The colorectal liver metastasis growth pattern phenotype is not dependent on genotype

Diederik J Höppener ¹, Sanne M L Verheul ², Pieter M H Nierop ¹

¹Departments of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
²Departments of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands. s.m.l.verheul@erasmusmc.nl.
³Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
⁴Department of Oncology, Addenbrooke's Hospital, Cambridge, UK.
⁵Leeds Institute of Medical Research at St James's, St James's University Hospital, University of Leeds, Leeds, UK.
⁶Departments of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁷Translational Cancer Research Unit, ZAS Augustinus, Antwerp, Belgium.
⁸Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁹UCL Cancer Institute, University College London, London, UK.
¹⁰MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
¹¹Department of Surgery, Erasmus MC, Rotterdam, the Netherlands.
¹²Department of Surgery, University of Southampton, Southampton, UK.

⁰Departments of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.

British Journal of Cancer +

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July 23, 2025

View abstract on PubMed

Summary

Histopathological growth patterns (HGPs) in colorectal cancer liver metastases are not strongly linked to specific gene mutations. However, B2M and PTEN mutations, along with higher tumor mutational burden, were associated with the favorable encapsulated HGP.

Area Of Science

Oncology
Genetics
Cancer Research

Background

Histopathological growth patterns (HGPs) of colorectal cancer liver metastases predict patient prognosis post-surgery.
Encapsulated HGP is associated with a more favorable outcome compared to non-encapsulated HGP.
The relationship between HGPs and specific genetic mutations remains largely unexplored.

Purpose Of The Study

To investigate the association between HGPs in colorectal cancer liver metastases and genetic mutations.
To determine if specific driver gene mutations, tumor mutational burden (TMB), or microsatellite instability (MSI) correlate with encapsulated or non-encapsulated HGPs.
To assess the prognostic significance of HGP independent of genetic factors.

Main Methods

Next-generation sequencing data from 461 patients with resected colorectal cancer liver metastases were analyzed.
Patients were categorized into encapsulated (104) and non-encapsulated (357) HGP groups.
Analysis included 19 putative colorectal cancer driver genes, TMB, MSI, and POLE-mediated hypermutation.

Main Results

Mutations in B2M and PTEN were significantly associated with the encapsulated HGP phenotype (p < 0.05).
Encapsulated HGP cases exhibited a higher tumor mutational burden (TMB) compared to non-encapsulated cases (p = 0.009).
The encapsulated HGP was confirmed as an independent prognostic factor for overall survival (aHR = 0.60).

Conclusions

The HGP phenotype in colorectal cancer liver metastases appears largely independent of common tumor genotypes.
While mutations in B2M and PTEN, and higher TMB, are linked to the encapsulated HGP, they likely explain only a subset of cases.
The encapsulated HGP is a robust independent prognostic indicator for patient survival.

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