Objective The mitochondrial apoptosis pathway is controlled by an interaction of multiple BCL-2 family proteins, and plays a key role in tumour progression and therapy responses. We assessed the prognostic potential of an experimentally validated, mathematical model of BCL-2 protein interactions (DR_MOMP) in patients with stage III colorectal cancer (CRC). Design Absolute protein levels of BCL-2 family proteins were determined in primary CRC tumours collected from n=128 resected and chemotherapy-treated patients with stage III CRC. We applied DR_MOMP to categorise patients as high or low risk based on model outputs, and compared model outputs with known prognostic factors (T-stage, N-stage, lymphovascular invasion). DR_MOMP signatures were validated on protein of n=156 patients with CRC from the Cancer Genome Atlas (TCGA) project. Results High-risk stage III patients identified by DR_MOMP had an approximately fivefold increased risk of death compared with patients identified as low risk (HR 5.2, 95% CI 1.4 to 17.9, p=0.02). The DR_MOMP signature ranked highest among all molecular and pathological features analysed. The prognostic signature was validated in the TCGA colon adenocarcinoma (COAD) cohort (HR 4.2, 95% CI 1.1 to 15.6, p=0.04). DR_MOMP also further stratified patients identified by supervised gene expression risk scores into low-risk and high-risk categories. BCL-2-dependent signalling critically contributed to treatment responses in consensus molecular subtypes 1 and 3, linking for the first time specific molecular subtypes to apoptosis signalling. Conclusions DR_MOMP delivers a system-based biomarker with significant potential as a prognostic tool for stage III CRC that significantly improves established histopathological risk factors.

中文翻译：

---

BCL-2系统分析识别高危结直肠癌患者

目的 线粒体凋亡通路受多种 BCL-2 家族蛋白的相互作用控制，在肿瘤进展和治疗反应中起关键作用。我们评估了经过实验验证的 BCL-2 蛋白相互作用数学模型 (DR_MOMP) 在 III 期结直肠癌 (CRC) 患者中的预后潜力。设计 BCL-2 家族蛋白的绝对蛋白水平在从 n=128 切除和化疗治疗的 III 期 CRC 患者收集的原发性 CRC 肿瘤中测定。我们应用 DR_MOMP 根据模型输出将患者分类为高风险或低风险，并将模型输出与已知的预后因素（T 期、N 期、淋巴血管浸润）进行比较。DR_MOMP 特征在来自癌症基因组图谱 (TCGA) 项目的 n=156 名 CRC 患者的蛋白质上得到验证。结果 与被确定为低风险的患者相比，由 DR_MOMP 确定的高风险 III 期患者的死亡风险增加了大约五倍（HR 5.2，95% CI 1.4 至 17.9，p=0.02）。DR_MOMP 签名在所有分析的分子和病​​理特征中排名最高。预后特征在 TCGA 结肠腺癌 (COAD) 队列中得到验证（HR 4.2，95% CI 1.1 至 15.6，p=0.04）。DR_MOMP 还进一步将通过监督基因表达风险评分确定的患者分为低风险和高风险类别。BCL-2 依赖性信号传导对共有分子亚型 1 和 3 的治疗反应起关键作用，首次将特定分子亚型与细胞凋亡信号传导联系起来。