Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
Department of Hepatobiliary and Pancreatic Surgery, Oxford University Hospitals NHS, Oxford OX3 7LE, UK.
Curr Oncol. 2022 Apr 6;29(4):2516-2529. doi: 10.3390/curroncol29040206.
Surgical resection remains the only curative treatment strategy for Pancreatic Ductal Adenocarcinoma (PDAC). A proportion of patients succumb to early disease recurrence post-operatively despite receiving adjuvant chemotherapy. The ability to identify these high-risk individuals at their initial diagnosis, prior to surgery, could potentially alter their treatment algorithm. This unique patient cohort may benefit from neo-adjuvant chemotherapy, even in the context of resectable disease, as this may secure systemic control over their disease burden. It may also improve patient selection for surgery. Using the Cancer Genome Atlas dataset, we first confirmed the poor overall survival associated with early disease recurrence (p < 0.0001). The transcriptomic profiles of these tumours were analysed, and we identified key aberrant signalling pathways involved in early disease relapse; downregulation across several immune signalling pathways was noted. Differentially expressed genes that could serve as biomarkers were identified (BPI, C6orf58, CD177, MCM7 and NUDT15). Receiver operating characteristic curves were constructed in order to identify biomarkers with a high diagnostic ability to identify patients who developed early disease recurrence. NUDT15 expression had the highest discriminatory capability as a biomarker (AUC 80.8%). Its expression was confirmed and validated in an independent cohort of patients with resected PDAC (n = 13). Patients who developed an early recurrence had a statistically higher tumour expression of NUDT15 when compared to patients who did not recur early (p < 0.01). Our results suggest that NUDT15 can be used as a prognostic biomarker that can stratify patients according to their risk of developing early disease recurrence.
手术切除仍然是治疗胰腺导管腺癌（PDAC）的唯一治愈性治疗策略。尽管接受了辅助化疗，仍有一部分患者在术后发生早期疾病复发而死亡。在手术前，能够在初始诊断时识别这些高风险个体，可能会改变他们的治疗方案。这部分独特的患者群体可能受益于新辅助化疗，即使在可切除疾病的情况下也是如此，因为这可能会控制全身性疾病负担。这也可能改善手术患者的选择。我们首先使用癌症基因组图谱数据集，证实了早期疾病复发与总体生存率较差相关（p<0.0001）。分析了这些肿瘤的转录组谱，确定了与早期疾病复发相关的关键异常信号通路；注意到几个免疫信号通路下调。鉴定出了可作为生物标志物的差异表达基因（BPI、C6orf58、CD177、MCM7 和 NUDT15）。构建了受试者工作特征曲线，以确定具有高诊断能力的生物标志物，以识别发生早期疾病复发的患者。NUDT15 表达作为生物标志物具有最高的鉴别能力（AUC 80.8%）。在另一组接受 PDAC 切除术的患者（n=13）中验证和验证了其表达。与未早期复发的患者相比，发生早期复发的患者的肿瘤 NUDT15 表达具有统计学意义（p<0.01）。我们的结果表明，NUDT15 可以用作预后生物标志物，根据患者发生早期疾病复发的风险对其进行分层。
