Spatial UBE2N protein expression indicates genomic instability in colorectal cancers

Timo Gemoll,Jens K Habermann,Annette Lischka,Oliver Klein,Murat Eravci,Christoph Thorns,Elena Miroll

doi:10.1186/s12885-019-5856-1

Timo Gemoll, Jens K Habermann + Show 5 more

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https://doi.org/10.1186/s12885-019-5856-1

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BackgroundOne major hallmark of colorectal cancers (CRC) is genomic instability with its contribution to tumor heterogeneity and therapy resistance. To facilitate the investigation of intra-sample phenotypes and the de novo identification of tumor sub-populations, imaging mass spectrometry (IMS) provides a powerful technique to elucidate the spatial distribution patterns of peptides and proteins in tissue sections.MethodsIn the present study, we analyzed an in-house compiled tissue microarray (n = 60) comprising CRCs and control tissues by IMS. After obtaining protein profiles through direct analysis of tissue sections, two validation sets were used for immunohistochemical evaluation.ResultsA total of 28 m/z values in the mass range 800–3500 Da distinguished euploid from aneuploid CRCs (p < 0.001, ROC AUC values < 0.385 or > 0.635). After liquid chromatograph-mass spectrometry identification, UBE2N could be successfully validated by immunohistochemistry in the initial sample cohort (p = 0.0274, ROC AUC = 0.7937) and in an independent sample set of 90 clinical specimens (p = 0.0070, ROC AUC = 0.6957).ConclusionsThe results showed that FFPE protein expression profiling of surgically resected CRC tissue extracts by MALDI-TOF MS has potential value for improved molecular classification. Particularly, the protein expression of UBE2N was validated in an independent clinical cohort to distinguish euploid from aneuploid CRCs.

Highlights

One major hallmark of colorectal cancers (CRC) is genomic instability with its contribution to tumor heterogeneity and therapy resistance
While the microsatellite instability (MSI) pathway is defined by failures in the DNA mismatch repair system (MMR) and an increased rate of mutations [5], the CpG island methylation (CIMP) pathway is characterized by the altered methylation of genes, which results in modified transcription, e.g., the silencing of tumor suppressor genes [2]
matrix-assisted laser desorption/ionization (MALDI)-imaging mass spectrometry (IMS) and statistical evaluation A total of 27 colorectal carcinoma (CRC) and 17 normal mucosa tissues could be evaluated by tissue microarray (TMA) based MALDI imaging

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Introduction

One major hallmark of colorectal cancers (CRC) is genomic instability with its contribution to tumor heterogeneity and therapy resistance. Spatial heterogeneity in the tissue samples has been limited to microscopy-based assessment, e.g., immunofluorescence and fluorescence in situ hybridization. By correlating molecular information with histology at spatial resolution, MALDI-IMS enables the analysis of both the relative abundance and distribution of proteins. In this context, we could already show that ploidy measurements and MALDI-IMS using fresh frozen material can identify prognostic markers in CRC, e.g. thymosin beta-4 [15]. Depicted targets could provide new insights into genomic instability, tumor heterogeneity and treatment options for individualized medicine

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