Background: Therapeutic management of stage II colon cancer remains difficult regarding the decision whether adjuvant chemotherapy should be administered or not. Low rates of recurrence are opposed to chemotherapy induced toxicity and current clinical features are limited in predicting disease relapse. Predictive biomarkers are urgently needed and we hypothesise that the spatial tissue composition of relapsed and non-relapsed colon cancer stage II patients reveals relevant biomarkers. Methods: The spatial tissue composition of stage II colon cancer patients was examined by in situ sequencing technology with sub-cellular resolution. A panel of 175 genes was designed investigating specific cancer-associated processes and components of the tumour microenvironment. We identified a tumour gene signature to subclassify tissue into neoplastic and non-neoplastic tissue compartments based on spatial expression patterns generated by in situ sequencing (GTC-tool (Genes-To-Count)). Results: The GTC-tool automatically identified tissue compartments that were used to quantify gene expression of biological processes upregulated within the neoplastic tissue in comparison to non-neoplastic tissue and within relapsed versus non-relapsed stage II colon patients. Three differentially expressed genes (FGFR2, MMP11 and OTOP2) in the neoplastic tissue compartments of relapsed patients in comparison to non-relapsed patients were identified predicting recurrence in stage II colon cancer. Conclusions: In depth spatial in situ sequencing revealed novel potential predictive biomarkers for disease relapse in colon cancer stage II patients. Our developed open-access GTC-tool allows to accurately capture the tumour compartment and quantify spatial gene expression in colon cancer tissue.

中文翻译：

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空间肿瘤基因特征区分结肠癌中的肿瘤和非肿瘤区室：揭示复发的预测生物标志物

背景：关于是否应给予辅助化疗的决定，II 期结肠癌的治疗管理仍然很困难。低复发率与化疗引起的毒性相反，目前的临床特征在预测疾病复发方面受到限制。迫切需要预测性生物标志物，我们假设复发和非复发结肠癌 II 期患者的空间组织组成揭示了相关的生物标志物。方法：采用亚细胞分辨率原位测序技术检测Ⅱ期结肠癌患者的空间组织组成。设计了一组 175 个基因来研究特定的癌症相关过程和肿瘤微环境的组成部分。我们根据原位测序（GTC-tool (Genes-To-Count)）产生的空间表达模式确定了肿瘤基因特征，将组织细分为肿瘤和非肿瘤组织区室。结果：GTC 工具自动识别组织隔室，用于量化与非肿瘤组织以及复发与非复发 II 期结肠患者相比，肿瘤组织内上调的生物过程的基因表达。与非复发患者相比，在复发患者的肿瘤组织隔室中鉴定出三种差异表达基因（FGFR2、MMP11 和 OTOP2），可预测 II 期结肠癌的复发。结论：深度空间原位测序揭示了结肠癌 II 期患者疾病复发的新的潜在预测生物标志物。我们开发的开放获取 GTC 工具允许准确捕获肿瘤隔室并量化结肠癌组织中的空间基因表达。