Department of Pathology, Santa Lucía General University Hospital, Cartagena, Spain.
Int J Cancer. 2013 Jan 15;132(2):297-307. doi: 10.1002/ijc.27674. Epub 2012 Jun 28.
Serrated adenocarcinoma (SAC) is a recently recognized colorectal cancer (CRC) subtype accounting for 7.5 to 8.7% of CRCs. It has been shown that SAC has a poorer prognosis and has different molecular and immunohistochemical features compared with conventional carcinoma (CC) but, to date, only one previous study has analyzed its mRNA expression profile by microarray. Using a different microarray platform, we have studied the molecular signature of 11 SACs and compared it with that of 15 matched CC with the aim of discerning the functions which characterize SAC biology and validating, at the mRNA and protein level, the most differentially expressed genes which were also tested using a validation set of 70 SACs and 70 CCs to assess their diagnostic and prognostic values. Microarray data showed a higher representation of morphogenesis-, hypoxia-, cytoskeleton- and vesicle transport-related functions and also an overexpression of fascin1 (actin-bundling protein associated with invasion) and the antiapoptotic gene hippocalcin in SAC all of which were validated both by quantitative real-time PCR (qPCR) and immunohistochemistry. Fascin1 expression was statistically associated with KRAS mutation with 88.6% sensitivity and 85.7% specificity for SAC diagnosis and the positivity of fascin1 or hippocalcin was highly suggestive of SAC diagnosis (sensitivity = 100%). Evaluation of these markers in CRCs showing histological and molecular characteristics of high-level microsatellite instability (MSI-H) also helped to distinguish SACs from MSI-H CRCs. Molecular profiling demonstrates that SAC shows activation of distinct signaling pathways and that immunohistochemical fascin1 and hippocalcin expression can be reliably used for its differentiation from other CRC subtypes.
锯齿状腺癌（SAC）是一种最近被认识的结直肠癌（CRC）亚型，占 CRC 的 7.5%至 8.7%。已经表明，SAC 的预后较差，与传统癌（CC）相比具有不同的分子和免疫组织化学特征，但迄今为止，只有一项先前的研究通过微阵列分析了其 mRNA 表达谱。我们使用不同的微阵列平台研究了 11 例 SAC 的分子特征，并将其与 15 例匹配的 CC 进行了比较，旨在辨别出 SAC 生物学的特征功能，并在 mRNA 和蛋白水平上验证那些差异表达最明显的基因，这些基因也使用 70 例 SAC 和 70 例 CC 的验证集进行了测试，以评估它们的诊断和预后价值。微阵列数据显示，形态发生、缺氧、细胞骨架和囊泡运输相关功能的代表性更高，并且 fascin1（与侵袭相关的肌动蛋白束蛋白）和抗凋亡基因 hippocalcin 的过度表达在 SAC 中也得到了验证，所有这些都通过定量实时 PCR（qPCR）和免疫组织化学进行了验证。Fascin1 的表达与 KRAS 突变具有统计学相关性，对 SAC 诊断的敏感性为 88.6%，特异性为 85.7%，Fascin1 或 hippocalcin 的阳性高度提示 SAC 诊断（敏感性=100%）。在显示高水平微卫星不稳定性（MSI-H）的组织学和分子特征的 CRC 中评估这些标志物也有助于将 SAC 与 MSI-H CRC 区分开来。分子分析表明，SAC 显示出不同信号通路的激活，免疫组织化学 fascin1 和 hippocalcin 的表达可以可靠地用于其与其他 CRC 亚型的区分。
