CRC Molecular Subtypes Linked to Clinical Patterns, Prognosis

Most colorectal cancer patients fall into one of four subgroups characterised by molecular patterns and clinical behaviour

medwireNews: Research suggests that colorectal cancer (CRC) patients could be classified according to one of four consensus molecular subtypes (CMSs), each associated with a clinical profile.

“We consider the CMS groups the most robust classification system currently available for CRC-with clear biological interpretability-and the basis for future clinical stratification and subtype-based targeted interventions”, say Justin Guinney, from Sage Bionetworks in Seattle, Washington, USA, and fellow CRC Subtyping Consortium investigators.

The team explains that six different CRC classification systems were applied to 18 gene expression data sets for a total of 4151 patients, allowing a network-based approach to identification of recurring patterns.

Four CMSs emerged, with 14% of patients classified as CMS1 (microsatellite instability [MSI] immune), 37% as CMS2 (canonical), 13% as CMS3 (metabolic) and 23% as CMS4 (mesenchymal). A further 7% of patients were classified as having a mixture of two subtypes, and the remainder had indeterminate samples.

Samples taken from the CMS2 and CMS4 groups had high chromosomal instability, as defined by number of somatic copy number alterations (SCNAs), while CMS1 and CMS3 had low SCNA, the researchers report in Nature Medicine.

Patients in the CMS1 group had CRC samples characterised by hypermutation and widespread hypermethylation, as well as overexpression of proteins involved in DNA damage repair. CMS1 also included the majority of tumours showing MSI, although some CMS3 tumours also showed MSI.

BRAF mutations were common in CMS1 and there was “nearly universal” activation of the receptor tyrosine kinase and mitogen-activated protein kinase pathway in CMS1 and CMS3, but the researchers emphasise that none of the CMSs were defined by a single gene mutation or SCNA.

“This supports the notion that tumors harboring commonly assumed driver events in CRC still vary markedly in their biology and highlights the very poor genotype-phenotype correlations in this disease”, they comment.

The CMSs also showed distinct patterns of gene expression: CMS1 samples showed upregulation of genes associated with immune infiltration and evasion, while CMS2 samples had increased expression of genes associated with epithelial differentiation and CRC carcinogenesis. CMS3 showed gene expression associated with metabolic alterations, while CMS4 tumours had gene expression patterns linked to epithelial-to-mesenchymal transition processes including angiogenesis.

Moreover, the CMSs showed distinct clinical and prognostic characteristics, such that CMS1 samples were associated with female patients and right-sided tumours with a high histopathological grade, CMS2 tumours tended to be left-sided and CMS4 tumours were more likely than other subtypes to be diagnosed at stage III or IV.

Indeed, in multivariate analysis, patients with CMS4 tumours had significantly poorer overall and relapse-free survival than other patients, whereas CMS2 patients had better survival after relapse.

In a comment to the press, co-author  Anguraj Sadanandam, from the Institute of Cancer Research in London, UK, said the results “could allow doctors to pick out those patients with more aggressive disease and treat them accordingly.”

“Ultimately, it could lead to development of new molecular diagnostic tests to diagnose patients by their particular type of bowel cancer, and give them the most effective treatments for that type”, he added.


Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med 2015; Advance online publication 12 October. doi:10.1038/nm.3967

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