Department of Pathology, Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Gyeonggi-do, Republic of Korea; Hallym Institute of Translational Genomics and Bioinformatics, Hallym University Medical Center, Anyang, Gyeonggi-do, Republic of Korea.
Hum Pathol. 2019 May;87:83-94. doi: 10.1016/j.humpath.2019.02.007. Epub 2019 Mar 6.
Rectal neuroendocrine tumors (NETs) are the most common gastrointestinal (GI) NETs with an uncertain malignant potential despite their small size. There are limited data about driver mutations in rectal NETs, which may explain the tumors' unexpected behavior or common histologic morphology with other GI-NETs. Here, we investigated the clinically and pathologically relevant mutations of rectal and nonrectal NETs and compared the frequency and clinical significance of detected mutations between them. We sequenced 84 primary GI-NETs (69 rectal, 7 gastric, 5 appendiceal, and 3 sigmoid colon NETs) and 3 metastatic GI-NETs using targeted next-generation sequencing. Twenty-one rectal NETs (30.4%) showed at least 1 mutation in 24 cancer-related genes; the most common mutations were TP53 (10.1%) and FBXW7 (7.2%), of which 73% were pathogenic/likely pathogenic mutations. TP53 (p.R337C and p.R213*), PTEN (p.W111*, p.Q214*), CDKN2A (p.W110*), FBXW7 (p.R465H), and AKT1 (p.R23Q) were repetitive mutations found exclusively in rectal NETs, whereas SMAD4 (p.R361C) and STK11 (p.D176N) were repetitive mutations found only in gastric NETs. PTEN (p.G129K), EGFR (p.E709K), and KIT (p.V555I) were shared mutations between rectal and appendiceal NETs, whereas SMAD4 (p.R361C), ALK (p.G1202R), VHL (p.Q132*), and IDH1 (p.R132H) were concurrently detected between rectal and gastric NETs. GI-NETs with higher histologic grades, lymphovascular invasion, or recurrence tended to have higher numbers of mutation variants than other tumors; however, there was no significant difference. In conclusion, rectal NETs commonly carried pathogenic/likely pathogenic mutations. Because most mutations were identified in nonhotspot positions, next-generation sequencing is useful in identifying potential drug targets in rectal NETs.
直肠神经内分泌肿瘤 (NET) 是最常见的胃肠道 (GI) NET，尽管体积较小，但恶性潜能不确定。关于直肠 NET 的驱动突变的资料有限，这可能解释了这些肿瘤的意外行为或与其他 GI-NET 常见的组织形态学。在这里，我们研究了直肠和非直肠 NET 的临床和病理相关突变，并比较了它们之间检测到的突变的频率和临床意义。我们使用靶向下一代测序对 84 例原发性 GI-NET（69 例直肠 NET、7 例胃 NET、5 例阑尾 NET 和 3 例乙状结肠 NET）和 3 例转移性 GI-NET 进行了测序。21 例直肠 NET（30.4%）在 24 个癌症相关基因中至少有 1 个突变；最常见的突变为 TP53（10.1%）和 FBXW7（7.2%），其中 73%为致病性/可能致病性突变。TP53（p.R337C 和 p.R213*）、PTEN（p.W111*、p.Q214*）、CDKN2A（p.W110*）、FBXW7（p.R465H）和 AKT1（p.R23Q）是仅在直肠 NET 中发现的重复突变，而 SMAD4（p.R361C）和 STK11（p.D176N）是仅在胃 NET 中发现的重复突变。PTEN（p.G129K）、EGFR（p.E709K）和 KIT（p.V555I）是直肠和阑尾 NET 之间的共享突变，而 SMAD4（p.R361C）、ALK（p.G1202R）、VHL（p.Q132*）和 IDH1（p.R132H）则同时存在于直肠和胃 NET 中。组织学分级较高、脉管侵犯或复发的 GI-NET 往往比其他肿瘤有更多的突变变异数；然而，差异无统计学意义。总之，直肠 NET 常见致病性/可能致病性突变。由于大多数突变发生在非热点位置，因此下一代测序在鉴定直肠 NET 中的潜在药物靶点方面是有用的。
