Traditional serrated adenoma (TSA) remains the least understood of all the colorectal adenomas, although these lesions have been associated with a significant cancer risk, twice that of the conventional adenoma (CAD) and of the sessile serrated adenoma (SSA/P). This study was performed to investigate the proteomic profiles of the different colorectal adenomas to better understand the pathogenesis of TSA. We performed a global quantitative proteome analysis using the label-free quantification (LFQ) method on 44 colorectal adenoma (12 TSAs, 15 CADs, and 17 SSA/Ps) and 17 normal colonic mucosa samples, archived as formalin-fixed paraffin-embedded blocks. Unsupervised consensus hierarchical clustering applied to the whole proteomic profile of the 44 colorectal adenomas identified four subtypes: C1 and C2 were well-individualized clusters composed of all the CADs (15/15) and most of the SSA/Ps (13/17), respectively. This is consistent with the fact that CADs and SSA/Ps are homogeneous and distinct colorectal adenoma entities. In contrast, TSAs were subdivided into C3 and C4 clusters, consistent with the more heterogeneous entity of TSA at the morphologic and molecular levels. Comparison of the proteome expression profile between the adenoma subtypes and normal colonic mucosa further confirmed the heterogeneous nature of TSAs, which overlapped either on CADs or SSA/Ps, whereas CADs and SSAs formed homogeneous and distinct entities. Furthermore, we identified LEFTY1 a new potential marker for TSAs that may be relevant for the pathogenesis of TSA. LEFTY1 is an inhibitor of the Nodal/TGFβ pathway, which we found to be one of the most overexpressed proteins specifically in TSAs. This finding was confirmed by immunohistochemistry. Our study confirms that CADs and SSA/Ps form homogeneous and distinct colorectal adenoma entities, whereas TSAs are a heterogeneous entity and may arise from either SSA/Ps or from normal mucosa evolving through a process related to the CAD pathway. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

中文翻译：

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对福尔马林固定石蜡包埋的结直肠腺瘤进行蛋白质组学分析，发现与其他结直肠腺瘤相比，传统锯齿状腺瘤具有异质性。

传统锯齿状腺瘤（TSA）仍是所有大肠腺瘤中最不了解的疾病，尽管这些病变与显着的癌症风险相关，是传统腺瘤（CAD）和无柄锯齿状腺瘤（SSA / P）的两倍。进行这项研究以研究不同结直肠腺瘤的蛋白质组学特征，以更好地了解TSA的发病机理。我们使用无标记定量（LFQ）方法对44个大肠腺瘤（12个TSA，15个CAD和17个SSA / Ps）和17个正常结肠粘膜样品进行了全球定量蛋白质组分析，这些样品被保存为福尔马林固定石蜡包埋的块。无监督共识分层聚类应用于44个大肠腺瘤的整个蛋白质组学特征，确定了四个亚型：C1和C2是分别由所有CAD（15/15）和大多数SSA / P（13/17）组成的个性化集群。这与CAD和SSA / P是同质且截然不同的结直肠腺瘤实体这一事实是一致的。相反，TSA细分为C3和C4簇，这与TSA在形态和分子水平上更具异质性。腺瘤亚型和正常结肠粘膜之间蛋白质组表达谱的比较进一步证实了TSA的异质性，它在CAD或SSA / P上重叠，而CAD和SSA形成均匀且不同的实体。此外，我们确定了LEFTY1是TSA的新潜在标志物，可能与TSA的发病机制有关。LEFTY1是Nodal /TGFβ途径的抑制剂，我们发现它是在TSA中最过表达的蛋白质之一。免疫组织化学证实了这一发现。我们的研究证实，CADs和SSA / Ps形成均质且截然不同的结直肠腺瘤实体，而TSA是异质实体，可能源自SSA / Ps或正常黏膜，其通过与CAD途径相关的过程演变而来。©2019英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版 ©2019英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版 ©2019英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版