A modified protein marker panel to identify four consensus molecular subtypes in colorectal cancer using immunohistochemistry

• Published in: Pathology, research and practice research and practice, 2021-04, Vol.220, p.153379-153379, Article 153379
• Main Authors: Li, Xingru, Larsson, Pär, Ljuslinder, Ingrid, Ling, Agnes, Löfgren-Burström, Anna, Zingmark, Carl, Edin, Sofia, Palmqvist, Richard
• Format: Article
• Language: English
• Subjects: Colorectal cancer; Consensus molecular subtypes; Immunohistochemistry; Protein marker panel; β-catenin
• ISSN: 0344-0338; 1618-0631; 1618-0631
• DOI: 10.1016/j.prp.2021.153379

Colorectal cancer (CRC) is a heterogeneous disease with different genetic and molecular backgrounds, leading to a diverse patient prognosis and treatment response. Four consensus molecular subtypes (CMS 1–4) have recently been proposed based on transcriptome profiling. A clinically practical immunohistochemistry (IHC) based CMS classifier consisting of the four markers FRMD6, ZEB1, HTR2B, and CDX2 was then demonstrated. However, the IHC-CMS classifier did not distinguish between CMS2 and CMS3 tumours. In this study, we have applied the proposed transcriptome based and IHC-based CMS classifiers in a CRC cohort of 65 patients and found a concordance of 77.5 %. Further, we modified the IHC-CMS classifier by analysing the differentially expressed genes between CMS2 and CMS3 tumours using RNA-sequencing data from the TCGA dataset. The result showed that WNT signalling was among the most upregulated pathways in CMS2 tumours, and the expression level of CTNNB1 (encoding β-catenin), a WNT pathway hallmark, was significantly upregulated (P = 1.15 × 10−6). We therefore introduced nuclear β-catenin staining to the IHC-CMS classifier. Using the modified classifier in our cohort, we found a 71.4 % concordance between the IHC and RNA-sequencing based CMS classifiers. Moreover, β-catenin staining could classify 16 out of the 19 CMS2/3 tumours into CMS2 or CMS3, thereby showing an 84.2 % concordance with the RNA-sequencing-based classifier. In conclusion, we evaluated CMS classifiers based on transcriptome and IHC analysis. We present a modified IHC panel that categorizes CRC tumours into the four CMS groups. To our knowledge, this is the first study using IHC to identify all four CMS groups.