Proteome analysis of formalin‐fixed paraffin‐embedded colorectal adenomas reveals the heterogeneous nature of traditional serrated adenomas compared to other colorectal adenomas

Abstract

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.

Proteomic analysis of the urothelial cancer landscape

“…While the latter can be problematic in large series 56 they reported high identification numbers for their FFPE samples comparable to FF samples 57 . These were collected prospectively under study conditions, presumably with standardized short fixation times, explaining the difference to our and others’ identification numbers with archival FFPE tissue 44 – 46 , 58 . Based on proteins expressed in 30% of all samples and with a dominance of MIBC samples (n = 71; 61%) they identified three proteomic clusters with significant survival stratification in univariate analysis (ibid.…”

Normics: Proteomic Normalization by Variance and Data-Inherent Correlation Structure

“…investigating the proteomic effects in the liver with knock down of a central metabolic enzyme (dC1; PXD002025; ebi.ac.uk/pride) [30] and a study in human tissue by Sohier et al, in which distinct pathological types of colorectal adenoma were compared on proteome level (dC2; PXD014511; proteomecentral.proteomexchange.org) [31].…”

Evolving pathologic concepts of serrated lesions of the colorectum

“…Specific biomarkers for the differential diagnosis of TSAs have not been established. However, Sohier et al [73] performed proteomic analysis using formalin-fixed, paraffin-embedded tissues of various types of serrated lesions and conventional adenomas and found that LEFTY1, an inhibitory protein of the Nodal/transforming growth factor β pathway, was overexpressed specifically in TSAs. Although this may be promising, more studies will be necessary to validate whether LEFTY1 immunohistochemistry is practically useful in the diagnosis of TSAs.…”

“…Third, immunohistochemical or molecular biomarkers should be further developed and validated to aid in the differential diagnosis or prognostic subgrouping of serrated colorectal lesions. Recently studied proteins such as AGRN and LEFTY1 are potential biomarkers which can aid in the differential diagnosis of serrated lesions [62,73].…”