SEATTLE–(BUSINESS WIRE)–A major collaborative study carried out through an international consortium has, for the very first time, established a consensus classification for colorectal cancer (CRC) based on genomic data. The study partners collected over 4,000 samples from patients and reached a consensus on the genomic subtyping of CRC, which enabled the identification of intrinsic biological underpinnings of each subtype as well as correlative analysis with clinical behavior and prognosis of patients. The research, published inNature Medicine, was coordinated by Justin Guinney from Sage Bionetworks in Seattle, and involved a large international team including co-authors Rodrigo Dienstmann from Vall d’Hebron, Spain; Louis Vermeulen from the Amsterdam Medical Center, the Netherlands; and Sabine Tejpar from UZ Leuven, Belgium.
Combining strengths and overcoming current obstacles in collaboration
Over recent years, the classification of certain cancers has been advanced significantly thanks to the study of the genetic expression of tumors, as is the case with breast cancer. Such important insights have undoubtedly rendered cancer treatment more precise. Despite the many efforts to date, the genomic classification of CRC has struggled to reach the clinic, hampering the stratification of patients for treatment decisions. While individual groups have previously proposed classifications, they differed in both the number of subtypes and the interpretation of results. The heterogeneity of the algorithms and the small number of samples analyzed in these previous studies hindered endorsement from the wider scientific community. This impasse led researchers to join forces as an International Consortium in order to combine numbers of patient samples, and share and exchange knowledge on the biology of CRC, as well as bioinformatics expertise in the analysis of big data. “We hope our work will serve as a model for future research teams using data-driven approaches to define consensus subtypes in cancer,” said Justin Guinney.
Novel classification and correlates in CRC
There are four main groups proposed by consensus: the Consensus Molecular Subtypes (CMS). CMS1 (Microsatellite Instability Immune, 15% of tumors) is the subtype that is characterized by a prominent immunological activation, and represents the group of patients who would most likely benefit from immunotherapies. CMS2 (canonical epithelial, 40% of tumors) is the group with the highest chromosomal instability, which follows the classical carcinogenesis of CRC with activation of the WNT, MYC, and EGFR pathways. CSM3 (metabolic epithelial, 15% of tumors) is characterized by deregulation of the metabolic pathways associated with mutations in the KRAS gene. Finally, CMS4 (mesenchymal, 30% of tumors) shows a very poor prognosis with standard treatment for CRC due to an activation of the TGFB pathways, angiogenesis, and stromal invasion.
From genomics to clinical practice: an Open Access Consortium
The consensus data from this new classification represents an important first step for clinical translation of the findings. For example, knowing which subtype has the worst prognosis or which has the best response to targeted molecular therapies could better guide therapeutic strategies. “The next step will be to study the clinical applicability of this classification. Clinical trials have already been designed and their results will determine which therapies are the most beneficial for each subtype of CRC,” explains Rodrigo Dienstmann. To conduct these analyses and to facilitate clinical implementation, the Consortium has developed open-access software tools that will allow any researcher from around the globe to classify CRC tumors using gene expression data.