Molecular genetic analysis of colorectal carcinoma with an aggressive extraintestinal immunohistochemical phenotype.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Colorectal Neoplasms*/genetics ; Colorectal Neoplasms*/pathology ; Colorectal Neoplasms*/metabolism ; Colorectal Neoplasms*/mortality ; Immunohistochemistry* ; Biomarkers, Tumor*/genetics ; Biomarkers, Tumor*/metabolism ; Matrix Attachment Region Binding Proteins*/genetics ; Matrix Attachment Region Binding Proteins*/metabolism; Humans ; Male ; Female ; Middle Aged ; Aged ; Keratin-7/metabolism ; Keratin-7/genetics ; Prognosis ; Mucin 5AC/genetics ; Mucin 5AC/metabolism ; Phenotype ; Mucin-6/genetics ; Mucin-6/metabolism ; Mucin-4/genetics ; Mucin-4/metabolism ; Mutation ; Proto-Oncogene Proteins B-raf/genetics ; Adult ; Aged, 80 and over ; Class I Phosphatidylinositol 3-Kinases/genetics ; Class I Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins p21(ras)/genetics ; High-Throughput Nucleotide Sequencing ; Transcription Factors

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.
(© 2024. The Author(s).)

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Cooperatio Medical Diagnostics and Basic Medical Sciences Univerzita Karlova v Praze; Cooperatio Medical Diagnostics and Basic Medical Sciences Univerzita Karlova v Praze; Cooperatio Medical Diagnostics and Basic Medical Sciences Univerzita Karlova v Praze

Keywords: Claudin 18; Colorectal carcinoma; Cytokeratin 7; Mucin; NGS; SATB2

0 (SATB2 protein, human)
0 (Biomarkers, Tumor)
0 (Matrix Attachment Region Binding Proteins)
0 (Keratin-7)
0 (Mucin 5AC)
0 (MUC5AC protein, human)
0 (Mucin-6)
0 (Mucin-4)
EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
0 (MUC4 protein, human)
0 (MUC6 protein, human)
0 (KRAS protein, human)
EC 2.7.11.1 (BRAF protein, human)
EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
EC 2.7.1.137 (PIK3CA protein, human)
EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
0 (Transcription Factors)

Date Created: 20240927 Date Completed: 20240927 Latest Revision: 20241001

20241002

PMC11437151

10.1038/s41598-024-72687-3

39333321