By Deborah Borfitz 

August 11, 2022 | A multi-national team of clinicians and scientists has determined that the consensus molecular subtype (CMS) classification of colorectal cancer needs updating to better reflect the molecular underpinnings of the disease. Using single cell techniques, they have uncovered a central dichotomy for colorectal cancer cells and are now recommending a refined “IMF” classification with five subtypes that combine intrinsic epithelial subtype (I), microsatellite instability status (M), and fibrosis (F).  

The study and proposal were published recently in Nature Genetics (DOI: 10.1038/s41588-022-01100-4). Two of the authors—Associate Professor Iain Tan, MBBS, Ph.D., senior consultant and director of the research division of medical oncology at the National Cancer Centre Singapore (NCCS), and Professor Shyam Prabhakar, Ph.D., associate director of spatial and single cell systems at the Genome Institute of Singapore (GIS)—submitted email responses to a few questions about the potential impact of the findings on drug development strategies and treatment stratification, which they answered together. 

The NCCS- and GIS-led research team analyzed 373,000 single cells from 141 tumor samples collected from 63 colorectal cancer patients in Singapore, Belgium, and South Korea. Single-cell and bulk transcriptomics were used to learn that malignant epithelial cells belong to two major epithelial subtypes that they have termed intrinsic-consensus molecular subtypes (iCMS), consisting of iCMS2 and iCMS3. 

“iCMS3 comprises one-third of MSS [microsatellite stable] and MSI-H [microsatellite unstable] cancers while i3MSS cancers are more similar in transcriptomic profiles, gene regulatory networks, and copy number profiles to MSI-H cancers than to other MSS cancers,” they say, in explaining their rationale for the suggested IMF classification system. “Fibrotic cancers [CMS4] can either have an i2 or i3 malignant epithelial cells and it is the fibrotic cancers with the i3 malignant cells... [that have] the worse prognosis.”  

Under the existing CMS system, clinical trials have classified MSS colorectal cancer as one group, all refractory to immunotherapy. “Different immunotherapy approaches target different immune cells, immunological checkpoint and signaling nodes or different mediators of immune cell exhaustion or exclusion,” Tan and Prabhakar state. 

Given the heterogeneity within the MSS group, they say, “it would be good for ongoing studies to review if the response to immunotherapy is related to the IMF subclasses. For new studies, or pipeline drugs in development, we propose that the tumor microenvironment features of the four MSS subsets [i2 and i3, fibrotic or nonfibrotic] be considered too, as we examined which immunotherapy approaches are best studied in which subset of MSS cancers.” 

While MSI-H cancers respond well to PD1 inhibition, none of the MSS tumors do, the researchers point out. “Amongst MSS cancers, i3 MSS have similar transcriptomic profiles to MSI-H cancers, and also a more inflammatory tumor microenvironment compared to i2 MSS cancers, albeit MSI-H cancers have a higher tumor mutation burden and neoantigen quality.”  

The team hypothesizes that “shared features between i3 MSS and MSI-H may be present that might render i3 MSS cancers to be particularly responsive to some immunotherapy drugs in development.”  

More studies on the biological, prognostic, and predictive implications of IMF in patient groups, including clinical trial cohorts, are being planned, Tan and Prabhakar report, in addition to experimental studies “to further understand phenotypic features and molecular vulnerabilities unique to the IMF subclasses.” 

Also in the planning stage are efforts to characterize the biological properties, interactions, and drug response of iCMS2 and iCMS3 cells, as well as to re-analyze data from clinical trials to identify differences in treatment response between these two cancer types.  

Colorectal cancer is the second deadliest cancer worldwide. Last year, in an article published in JAMA Network Open (DOI: 10.1001/jamanetworkopen.2021.4708), researchers predicted that by 2030 colorectal cancer would become the leading cause of cancer-related deaths in adults under 50. 

Might Tan and Prabhakar, and their collaborators, explore why so many younger people are getting colorectal cancer, or at least the ones genetically susceptible if they make lifestyle choices that put them at risk? “Indeed, these epidemiological associations are something we are looking into,” they say, “though it is not yet clear if the transcriptomic heterogeneity is related to age of onset.”