Kaczorowski Maciej, Ylaya Kris, Chłopek Małgorzata, Taniyama Daiki, Pommier Yves, Lasota Jerzy, Miettinen Markku
Laboratory of Pathology, National Cancer Institute, Bethesda, MD.
Department of Clinical and Experimental Pathology, Wroclaw Medical University, Wrocław, Poland.
Am J Surg Pathol. 2024 Aug 26. doi: 10.1097/PAS.0000000000002299.
Schlafen 11 (SLFN11), a DNA/RNA helicase, acts as a regulator of cellular response to replicative stress and irreversibly triggers replication block and cell death. Several preclinical in vitro studies and clinical trials established that SLFN11 expression predicts outcomes in patients with advanced cancer treated with DNA-damaging chemotherapeutics and more recently with poly(ADP-ribose) polymerase inhibitors. SLFN11 expression status remains unknown in many cancer types, especially in mesenchymal tumors. This study evaluated a cohort of well characterized 3808 epithelial and 2850 mesenchymal and neuroectodermal tumors for SLFN11 expression using immunohistochemistry. Nuclear SLFN11 expression was rare in some of the most common carcinomas, for example, hepatocellular (1%), prostatic (2%), colorectal (5%), or breast (16%) cancers. In contrast, other epithelial tumors including mesotheliomas (92%), clear cell renal cell carcinomas (79%), small cell lung cancers (76%), squamous cell carcinomas of the tonsil (89%) and larynx (71%), or ovarian serous carcinomas (69%) were mostly SLFN11-positive. Compared with epithelial malignancies, SLFN11 expression was overall higher in neuroectodermal and mesenchymal tumors. Most positive entities included desmoplastic small round cell tumor (100%), Ewing sarcoma (92%), undifferentiated sarcoma (92%), solitary fibrous tumor (91%), dedifferentiated liposarcoma (89%), synovial sarcoma (86%), and malignant peripheral nerve sheath tumor (85%). Also, this study identifies tumors with potentially worse response to DNA-damaging drugs including antibody drug conjugates due to the absence of SLFN11 expression. Such entities may benefit from alternative treatments or strategies to overcome SLFN11 deficiency-related drug resistance. Our approach and results should serve as a foundation for future biomarker-associated clinical trials.
Schlafen 11（SLFN11）是一种DNA/RNA解旋酶，作为细胞对复制应激反应的调节因子，可不可逆地引发复制阻滞和细胞死亡。多项临床前体外研究和临床试验证实，SLFN11表达可预测晚期癌症患者接受DNA损伤化疗药物以及最近接受聚（ADP - 核糖）聚合酶抑制剂治疗后的预后。SLFN11的表达状态在许多癌症类型中仍然未知，尤其是间充质肿瘤。本研究使用免疫组织化学方法评估了一组特征明确的3808例上皮性肿瘤以及2850例间充质和神经外胚层肿瘤中的SLFN11表达情况。在一些最常见的癌中，核SLFN11表达罕见，例如肝细胞癌（1%）、前列腺癌（2%）、结直肠癌（5%）或乳腺癌（16%）。相比之下，其他上皮性肿瘤，包括间皮瘤（92%）、透明细胞肾细胞癌（79%）、小细胞肺癌（76%）、扁桃体鳞状细胞癌（89%）和喉癌（71%）或卵巢浆液性癌（69%）大多为SLFN11阳性。与上皮性恶性肿瘤相比，SLFN11在神经外胚层和间充质肿瘤中的表达总体较高。大多数阳性实体包括促纤维组织增生性小圆细胞肿瘤（100%）、尤因肉瘤（92%）、未分化肉瘤（92%）、孤立性纤维性肿瘤（91%）、去分化脂肪肉瘤（89%）、滑膜肉瘤（86%）和恶性外周神经鞘瘤（85%）。此外，本研究还确定了由于缺乏SLFN11表达而对包括抗体药物偶联物在内的DNA损伤药物反应可能较差的肿瘤。这些实体可能受益于替代治疗或克服SLFN11缺陷相关耐药性的策略。我们的方法和结果应为未来与生物标志物相关的临床试验奠定基础。
