Colorectal cancer (CRC) is a leading global cause of illness and death. There is a need for identification of better prognostic markers beyond traditional clinical variables like grade and stage. Previous research revealed that abnormal expression of cytokeratin 7 (CK7) and loss of the intestinal-specific Special AT-rich sequence-binding protein 2 (SATB2) are linked to poor CRC prognosis. This study aimed to explore these markers' prognostic significance alongside two extraintestinal mucins (MUC5AC, MUC6), claudin 18, and MUC4 in 285 CRC cases using immunohistochemistry on tissue microarrays (TMAs). CK7 expression and SATB2-loss were associated with MUC5AC, MUC6, and claudin 18 positivity. These findings suggest a distinct "non-intestinal" immunohistochemical profile in CRC, often right-sided, SATB2-low, with atypical expression of CK7 and non-colorectal mucins (MUC5AC, MUC6). Strong MUC4 expression negatively impacted cancer-specific survival (hazard ratio = 2.7, p = 0.044). Genetic analysis via next-generation sequencing (NGS) in CK7 + CRCs and those with high MUC4 expression revealed prevalent mutations in TP53, APC, BRAF, KRAS, PIK3CA, FBXW7, and SMAD4, consistent with known CRC mutation patterns. NGS also identified druggable variants in BRAF, PIK3CA, and KRAS. CK7 + tumors showed intriguingly common (31.6%) BRAF V600E mutations corelating with poor prognosis, compared to the frequency described in the literature and databases. Further research on larger cohorts with a non-colorectal immunophenotype and high MUC4 expression is needed.

Central Laboratories University Hospital Kralovske Vinohrady Prague Czech Republic

Department of Anaesthesia and Intensive Care Medicine 3rd Faculty of Medicine Charles University University Hospital Kralovske Vinohrady Prague Czech Republic

Department of General Surgery 3rd Faculty of Medicine Charles University University Hospital Kralovske Vinohrady Prague Czech Republic

Department of Pathology 1st Faculty of Medicine Charles University General University Hospital Prague Czech Republic

Department of Pathology 3rd Faculty of Medicine Charles University University Hospital Kralovske Vinohrady Šrobárova 1150 50 Praha 10 10034 Prague Czech Republic

Department of Pathology and Molecular Medicine 3rd Faculty of Medicine Charles University Thomayer University Hospital Prague Czech Republic

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Morgan, E. et al. Global burden of colorectal cancer in 2020 and 2040: Incidence and mortality estimates from GLOBOCAN. Gut72, 338–344 (2023). PubMed

Sung, H. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA. Cancer J. Clin.71, 209–249 (2021). PubMed

Hrudka, J., Fišerová, H., Jelínková, K., Matěj, R. & Waldauf, P. Cytokeratin 7 expression as a predictor of an unfavorable prognosis in colorectal carcinoma. Sci. Rep.11, 17863 (2021). PubMed PMC

Hrudka, J. et al. Loss of SATB2 expression correlates with cytokeratin 7 and PD-L1 tumor cell positivity and aggressiveness in colorectal cancer. Sci. Rep.12, 19152 (2022). PubMed PMC

Shanmugam, C. et al. Prognostic value of mucin 4 expression in colorectal adenocarcinomas. Cancer116, 3577–3586 (2010). PubMed PMC

Kubota, Y. et al. Comprehensive clinical and molecular characterization of claudin 18.2 expression in advanced gastric or gastroesophageal junction cancer. ESMO Open.8, 100762 (2023). PubMed PMC

Hrudka, J. et al. Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas: Molecular genetic analysis of 13 cases. Int. J. Mol. Sci.25, 3285 (2024). PubMed PMC

Erlenbach-Wünsch, K. Histomorphologische und molekularpathologische Prognosefaktoren beim kolorektalen Karzinom. Pathologe.41, 70–75 (2020). PubMed

Eberhard, J. et al. A cohort study of the prognostic and treatment predictive value of SATB2 expression in colorectal cancer. Br. J. Cancer.106, 931–938 (2012). PubMed PMC

Kim, C. J. et al. Value of SATB2 immunostaining in the distinction between small intestinal and colorectal adenocarcinomas. J. Clin. Pathol.69, 1046–1050 (2016). PubMed

Imai, Y. et al. Differential mucin phenotypes and their significance in a variation of colorectal carcinoma. World J. Gastroenterol.19, 3957–3968 (2013). PubMed PMC

Betge, J. et al. MUC1, MUC2, MUC5AC, and MUC6 in colorectal cancer: Expression profiles and clinical significance. Virchows Arch.469, 255–265 (2016). PubMed PMC

Kocer, B. et al. Expression of MUC5AC in colorectal carcinoma and relationship with prognosis. Pathol. Int.52, 470–477 (2002). PubMed

Wang, H. et al. Expression of survivin, MUC2 and MUC5 in colorectal cancer and their association with clinicopathological characteristics. Oncol. Lett.14, 1011–1016 (2017). PubMed PMC

Cox, K. E. et al. The mucin family of proteins: Candidates as potential biomarkers for colon cancer. Cancers (Basel).15, 1491 (2023). PubMed PMC

Bartman, A. E. et al. Aberrant expression of MUC5AC and MUC6 gastric mucin genes in colorectal polyps. Int. J. Cancer.80, 210–218 (1999). PubMed

Owens, S. R., Chiosea, S. I. & Kuan, S. F. Selective expression of gastric mucin MUC6 in colonic sessile serrated adenoma but not in hyperplastic polyp aids in morphological diagnosis of serrated polyps. Mod. Pathol.21, 660–669 (2008). PubMed

Leir, S. H. & Harris, A. MUC6 mucin expression inhibits tumor cell invasion. Exp. Cell Res.317, 2408–2419 (2011). PubMed

Sanada, Y. et al. Down-regulation of the claudin-18 gene, identified through serial analysis of gene expression data analysis, in gastric cancer with an intestinal phenotype. J. Pathol.208, 633–642 (2006). PubMed

Kyuno, D. et al. Claudin-18.2 as a therapeutic target in cancers: cumulative findings from basic research and clinical trials. Tissue Barriers.10, 1967080 (2022). PubMed PMC

Sentani, K. et al. Immunohistochemical staining of Reg IV and claudin-18 is useful in the diagnosis of gastrointestinal signet ring cell carcinoma. Am. J. Surg. Pathol.32, 1182–1189 (2008). PubMed

Ungureanu, B. S. et al. Clinicopathologic relevance of Claudin 18.2 expression in gastric cancer: A meta-analysis. Front. Oncol.11, 643872 (2021). PubMed PMC

Arpa, G. et al. Claudin-18 expression in small bowel adenocarcinoma: A clinico-pathologic study. Virchows Arch.481, 853–863 (2022). PubMed PMC

Matsuda, M. et al. Immunohistochemical analysis of colorectal cancer with gastric phenotype: Claudin-18 is associated with poor prognosis. Pathol. Int.60, 673–680 (2010). PubMed

Moniaux, N. et al. Human MUC4 mucin induces ultra-structural changes and tumorigenicity in pancreatic cancer cells. Br. J. Cancer.97, 345–357 (2007). PubMed PMC

Chaturvedi, P., Singh, A. P. & Batra, S. K. Structure, evolution, and biology of the MUC4 mucin. FASEB J.22, 966–981 (2008). PubMed PMC

Chaturvedi, P. et al. MUC4 mucin interacts with and stabilizes the HER2 oncoprotein in human pancreatic cancer cells. Cancer Res.68, 2065–2070 (2008). PubMed PMC

Miyahara, N. et al. MUC4 interacts with ErbB2 in human gallbladder carcinoma: potential pathobiological implications. Eur. J. Cancer.44, 1048–1056 (2008). PubMed

Komatsu, M., Jepson, S., Arango, M. E., Carothers Carraway, C. A. & Carraway, K. L. Muc4/sialomucin complex, an intramembrane modulator of ErbB2/HER2/Neu, potentiates primary tumor growth and suppresses apoptosis in a xenotransplanted tumor. Oncogene20, 461–470 (2001). PubMed

Chaturvedi, P. et al. MUC4 mucin potentiates pancreatic tumor cell proliferation, survival, and invasive properties and interferes with its interaction to extracellular matrix proteins. Mol. Cancer Res.5, 309–320 (2007). PubMed

Biemer-Hüttmann, A. E. et al. Mucin core protein expression in colorectal cancers with high levels of microsatellite instability indicates a novel pathway of morphogenesis. Clin. Cancer Res.6, 1909–1916 (2000). PubMed

Pai, P. et al. MUC4 is negatively regulated through the Wnt/β-catenin pathway via the Notch effector Hath1 in colorectal cancer. Genes Cancer.7, 154–168 (2016). PubMed PMC

Huang, X. et al. Clinicopathological and prognostic significance of MUC4 expression in cancers: Evidence from meta-analysis. Int. J. Clin. Exp. Med.8, 10274–10283 (2015). PubMed PMC

Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell.61, 759–767 (1990). PubMed

Pino, M. S. & Chung, D. C. The chromosomal instability pathway in colon cancer. Gastroenterology.138, 2059–2072 (2010). PubMed PMC

Müller, M. F., Ibrahim, A. E. & Arends, M. J. Molecular pathological classification of colorectal cancer. Virchows Arch.469, 125–134 (2016). PubMed PMC

Wood, L. D. et al. The genomic landscapes of human breast and colorectal cancers. Science.318, 1108–1113 (2007). PubMed

Zhuang, Y. et al. Multi gene mutation signatures in colorectal cancer patients: Predict for the diagnosis, pathological classification, staging and prognosis. BMC Cancer.21, 380 (2021). PubMed PMC

Liu, Z. et al. The landscape of somatic mutation in sporadic Chinese colorectal cancer. Oncotarget.9, 27412–27422 (2018). PubMed PMC

Network, C. G. A. Comprehensive molecular characterization of human colon and rectal cancer. Nature.487, 330–337 (2012). PubMed PMC

Al-Shamsi, H. O. et al. Molecular spectrum of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC somatic gene mutations in Arab patients with colorectal cancer: Determination of frequency and distribution pattern. J. Gastrointest. Oncol.7, 882–902 (2016). PubMed PMC

Hino, H. et al. Comprehensive genetic characterization of rectal cancer in a large cohort of Japanese patients: differences according to tumor location. J. Gastroenterol.57, 476–485 (2022). PubMed

Oncokb.org. (accessed 19th Mar 2024).

Chen, D. et al. BRAFV600E mutation and its association with clinicopathological features of colorectal cancer: A systematic review and meta-analysis. PLoS One9, e90607 (2014). PubMed PMC

Li, Y. & Li, W. BRAF mutation is associated with poor clinicopathological outcomes in colorectal cancer: A meta-analysis. Saudi J. Gastroenterol.23, 144–149 (2017). PubMed PMC

Toon, C. W. et al. BRAFV600E immunohistochemistry in conjunction with mismatch repair status predicts survival in patients with colorectal cancer. Mod. Pathol.27, 644–650 (2014). PubMed PMC

Loupakis, F. et al. CK7 and consensus molecular subtypes as major prognosticators in V600EBRAF mutated metastatic colorectal cancer. Br. J. Cancer121, 593–599 (2019). PubMed PMC

Varkaris, A. et al. Discovery and clinical proof-of-concept of RLY-2608, a first-in-class mutant-selective allosteric PI3Kα inhibitor that decouples antitumor activity from hyperinsulinemia. Cancer Discov.14, 240–257 (2024). PubMed PMC