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Mapping of colorectal carcinoma diseases with activation of Wnt/beta-catenin signalling pathway using hierarchical clustering approach
  1. Jean-François Mosnier1,
  2. Fabrice Airaud2,
  3. Sylvie Métairie3,
  4. Christelle Volteau4,
  5. Stéphane Bezieau2,
  6. Marc Denis5
  1. 1Pathology, CHU Nantes, Nantes, France
  2. 2Department of Genetics, Centre Hospitalier Universitaire de Nantes, Nantes, France
  3. 3Department of Digestive and Endocrinology Surgeries, Centre Hospitalier Universitaire de Nantes, Nantes, France
  4. 4Biostatistics Department, Centre Hospitalier Universitaire de Nantes, Nantes, France
  5. 5Department of Biochemistry and Oncogenomics, Centre Hospitalier Universitaire, Nantes, France
  1. Correspondence to Professor Jean-François Mosnier, Pathology, CHU Nantes, Nantes F-44093, France; jfmosnier{at}


Aims To map the colorectal carcinoma (CRC) diseases with significant Wnt signalling pathway activation for delineating their clinicopathological and molecular profiles.

Methods Mapping is based on hierarchical clustering analyses of a series of 283 CRCs. Data tabulated were histopathological patterns, immunophenotypic differentiation, RAS, RAF, CTNNB1 mutations and microsatellite instability status, tumour-infiltrating lymphocytes (TILs) and genetic setting. Beta-catenin expression in more than 10% of cell nuclei in the centre of tumour serves as a surrogate marker of significant activation of Wnt signalling pathway.

Results Nuclei beta-catenin expression was present in 95% of CRCs; 56% of them met the criteria of high level of nuclei beta-catenin expression (≥10%). Proportion of beta-catenin positive nuclei was significantly higher in younger patients, rectal and left-sided colonic carcinomas. CRCs with high level of nuclei beta-catenin expression were regrouped into three clusters: (1) microsatellite stability (MSS) CRCs with no constitutive MAPK pathway activation including 90% of low-grade adenocarcinoma, NOS, with intestinal differentiation without TILs; (2) RAS-mutated MSS CRCs including low-grade adenocarcinoma, NOS, with intestinal differentiation and mucinous adenocarcinoma without TILs; (3) MSI-H CRCs including both BRAF-mutated CRCs evolving from serrated pathway and CTNNB1-mutated CRCs associated with Lynch syndrome.

Conclusions MSS low-grade adenocarcinoma, NOS, with intestinal differentiation without TILs (‘crypt-like adenocarcinoma’) might be the morphological pending of canonical molecular subtype of CRC defined as displayed molecular epithelial differentiation and upregulation of WNT in consensus molecular classification of CRC.

  • colorectal neoplasms
  • immunohistochemistry
  • biomarkers
  • tumor
  • cell differentiation

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  • Handling editor Runjan Chetty.

  • Contributors J-FM written and designed the study. FA, SM, SB and MD generated data. CV managed statistical study.

  • Funding This work was co-funded by the French Direction de l'Hospitalisation et de l'Organisation des Soins (DHOS) and INSERM (PROG/09/03).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplemental information.

  • Author note Tumorothéque du CHU de Nantes: Management of specimen collection

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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