表达显着高于P-SCLC。此外，它是 C-SCLC 而非 P-SCLC 中 OS 的不利预测因子，这表明具有变异 YAP1 表达的小细胞成分的不同实体和 C-SCLC 和 P-SCLC 之间潜在的不同靶向致癌途径。