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.

• Keywords
• Claudin 18, Colorectal carcinoma, Cytokeratin 7, Mucin, NGS, SATB2,
• MeSH
• Adult MeSH
• Phenotype MeSH
• Class I Phosphatidylinositol 3-Kinases genetics   metabolism   MeSH
• Immunohistochemistry * MeSH
• Keratin-7 metabolism   genetics   MeSH
• Colorectal Neoplasms * genetics   pathology   metabolism   mortality   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mucin-4 genetics   metabolism   MeSH
• Mucin 5AC genetics   metabolism   MeSH
• Mucin-6 genetics   metabolism   MeSH
• Mutation MeSH
• Biomarkers, Tumor * genetics   metabolism   MeSH
• Prognosis MeSH
• Proto-Oncogene Proteins B-raf genetics   MeSH
• Proto-Oncogene Proteins p21(ras) genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Transcription Factors MeSH
• Matrix Attachment Region Binding Proteins * genetics   metabolism   MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• BRAF protein, human MeSH Browser
• Class I Phosphatidylinositol 3-Kinases MeSH
• Keratin-7 MeSH
• KRAS protein, human MeSH Browser
• MUC4 protein, human MeSH Browser
• MUC5AC protein, human MeSH Browser
• MUC6 protein, human MeSH Browser
• Mucin-4 MeSH
• Mucin 5AC MeSH
• Mucin-6 MeSH
• Biomarkers, Tumor * MeSH
• PIK3CA protein, human MeSH Browser
• Proto-Oncogene Proteins B-raf MeSH
• Proto-Oncogene Proteins p21(ras) MeSH
• SATB2 protein, human MeSH Browser
• Transcription Factors MeSH
• Matrix Attachment Region Binding Proteins * MeSH