Department of Surgical Oncology, Lab Translational Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands.
Br J Cancer. 2022 Jul;127(1):145-155. doi: 10.1038/s41416-022-01748-z. Epub 2022 Mar 16.
In colorectal cancer (CRC), the consensus molecular subtype 4 (CMS4) is associated with therapy resistance and poor prognosis. Clinical diagnosis of CMS4 is hampered by locoregional and temporal variables influencing CMS classification. Diagnostic tools that comprehensively detect CMS4 are therefore urgently needed.
To identify targets for molecular CMS4 imaging, RNA sequencing data of 3232 primary CRC patients were explored. Heterogeneity of marker expression in relation to CMS4 status was assessed by analysing 3-5 tumour regions and 91.103 single-tumour cells (7 and 29 tumours, respectively). Candidate marker expression was validated in CMS4 peritoneal metastases (PM; n = 59). Molecular imaging was performed using the Ga-DOTA-FAPI-46 PET tracer.
Fibroblast activation protein (FAP) mRNA identified CMS4 with very high sensitivity and specificity (AUROC > 0.91), and was associated with significantly shorter relapse-free survival (P = 0.0038). Heterogeneous expression of FAP among and within tumour lesions correlated with CMS4 heterogeneity (AUROC = 1.00). FAP expression was homogeneously high in PM, a near-homogeneous CMS4 entity. FAPI-PET identified focal and diffuse PM that were missed using conventional imaging. Extra-peritoneal metastases displayed extensive heterogeneity of tracer uptake.
FAP expression identifies CMS4 CRC. FAPI-PET may have value in the comprehensive detection of CMS4 tumours in CRC. This is especially relevant in patients with PM, for whom effective imaging tools are currently lacking.
在结直肠癌（CRC）中，共识分子亚型 4（CMS4）与治疗耐药性和预后不良相关。CMS 分类受影响局部和时间变量的限制，临床诊断 CMS4 存在障碍。因此，迫切需要全面检测 CMS4 的诊断工具。
为了确定分子 CMS4 成像的靶点，对 3232 例原发性 CRC 患者的 RNA 测序数据进行了探索。通过分析 3-5 个肿瘤区域和 91103 个单细胞（分别为 7 个和 29 个肿瘤），评估了标记物表达与 CMS4 状态的异质性。在 CMS4 腹膜转移（PM；n=59）中验证候选标记物的表达。使用 Ga-DOTA-FAPI-46 PET 示踪剂进行分子成像。
成纤维细胞激活蛋白（FAP）mRNA 以非常高的灵敏度和特异性（AUROC>0.91）识别 CMS4，与明显较短的无复发生存期相关（P=0.0038）。肿瘤病变内和之间 FAP 的异质性表达与 CMS4 的异质性相关（AUROC=1.00）。PM 中 FAP 表达均匀高，PM 是一种近乎同质的 CMS4 实体。FAPI-PET 识别出常规成像遗漏的局灶性和弥漫性 PM。腹膜外转移显示示踪剂摄取的广泛异质性。
FAP 表达可识别 CMS4 CRC。FAPI-PET 可能在 CRC 中 CMS4 肿瘤的全面检测中具有价值。对于目前缺乏有效成像工具的 PM 患者，这尤其重要。
