Zhang Wenjuan, Cao Jian, Liu Ke, Qu Ziwei, Zheng Ying, Yu Jun, Yu Yishan, Wang Yongsheng, Wu Wendy
Berry Oncology Corporation, Beijing, China.
Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
Cell Death Discov. 2023 Jan 30;9(1):35. doi: 10.1038/s41420-023-01316-1.
Immunotherapy is now the main choice of systemic therapy for many cancer patients, while current biomarkers for tumor immunotherapy may be limited by the accessibility of patient tumor tissue or tumor neoplastic content. Rare mutation in the 5' and 3'-untranslated region (UTR) of CD274 gene (Protein name: PD-L1) has been recently reported in hematologic and solid tumors as a potential biomarker for assessing efficacy during immunotherapy. However, multi-omics analysis for CD274 UTR region, especially circulating tumor DNA (ctDNA), have been little explored in the pan-cancer perspective. We developed a cSMART2.0 technology featured with higher capture efficiency and homogeneity to detect this rare structural variant in 2249 Chinese patients' cohort with multiple cancers. An incidence of 0.36% was detected in this cohort, consistent with TCGA (The Cancer Genome Atlas), while the prevalence of SV in CD274 UTR region in liver and breast cancer were significantly higher than TCGA. The liquid biopsy result from ctDNA was 100% concordance with gDNA result getting from tumor tissue detection, and further validated by immunohistochemistry (IHC) and multiplex immunofluorescence (mIF) experiments. Patients carrying this SV in CD274 UTR region without driver gene mutation responded to immune checkpoint inhibitors (ICIs). This study proves that rare structural variants in CD274 UTR region exist in various cancer in Chinese population for the first time, which can induce immune escape and be used for prediction of response to ICIs. Liquid biopsy based cSMART 2.0 technology could offer more sensitive and accurate detection to navigate potential ICIs patients and to benefit patients with advanced disease when tissue samples are not available.
免疫疗法现已成为许多癌症患者全身治疗的主要选择，而目前用于肿瘤免疫治疗的生物标志物可能受到患者肿瘤组织可及性或肿瘤瘤细胞含量的限制。最近在血液系统肿瘤和实体瘤中报道，CD274基因（蛋白名称：PD-L1）5'和3'非翻译区（UTR）的罕见突变可作为评估免疫治疗疗效的潜在生物标志物。然而，从泛癌角度对CD274 UTR区域进行的多组学分析，尤其是循环肿瘤DNA（ctDNA）分析，尚未得到充分探索。我们开发了一种具有更高捕获效率和均一性的cSMART2.0技术，用于检测2249例患有多种癌症的中国患者队列中的这种罕见结构变异。在该队列中检测到的发生率为0.36%，与癌症基因组图谱（TCGA）一致，而CD274 UTR区域在肝癌和乳腺癌中的结构变异发生率显著高于TCGA。ctDNA的液体活检结果与肿瘤组织检测获得的基因组DNA（gDNA）结果100%一致，并通过免疫组织化学（IHC）和多重免疫荧光（mIF）实验进一步验证。在CD274 UTR区域携带这种结构变异且无驱动基因突变的患者对免疫检查点抑制剂（ICI）有反应。本研究首次证明，中国人群中多种癌症存在CD274 UTR区域的罕见结构变异，其可诱导免疫逃逸，并可用于预测对ICI的反应。基于液体活检的cSMART 2.0技术可提供更灵敏和准确的检测，以指导潜在的ICI患者，并在无法获得组织样本时使晚期疾病患者受益。
