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Loss of SATB2 and CDX2 expression is associated with DNA mismatch repair protein deficiency and BRAF mutation in colorectal cancer

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Abstract

The relationship between the expression of the SATB2 and CDX2 proteins and common molecular changes and clinical prognosis in colorectal cancer (CRC) still needs further clarification. We collected 1180 cases of CRC and explored the association between the expression of SATB2 and CDX2 and clinicopathological characteristics, molecular alterations, and overall survival of CRC using whole-slide immunohistochemistry. Our results showed that negative expression of SATB2 and CDX2 was more common in MMR-protein-deficient CRC than in MMR-protein-proficient CRC (15.8% vs. 6.0%, P = 0.001; 14.5% vs. 4.0%, P = 0.000, respectively). Negative expression of SATB2 and CDX2 was more common in BRAF-mutant CRC than in BRAF wild-type CRC (17.2% vs. 6.1%, P = 0.003; 13.8% vs. 4. 2%; P = 0.004, respectively). There was no relationship between SATB2 and/or CDX2 negative expression and KRAS, NRAS, and PIK3CA mutations. The lack of expression of SATB2 and CDX2 was associated with poor histopathological features of CRC. In multivariate analysis, negative expression of SATB2 (P = 0.030), negative expression of CDX2 (P = 0.043) and late clinical stage (P = 0.000) were associated with decreased overall survival of CRC. In conclusion, the lack of SATB2 and CDX2 expression in CRC was associated with MMR protein deficiency and BRAF mutation, but not with KRAS, NRAS and PIK3CA mutation. SATB2 and CDX2 are prognostic biomarkers in patients with CRC.

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Availability of data and materials

The datasets generated and/or analyzed in the present study are available from the corresponding author on reasonable request.

References

  1. Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F (2017) Global patterns and trends in colorectal cancer incidence and mortality. Gut 66:683–691. https://doi.org/10.1136/gutjnl-2015-310912

    Article  PubMed  Google Scholar 

  2. Kambara T, Simms LA, Whitehall VL, Spring KJ, Wynter CV, Walsh MD, Barker MA et al (2004) BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut 53:1137–1144. https://doi.org/10.1136/gut.2003.037671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Jass JR (2007) Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 50:113–130. https://doi.org/10.1111/j.1365-2559.2006.02549.x

    Article  CAS  PubMed  Google Scholar 

  4. Lugli A, Tzankov A, Zlobec I, Terracciano LM (2008) Differential diagnostic and functional role of the multi-marker phenotype CDX2/CK20/CK7 in colorectal cancer stratified by mismatch repair status. Mod Pathol 21:1403–1412. https://doi.org/10.1038/modpathol.2008.117

    Article  CAS  PubMed  Google Scholar 

  5. Ma C, Olevian D, Miller C, Herbst C, Jayachandran P, Kozak MM et al (2019) SATB2 and CDX2 are prognostic biomarkers in DNA mismatch repair protein deficient colon cancer. Mod Pathol 32:1217–1231. https://doi.org/10.1038/s41379-019-0265-1

    Article  CAS  PubMed  Google Scholar 

  6. Ma C, Olevian DC, Lowenthal BM, Jayachandran P, Kozak MM, Chang DT et al (2018) Loss of SATB2 expression in colorectal carcinoma is associated with DNA mismatch repair protein deficiency and BRAF mutation. Am J Surg Pathol 42:1409–1417. https://doi.org/10.1097/PAS.0000000000001116

    Article  PubMed  Google Scholar 

  7. Kim JH, Rhee YY, Bae JM, Kwon HJ, Cho NY, Kim MJ et al (2013) Subsets of microsatellite-unstable colorectal cancers exhibit discordance between the CpG island methylator phenotype and MLH1 methylation status. Mod Pathol 26:1013–1022. https://doi.org/10.1038/modpathol.2012.241

    Article  CAS  PubMed  Google Scholar 

  8. Bae JM (2015) Loss of CDX2 expression is associated with poor prognosis in colorectal cancer patients. World J Gastroenterol 21:1457. https://doi.org/10.3748/wjg.v21.i5.1457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lin F, Shi J, Zhu S, Chen Z, Li A, Chen T et al (2014) Cadherin-17 and SATB2 are sensitive and specific immunomarkers for medullary carcinoma of the large intestine. Arch Pathol Lab Med 138:1015–1026. https://doi.org/10.5858/arpa.2013-0452-OA

    Article  PubMed  Google Scholar 

  10. Dragomir A, de Wit M, Johansson C, Uhlen M, Ponten F (2014) The role of SATB2 as a diagnostic marker for tumors of colorectal origin: results of a pathology-based clinical prospective study. Am J Clin Pathol 141:630–638. https://doi.org/10.1309/AJCPWW2URZ9JKQJU

    Article  PubMed  Google Scholar 

  11. Kaimaktchiev V, Terracciano L, Tornillo L, Spichtin H, Stoios D, Bundi M et al (2004) The homeobox intestinal differentiation factor CDX2 is selectively expressed in gastrointestinal adenocarcinomas. Mod Pathol 17: 1392–1399. https://doi.org/10.1038/modpathol.3800205

  12. Berg KB, Schaeffer DF (2017) SATB2 as an immunohistochemical marker for colorectal adenocarcinoma: a concise review of benefits and pitfalls. Arch Pathol Lab Med 141:1428–1433. https://doi.org/10.5858/arpa.2016-0243-RS

    Article  CAS  PubMed  Google Scholar 

  13. Magnusson K, de Wit M, Brennan DJ, Johnson LB, McGee SF, Lundberg E et al (2011) SATB2 in combination with cytokeratin 20 identifies over 95% of all colorectal carcinomas. Am J Surg Pathol 35: 937–948. https://doi.org/10.1097/PAS.0b013e31821c3dae

  14. FitzPatrick DR, Carr IM, McLaren L, Leek JP, Wightman P, Williamson K et al (2003) Identification of SATB2 as the cleft palate gene on 2q32-q33. Hum Mol Genet 12: 2491–2501. https://doi.org/10.1093/hmg/ddg248

  15. Mezheyeuski A, Ponten F, Edqvist P-H, Sundström M, Thunberg U, Qvortrup C et al (2019) Metastatic colorectal carcinomas with high SATB2 expression are associated with better prognosis and response to chemotherapy: a population-based Scandinavian study. Acta Oncolog 59:284–290. https://doi.org/10.1080/0284186X.2019.1691258

    Article  Google Scholar 

  16. Cigerova V, Adamkov M, Drahosova S, Grendar M (2021) Immunohistochemical expression and significance of SATB2 protein in colorectal cancer. Ann Diagn Pathol 52: 151731. https://doi.org/10.1016/j.anndiagpath.2021.151731

  17. Ma C, Henn P, Miller C, Herbst C, Hartman DJ, Pai RK (2019) Loss of SATB2 expression is a biomarker of inflammatory bowel disease-associated colorectal dysplasia and adenocarcinoma. Am J Surg Pathol 43:1314–1322. https://doi.org/10.1097/PAS.0000000000001330

    Article  PubMed  Google Scholar 

  18. Iwaya M, Ota H, Tateishi Y, Nakajima T, Riddell R, Conner JR (2019) Colitis-associated colorectal adenocarcinomas are frequently associated with non-intestinal mucin profiles and loss of SATB2 expression. Mod Pathol 32:884–892. https://doi.org/10.1038/s41379-018-0198-0

    Article  CAS  PubMed  Google Scholar 

  19. Mansour MA, Hyodo T, Ito S, Kurita K, Kokuryo T, Uehara K et al (2015) SATB2 suppresses the progression of colorectal cancer cells via inactivation of MEK5/ERK5 signaling. FEBS J 282:1394–1405. https://doi.org/10.1111/febs.13227

    Article  CAS  PubMed  Google Scholar 

  20. Schmitt M, Silva M, Konukiewitz B et al (2021) Loss of SATB2 occurs more frequently than CDX2 loss in colorectal carcinoma and identifies particularly aggressive cancers in high-risk subgroups. Cancers (Basel) 13(24):6177. https://doi.org/10.3390/cancers13246177

    Article  CAS  PubMed  Google Scholar 

  21. Eberhard J, Gaber A, Wangefjord S, Nodin B, Uhlen M, Ericson Lindquist K et al (2012) A cohort study of the prognostic and treatment predictive value of SATB2 expression in colorectal cancer. Br J Cancer 106:931–938. https://doi.org/10.1038/bjc.2012.34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang S, Zhou J, Wang XY, Hao JM, Chen JZ, Zhang XM et al (2009) Down-regulated expression of SATB2 is associated with metastasis and poor prognosis in colorectal cancer. J Pathol 219:114–122. https://doi.org/10.1002/path.2575

    Article  CAS  PubMed  Google Scholar 

  23. Guo RJ, Suh ER, Lynch JP (2004) The role of Cdx proteins in intestinal development and cancer. Cancer Biol Ther 3:593–601. https://doi.org/10.4161/cbt.3.7.913

    Article  CAS  PubMed  Google Scholar 

  24. Dalerba P, Sahoo D, Paik S, Guo X, Yothers G, Song N et al (2016) CDX2 as a prognostic biomarker in stage II and stage III colon cancer. New Eng J Med 374: 211–222. https://doi.org/10.1056/NEJMoa1506597

  25. Slik K, Turkki R, Carpen O, Kurki S, Korkeila E, Sundstrom J et al (2019) CDX2 loss with microsatellite stable phenotype predicts poor clinical outcome in stage II colorectal carcinoma. Am J Surg Pathol 43: 1473–1482. https://doi.org/10.1097/PAS.0000000000001356

  26. Cecchini MJ, Walsh JC, Parfitt J, Chakrabarti S, Correa RJ, MacKenzie MJ et al (2019) CDX2 and Muc2 immunohistochemistry as prognostic markers in stage II colon cancer. Hum Pathol 90: 70–79. https://doi.org/10.1016/j.humpath.2019.05.005

  27. Olsen J, Espersen ML, Jess P, Kirkeby LT, Troelsen JT (2014) The clinical perspectives of CDX2 expression in colorectal cancer: a qualitative systematic review. Surg Oncol 23:167–176. https://doi.org/10.1016/j.suronc.2014.07.003

    Article  CAS  PubMed  Google Scholar 

  28. Baba Y, Nosho K, Shima K, Freed E, Irahara N, Philips J et al (2009) Relationship of CDX2 loss with molecular features and prognosis in colorectal cancer. Clin Cancer Res 15: 4665–4673. https://doi.org/10.1158/1078-0432.CCR-09-0401

  29. Chen K, Collins G, Wang H, Toh JWT (2021) Pathological features and prognostication in colorectal cancer. Curr Oncol 28:5356–5383. https://doi.org/10.3390/curroncol28060447

    Article  PubMed  PubMed Central  Google Scholar 

  30. Zhang JF, Qu LS, Qian XF, Xia BL, Mao ZB, Chen WC (2015) Nuclear transcription factor CDX2 inhibits gastric cancer-cell growth and reverses epithelial-to-mesenchymal transition in vitro and in vivo. Mol Med Rep 12:5231–5238. https://doi.org/10.3892/mmr.2015.4114

    Article  CAS  PubMed  Google Scholar 

  31. Salari K, Spulak ME, Cuff J, Forster AD, Giacomini CP, Huang S et al (2012) CDX2 is an amplified lineage-survival oncogene in colorectal cancer. Proc Natl Acad Sci USA 109:E3196–E3205. https://doi.org/10.1073/pnas.1206004109

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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Funding

Research works in this paper are financially supported by Qihang Fund General Project of Fujian Medical University (2022QH1301).

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Authors and Affiliations

  1. Department of Pathology, Fujian Provincial Hospital, Fuzhou, 350001, China

    Jiezhen Li, Jie Lin, Haijian Huang & Lingfeng Chen

  2. Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350004, China

    Qiang Zeng

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Correspondence to Qiang Zeng.

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The study complied with the Helsinki Declaration, and the study protocol and exemption of informed consent were approved by the Institutional Ethics Committee of Fujian Provincial Hospital, Fuzhou, China (K2021-09-042).

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Li, J., Zeng, Q., Lin, J. et al. Loss of SATB2 and CDX2 expression is associated with DNA mismatch repair protein deficiency and BRAF mutation in colorectal cancer. Med Mol Morphol 57, 1–10 (2024). https://doi.org/10.1007/s00795-023-00366-9

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  • DOI: https://doi.org/10.1007/s00795-023-00366-9

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