Institute of Pathology, Technical University of Munich, Munich, Germany.
German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany.
Mod Pathol. 2018 May;31(5):829-839. doi: 10.1038/modpathol.2017.184. Epub 2018 Jan 12.
The appendix gives rise to goblet cell carcinoids, which represent special carcinomas with distinct biological and histological features. Their genetic background and molecular relationship to colorectal adenocarcinoma is largely unknown. We therefore performed a next-generation sequencing analysis of 25 appendiceal carcinomas including 11 goblet cell carcinoids, 7 adenocarcinomas ex-goblet cell carcinoid, and 7 primary colorectal-type adenocarcinomas, using a modified Colorectal Cancer specific Panel comprising 32 genes linked to colorectal and neuroendocrine tumorigenesis. The mutational profiles of these neoplasms were compared with those of conventional adenocarcinomas, mixed adenoneuroendocrine carcinomas, and neuroendocrine carcinomas of the colorectum. In addition, a large-scale pan-cancer sequencing panel covering 409 genes was applied to selected cases of goblet cell carcinoid/adenocarcinoma ex-goblet cell carcinoid (n=2, respectively). Mutations in colorectal cancer-related genes (eg, TP53, KRAS, APC) were rare to absent in both, goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid, but frequent in primary colorectal-type adenocarcinomas of the appendix. Additional large-scale sequencing of selected goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid revealed mutations in Wnt-signaling-associated genes (USP9X, NOTCH1, CTNNA1, CTNNB1, TRRAP). These data suggest that appendiceal goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid constitute a morphomolecular entity, histologically and genetically distinct from appendiceal colorectal-type adenocarcinomas and its colorectal counterparts. Altered Wnt-signaling associated genes, apart from APC, may act as potential drivers of these neoplasms. The absence of KRAS/NRAS mutations might render some of these tumors eligible for anti-EGFR directed therapy regimens.
阑尾可发生杯状细胞类癌，这是一种具有独特生物学和组织学特征的特殊癌。其遗传背景及其与结直肠腺癌的分子关系在很大程度上尚不清楚。因此，我们对 25 例阑尾癌进行了下一代测序分析，包括 11 例杯状细胞类癌、7 例类癌去杯状细胞化生腺癌和 7 例原发性结直肠型腺癌，使用改良的包含 32 个与结直肠和神经内分泌肿瘤发生相关基因的 Colorectal Cancer specific Panel。这些肿瘤的突变谱与常规腺癌、混合性腺神经内分泌癌和结直肠神经内分泌癌进行了比较。此外，还对选定的杯状细胞类癌/去杯状细胞化生腺癌病例（n=2）应用了大规模泛癌测序面板，以涵盖 409 个基因。结直肠癌相关基因（如 TP53、KRAS、APC）的突变在杯状细胞类癌和去杯状细胞化生腺癌中均罕见或缺失，但在阑尾原发性结直肠型腺癌中则常见。对选定的杯状细胞类癌和去杯状细胞化生腺癌的进一步大规模测序揭示了 Wnt 信号相关基因（USP9X、NOTCH1、CTNNA1、CTNNB1、TRRAP）的突变。这些数据表明，阑尾杯状细胞类癌和去杯状细胞化生腺癌构成了一种形态学和分子学上不同于阑尾结直肠型腺癌及其结直肠对应物的实体。除 APC 外，改变的 Wnt 信号相关基因可能作为这些肿瘤的潜在驱动基因。缺乏 KRAS/NRAS 突变可能使这些肿瘤中的一些有资格接受抗 EGFR 靶向治疗方案。
