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

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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.

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Data Availability

TCGA-COAD and TCGA-READ datasets are publicly available (https://portal.gdc.cancer.gov/). The other datasets generated and/or analyzed during the current study are available from the corresponding authors on reasonable request.

Code availability

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Acknowledgements

The results published here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga.

Funding

This study was supported by a grant from the Seoul National University Hospital Research Fund (04–2020-0550), a grant from the Seoul National University (800–20210387), and the National Research Foundation of Korea grants funded by the Korea government (Ministry of Science and ICT) (NRF-2016R1C1B2010627; NRF-2019R1F1A1059535).

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Authors and Affiliations

  1. Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea

    Ji Ae Lee, Seung-Yeon Yoo, Yoonjin Kwak, Kyoungbun Lee, Jung Ho Kim & Gyeong Hoon Kang

  2. Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea

    Ji Ae Lee, Mi-Kyoung Seo, Seung-Yeon Yoo, Nam-Yun Cho, Jung Ho Kim & Gyeong Hoon Kang

  3. Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, South Korea

    Mi-Kyoung Seo

  4. Department of Nuclear Medicine, Seoul National University Hospital, Seoul, South Korea

    Mi-Kyoung Seo

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  1. Ji Ae Lee
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Contributions

JHK designed the study. JAL, YK, KL, JHK, and GHK collected tissue samples and clinical data and performed histologic and immunohistochemical examination. JAL, M-KS, S-YY, and JHK analyzed the data. JAL and N-YC conducted the experiments. JAL, M-KS, JHK, and GHK wrote the draft. JHK and GHK revised the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Jung Ho Kim or Gyeong Hoon Kang.

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This study was conducted in compliance with the ethical guidelines of the 2013 Declaration of Helsinki and was approved by the Institutional Review Board of Seoul National University Hospital (IRB No. 1804–036-935).

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All tissue samples used in this study were previously registered in the Cancer Tissue Bank of Seoul National University Hospital with informed consent obtained from all patients about the research use of their tissues.

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The authors declare no competing interests.

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Ji Ae Lee and Mi-Kyoung Seo contributed equally to this work.

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Lee, J.A., Seo, MK., Yoo, SY. et al. Comprehensive clinicopathologic, molecular, and immunologic characterization of colorectal carcinomas with loss of three intestinal markers, CDX2, SATB2, and KRT20. Virchows Arch 480, 543–555 (2022). https://doi.org/10.1007/s00428-021-03260-w

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