Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
Mod Pathol. 2018 Jun;31(6):989-996. doi: 10.1038/s41379-018-0003-0. Epub 2018 Feb 8.
There is limited data on the spectrum of molecular alterations in goblet cell carcinoids and adenocarcinoma ex goblet cell carcinoids of the appendix. We used next generation sequencing to determine mutations of potential pathogenetic and therapeutic significance in this rare group of tumors. Adequate DNA was successfully extracted in 34/46 cases and the final group included 18 goblet cell carcinoids and 16 adenocarcinoma ex goblet cell carcinoids. Illumina TruSeq™ was used for sequencing exons of a custom 282 gene panel using an Illumina HiSeq 2000. All cases had a minimum coverage depth of at least 50 reads. After filtering through the Exome Sequencing Project, the number of mutations per case ranged from 0-9 (mean:3). The mutational burden in adenocarcinoma ex goblet cell carcinoids was significantly higher than goblet cell carcinoids (mean 5 vs. 3; p < 0.05) but the spectrum of alterations overlapped between the two groups. The most frequent mutations included ARID1A (4/34), ARID2 (4/34), CDH1 (4/34), RHPN2 (4/34), and MLL2 (3/34). Some mutations typically seen in conventional colorectal adenocarcinomas were also identified but with much lower frequency (APC :4/34; KRAS :2/34). MLL2 and KRAS mutations were only seen in adenocarcinoma ex goblet cell carcinoids and TP53 mutations were limited to poorly differentiated adenocarcinoma ex goblet cell carcinoids (2/34). Copy number changes could be evaluated in 15/34 cases and showed low copy number gains in CDKN1B (6/15) and NFKBIA (6/15), among others. The overlapping molecular alterations suggest that goblet cell carcinoids and adenocarcinoma ex goblet cell carcinoids are best considered two grades of differentiation of the same tumor rather than two distinct histological types. Mutations in TP53, CDH1 and MLL2 mutations were predominantly present in the adenocarcinoma ex goblet cell carcinoid group consistent with transformation to a higher grade lesion. The unique mutational profile also offers an explanation for the poor chemosensitivity in these tumors and highlights the need for developing new targeted therapies.
关于阑尾杯状细胞类癌和杯状细胞类癌衍生腺癌的分子改变谱，相关数据有限。我们使用下一代测序技术来确定这组罕见肿瘤中具有潜在致病和治疗意义的突变。在 46 例中，有 34 例成功提取了足够的 DNA，最终的研究组包括 18 例杯状细胞类癌和 16 例杯状细胞类癌衍生腺癌。使用 Illumina TruSeqTM 对定制的 282 个基因面板的外显子进行测序，使用 Illumina HiSeq 2000。所有病例的最低覆盖深度均至少为 50 个读数。通过外显子测序项目筛选后，每个病例的突变数量范围为 0-9（平均值：3）。杯状细胞类癌衍生腺癌的突变负担明显高于杯状细胞类癌（平均值 5 对 3；p<0.05），但两组之间的改变谱重叠。最常见的突变包括 ARID1A（4/34）、ARID2（4/34）、CDH1（4/34）、RHPN2（4/34）和 MLL2（3/34）。还发现了一些通常见于传统结直肠腺癌的突变，但频率要低得多（APC：4/34；KRAS：2/34）。MLL2 和 KRAS 突变仅见于杯状细胞类癌衍生腺癌，TP53 突变仅限于分化差的杯状细胞类癌衍生腺癌（2/34）。在 15/34 例病例中可以评估拷贝数变化，并显示 CDKN1B（6/15）和 NFKBIA（6/15）等基因的低拷贝数增益。重叠的分子改变表明，杯状细胞类癌和杯状细胞类癌衍生腺癌最好被视为同一种肿瘤的两种分化程度，而不是两种不同的组织学类型。TP53、CDH1 和 MLL2 突变主要存在于杯状细胞类癌衍生腺癌组中，这与向更高等级病变的转化一致。独特的突变谱也解释了这些肿瘤的化疗敏感性差，并强调了开发新的靶向治疗方法的必要性。
