Investigating the concordance in molecular subtypes of primary colorectal tumors and their matched synchronous liver metastasis

Andreas Schlicker, Architha Ellappalayam, Ines J Beumer, Mireille H J Snel, Lorenza Mittempergher, Begona Diosdado, Christa Dreezen, Sun Tian, Ramon Salazar, Fotios Loupakis, Filippo Pietrantonio, Cristina Santos Vivas, Maria Mercedes Martinez-Villacampa, Alberto Villanueva, Xavier Sanjuán, Marta Schirripa, Matteo Fassan, Antonia Martinetti, Giovanni Fucà, Sara LonardiUlrich Keilholz, Annuska M Glas, René Bernards, Loredana Vecchione

Research output: Contribution to journalArticlepeer-review


To date, no systematic analyses are available assessing concordance of molecular classifications between primary tumors (PT) and matched liver metastases (LM) of metastatic colorectal cancer (mCRC). We investigated concordance between PT and LM for four clinically relevant CRC gene signatures. Twenty-seven fresh and 55 formalin-fixed paraffin-embedded pairs of PT and synchronous LM of untreated mCRC patients were retrospectively collected and classified according to the MSI-like, BRAF-like, TGFB activated-like and the Consensus Molecular Subtypes (CMS) classification. We investigated classification concordance between PT and LM and association of TGFBa-like and CMS classification with overall survival. Fifty-one successfully profiled matched pairs were used for analyses. PT and matched LM were highly concordant in terms of BRAF-like and MSI-like signatures, (90.2% and 98% concordance, respectively). In contrast, 40% to 70% of PT that were classified as mesenchymal-like, based on the CMS and the TGFBa-like signature, respectively, lost this phenotype in their matched LM (60.8% and 76.5% concordance, respectively). This molecular switch was independent of the microenvironment composition. In addition, the significant change in subtypes was observed also by using methods developed to detect cancer cell-intrinsic subtypes. More importantly, the molecular switch did not influence the survival. PT classified as mesenchymal had worse survival as compared to nonmesenchymal PT (CMS4 vs CMS2, hazard ratio [HR] = 5.2, 95% CI = 1.5-18.5, P = .0048; TGFBa-like vs TGFBi-like, HR = 2.5, 95% CI = 1.1-5.6, P = .028). The same was not true for LM. Our study highlights that the origin of the tissue may have major consequences for precision medicine in mCRC.

Original languageEnglish
Pages (from-to)2303-2315
Number of pages13
JournalInt. J. Cancer
Issue number8
Publication statusPublished - Oct 15 2020


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