应用手术和 EUS-FNB 标本对胰腺导管腺癌形态亚型的基因表达谱进行分析。
Gene expression profiling of morphologic subtypes of pancreatic ductal adenocarcinoma using surgical and EUS-FNB specimens.
机构信息
Department of Pathology, Odense University Hospital, Odense, Denmark; Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
Department of Pathology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
出版信息
Pancreatology. 2021 Apr;21(3):530-543. doi: 10.1016/j.pan.2021.01.025. Epub 2021 Feb 9.
BACKGROUND/OBJECTIVES: Various classifications of pancreatic ductal adenocarcinoma (PDAC) based on RNA profiling resulted in two main subtypes. Kalimuthu and coworkers proposed a morphology-based classification that concurred with these subtypes. Immune therapy approaches in PDAC were so far disappointing. Morphologic PDAC subtypes may differ regarding key immune-oncology pathways. We aimed to examine the reproducibility and prognostic value of Kalimuthu's morphologic classification, and to evaluate differences between subtypes regarding gene expression related to tumor biology and immune-oncology.
METHODS
PDAC specimens from 196 patients were included, 108 consecutive chemotherapy-naïve surgical specimens and 88 endoscopic ultrasound-guided fine needle biopsies (EUS-FNBs). The specimens were evaluated as per Kalimuthu by two pancreatic pathologists, resulting in Group A and Group B tumors. Digital mRNA expression profiling was performed, on the surgical specimens using the NanoString IO360 panel of 770 key tumor biology related and 30 custom-genes, and on the EUS-FNBs using a targeted panel of 123 genes.
RESULTS
Morphologic subtyping reached substantial interobserver agreement between the two pathologists. In the surgical and EUS-FNB cohorts, 44.4% and 38.6% were Group A tumors, which were associated with improved survival. Group A showed higher expression of immune-related genes and cytokine/chemokine/interleukin signaling and Group B of genes related to cancer cell proliferation and cell cycle regulation. Hierarchical clustering based on significant differences in gene expression levels between Groups A and B revealed clusters with prognostic value.
CONCLUSIONS
Morphologic subtyping according to Kalimuthu is reproducible and holds prognostic value, in surgical as well as EUS-FNB specimens. As upregulation of immune-related genes was found in Group A, future studies should evaluate the potential of immune therapy approaches with special emphasis on this subtype of PDAC.
背景/目的：基于 RNA 谱分析的胰腺导管腺癌 (PDAC) 有多种分类方法，由此产生了两种主要亚型。Kalimuthu 及其同事提出了一种基于形态的分类方法，与这些亚型一致。迄今为止，PDAC 的免疫治疗方法并不理想。形态 PDAC 亚型在关键的免疫肿瘤学途径上可能存在差异。我们旨在检查 Kalimuthu 形态分类的可重复性和预后价值，并评估亚型之间在与肿瘤生物学和免疫肿瘤学相关的基因表达方面的差异。
方法
纳入 196 例 PDAC 标本，包括 108 例连续的化疗初治手术标本和 88 例内镜超声引导下细针活检 (EUS-FNB)。两位胰腺病理学家根据 Kalimuthu 的方法对标本进行评估，结果分为 A 组和 B 组肿瘤。对手术标本进行数字 mRNA 表达谱分析，使用 NanoString IO360 面板检测 770 个与肿瘤生物学相关的关键基因和 30 个定制基因，对 EUS-FNB 标本使用 123 个基因的靶向面板进行检测。
结果
形态亚型在两位病理学家之间达到了相当大的观察者间一致性。在手术和 EUS-FNB 队列中，44.4%和 38.6%为 A 组肿瘤，与生存改善相关。A 组显示出更高水平的免疫相关基因和细胞因子/趋化因子/白细胞介素信号，而 B 组显示出与癌细胞增殖和细胞周期调节相关的基因。基于 A、B 两组间基因表达水平的显著差异进行层次聚类，揭示了具有预后价值的聚类。
结论
根据 Kalimuthu 的形态学分类具有可重复性和预后价值，不仅在手术标本中如此，在 EUS-FNB 标本中也是如此。由于 A 组中上调了免疫相关基因，因此未来的研究应该评估免疫治疗方法的潜力，特别关注这种 PDAC 亚型。
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