Department of Gastroenterology and Metabolism, Institute of Biomedical and Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Department of Regeneration and Medicine Medical Center for Translation and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan.
PLoS One. 2019 Feb 20;14(2):e0211477. doi: 10.1371/journal.pone.0211477. eCollection 2019.
Serrated adenocarcinoma (SAC) is considered the end stage of the serrated neoplasia pathway. Although SAC prognosis is not widely recognized, the serrated pathway-associated subtype consistently exhibits unfavorable prognosis in genetic studies. Herein, we classified molecularly distinct subtypes of serrated adenocarcinomas and clarified their associated clinicopathological characteristics and genetic changes. We examined 38 early-stage colorectal SACs. Of these, 24 were classified into three molecularly distinct groups by colon cancer subtyping (CCS). The clinicopathological characteristics, Ki 67 labeling index (LI), and SAC epithelial serration were assessed. The DNA from carcinomas and normal tissue/adenoma was extracted by laser microdissection and sequenced by next-generation sequencing, and mutation numbers and patterns of a 15-oncogene panel were determined. The CCS groups included CCS1 (CDX2+, HTR2B-, FRMD6-, ZEB1-, and microsatellite instable-low [MSI-L]/microsatellite stable [MSS]; 14 cases), CCS2 (microsatellite instable-high [MSI-H], 5 cases), and CCS3 (CDX2-, HTR2B+, FRMD6+, ZEB1+, and MSI-L/MSS; 5 cases). Invasive cancer was significantly more frequent in CCS3 than in CCS1 (5/5 versus 3/14, respectively). Ki67 LI and epithelial serration were higher in CCS3 than in CCS1 (83.0 ± 5.8 versus 65.4 ± 4.0 and 5/5 versus 3/14, respectively; p = 0.031 and 0.0048). CCS2 showed the highest mutation number, whereas KRAS and BRAF mutation numbers were higher in CCS3 than in CCS1. Early-stage SACs were classified into three molecularly distinct subtypes with different clinicopathological and genetic characteristics.
锯齿状腺癌（SAC）被认为是锯齿状肿瘤发生途径的终末阶段。尽管 SAC 的预后尚未得到广泛认可，但在遗传研究中，锯齿状途径相关的亚型始终表现出不良的预后。在此，我们对锯齿状腺癌进行了分子分类，并阐明了它们相关的临床病理特征和遗传变化。我们检查了 38 例早期结直肠 SAC，其中 24 例根据结肠癌亚分型（CCS）分为三个分子上不同的组。评估了临床病理特征、Ki67 标记指数（LI）和 SAC 上皮锯齿状。通过激光显微切割提取癌组织和正常组织/腺瘤的 DNA，通过下一代测序进行测序，并确定 15 个癌基因panel 的突变数量和模式。CCS 组包括 CCS1（CDX2+，HTR2B-，FRMD6-，ZEB1-，微卫星不稳定低[MSI-L]/微卫星稳定[MSS]；14 例），CCS2（微卫星不稳定高[MSI-H]，5 例）和 CCS3（CDX2-，HTR2B+，FRMD6+，ZEB1+，MSI-L/MSS；5 例）。CCS3 中浸润性癌的发生率明显高于 CCS1（5/5 与 3/14 相比）。CCS3 中 Ki67 LI 和上皮锯齿状比 CCS1 更高（83.0±5.8 与 65.4±4.0 和 5/5 与 3/14 相比；p=0.031 和 0.0048）。CCS2 显示出最高的突变数量，而 KRAS 和 BRAF 突变数量在 CCS3 中高于 CCS1。早期 SAC 分为具有不同临床病理和遗传特征的三个分子上不同的亚型。
