Comprehensive clinicopathologic, molecular, and immunologic characterization of colorectal carcinomas with loss of three intestinal markers, CDX2, SATB2, and KRT20.

Abstract

Caudal-type homeobox 2 (CDX2), special AT-rich sequence-binding protein 2 (SATB2), and keratin 20 (KRT20) are frequently used as intestinal epithelium-specific markers in immunohistochemical studies. However, subsets of colorectal carcinomas (CRCs) show loss of these markers. We analyzed The Cancer Genome Atlas data to explore molecular correlates of CDX2, SATB2, and KRT20 genes in 390 CRCs. The decreased mRNA expression of each of the three genes commonly correlated with microsatellite instability-high (MSI-H), CpG island methylator phenotype-high (CIMP-H), BRAF/RNF43 mutations, consensus molecular subtype 1, and high tumor mutational burden. The downregulation of CDX2 or SATB2 was dependent on both MSI-H and CIMP-H, whereas that of KRT20 was more dependent on MSI-H than on CIMP-H. Next, we evaluated the immunohistochemical expression of CDX2, SATB2, and KRT20 in 436 primary CRCs. In contrast to RNA-level expression, decreased expression of CDX2 and SATB2 was more dependent on CIMP-H than on MSI-H. However, consistent with RNA-level expression, decreased expression of KRT20 was more dependent on MSI-H than on CIMP-H. CIMP-H and lymphatic invasion were consistently associated with both CDX2 loss and SATB2 loss in CRCs, regardless of MSI status. In microsatellite stable CRCs, CDX2 loss correlated with BRAF mutation, whereas SATB2 loss was associated with KRAS mutations and decreased T-cell infiltration. Cases with concurrent loss of all three markers were found exclusively in MLH1-methylated MSI-H/CIMP-H CRCs. In conclusion, MSI-H and/or CIMP-H are major common correlates of decreased CDX2/SATB2/KRT20 expression in CRCs, but the specific features associated with the loss of each marker are different in CRCs.

• Authors: Ji Ae Lee, Mi-Kyoung Seo, Seung-Yeon Yoo, Nam-Yun Cho, Yoonjin Kwak, Kyoungbun Lee, Jung Ho Kim, Gyeong Hoon Kang
• Journal: Virchows Archiv : an international journal of pathology (Virchows Arch) Vol. 480 Issue 3 Pg. 543-555 (Mar 2022) ISSN: 1432-2307 [Electronic] Germany
• PMID: 35029777 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Chemical References

• CDX2 Transcription Factor
• CDX2 protein, human
• KRT20 protein, human
• Keratin-20
• Matrix Attachment Region Binding Proteins
• SATB2 protein, human
• Transcription Factors
• RNA
• Proto-Oncogene Proteins B-raf

Topics

• CDX2 Transcription Factor (genetics, metabolism)
• Colorectal Neoplasms (pathology)
• CpG Islands
• DNA Methylation
• Humans
• Keratin-20 (genetics)
• Matrix Attachment Region Binding Proteins (genetics, metabolism)
• Microsatellite Instability
• Mutation
• Phenotype
• Proto-Oncogene Proteins B-raf (genetics)
• RNA (metabolism)
• Transcription Factors (genetics, metabolism)