Loss of SATB2 Occurs More Frequently Than CDX2 Loss in Colorectal Carcinoma and Identifies Particularly Aggressive Cancers in High-Risk Subgroups

Maxime Schmitt,Miguel Silva,Markus Tschurtschenthaler,Björn Konukiewitz,Corinna Lang,Jutta Engel,Kathrin Halfter,Dirk Wilhelm,Paul Jank,Nicole Pfarr,Carsten Denkert,Sebastian Foersch,Moritz Jesinghaus,Katja Steiger,Wilko Weichert

doi:10.3390/cancers13246177

Abstract

Simple SummaryThe immunohistochemical analysis of Special AT-rich sequence-binding protein 2 (SATB2) is increasingly being used to detect colorectal differentiation. Our study aimed to investigate SATB2 expression levels and the prognostic relevance of SATB2 loss in colorectal carcinoma (CRC), especially in comparison with CDX2, the standard marker of colorectal differentiation. We tested SATB2 expression in 1039 CRCs and identified SATB2 as a strong prognosticator in the overall cohort as well as in specific subcohorts, including high-risk subgroups. Compared to CDX2, SATB2 showed a higher prognostic power but was lost at a much higher frequency, generally rendering SATB2 as the less sensitive marker for colorectal differentiation compared to CDX2.Background: Special AT-rich sequence-binding protein 2 (SATB2) has emerged as an alternative immunohistochemical marker to CDX2 for colorectal differentiation. However, the distribution and prognostic relevance of SATB2 expression in colorectal carcinoma (CRC) have to be further elucidated. Methods: SATB2 expression was analysed in 1039 CRCs and correlated with clinicopathological and morphological factors, CDX2 expression as well as survival parameters within the overall cohort and in clinicopathological subgroups. Results: SATB2 loss was a strong prognosticator in univariate analyses of the overall cohort (p < 0.001 for all survival comparisons) and in numerous subcohorts including high-risk scenarios (UICC stage III/high tumour budding). SATB2 retained its prognostic relevance in multivariate analyses of these high-risk scenarios (e.g., UICC stage III: DSS: p = 0.007, HR: 1.95), but not in the overall cohort (DSS: p = 0.1, HR: 1.25). SATB2 loss was more frequent than CDX2 loss (22.2% vs. 10.2%, p < 0.001) and of higher prognostic relevance with only moderate overlap between SATB2/CDX2 expression groups. Conclusions: SATB2 loss is able to identify especially aggressive CRCs in high-risk subgroups. While SATB2 is the prognostically superior immunohistochemical parameter compared to CDX2 in univariate analyses, it appears to be the less sensitive marker for colorectal differentiation as it is lost more frequently.

Highlights

We investigated the expression of Special AT-rich sequence-binding protein 2 (SATB2) in one thousand and thirty-nine resected CRCs, correlated the results with histomorphologic parameters (CRC subtypes, tumour budding activity, WHO grade) [17], expression of CDX2 [18] as well as clinicopathological parameters and analysed the prognostic relevance of SATB2 in the overall cohort and in specific subcohorts
In our cohort of more than one thousand tumours, SATB2 low/absent CRCs were significantly associated with higher UICC stages and massively enriched in tumours with high-risk histomorphological features such as high tumour budding (Bd3) or poorly differentiated carcinomas according to the WHO grade, which is in line with the functional studies postulating the tumour suppressive properties of SATB2 [12,27,28]
Our study has five major findings: (1) a low/absent SATB2 expression is significantly enriched in advanced stage CRCs that have an aggressive histomorphological phenotype with high tumour budding activity and/or a poor differentiation according to the WHO

Summary

Introduction

Previous immunohistochemical assessments of SATB2 in CRC showed a general association of a diminished SATB2 expression with poorer survival characteristics and microsatellite status [12,13,14,15,16] It remains unclear whether SATB2 is differently expressed within purely morphological (adenocarcinoma NOS vs specific CRC subtypes, tumour budding subcategories (Bd1/2/3), WHO low- vs high-grade carcinomas), immunohistochemical (CDX2 expression) and pTNM/UICC stage subgroups. It remains to be elucidated, how frequently the loss of SATB2 occurs in comparison to the loss of CDX2 and whether SATB2 can identify distinct prognostic groups within these colorectal cancer subsets. While SATB2 is the prognostically superior immunohistochemical parameter compared to CDX2 in univariate analyses, it appears to be the less sensitive marker for colorectal differentiation as it is lost more frequently

Methods

Results

Discussion

Conclusion