A colorectal cancer classification system that associates cellular phenotype and responses to therapy

Abstract

Colorectal cancer (CRC) is a major cause of cancer mortality. Whereas some patients respond well to therapy, others do not, and thus more precise, individualized treatment strategies are needed. To that end, we analyzed gene expression profiles from 1,290 CRC tumors using consensus-based unsupervised clustering. The resultant clusters were then associated with therapeutic response data to the epidermal growth factor receptor–targeted drug cetuximab in 80 patients. The results of these studies define six clinically relevant CRC subtypes. Each subtype shares similarities to distinct cell types within the normal colon crypt and shows differing degrees of ‘stemness’ and Wnt signaling. Subtype-specific gene signatures are proposed to identify these subtypes. Three subtypes have markedly better disease-free survival (DFS) after surgical resection, suggesting these patients might be spared from the adverse effects of chemotherapy when they have localized disease. One of these three subtypes, identified by filamin A expression, does not respond to cetuximab but may respond to cMET receptor tyrosine kinase inhibitors in the metastatic setting. Two other subtypes, with poor and intermediate DFS, associate with improved response to the chemotherapy regimen FOLFIRI1 in adjuvant or metastatic settings. Development of clinically deployable assays for these subtypes and of subtype-specific therapies may contribute to more effective management of this challenging disease.

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

“…Next, we determined whether oncogenic BRAF modulates expression of Birc5 and Axin2, which are highly active in stem cell-like colon cancers, as well as Muc2 and Krt20, which are active in Goblet celllike colon cancers. 2 We found that Birc5 and Axin2 were gradually inhibited by increasing amounts of BRAF V600E or BRAF V600K , whereas Muc2 and Krt20 were progressively activated ( Figures 1d and e). These results suggest that activation of the BRAF/MAPK signaling axis can affect cell fate-associated transcriptional activity in colon cancer cells and thus may modulate cell differentiation choices during intestinal tumor initiation and progression.…”

“…Consequently, colon cancers can therefore exhibit gene activity characteristic for different intestinal cell types and colon cancer subtypes defined by such expression patterns differ in their therapeutic response. 2 It is largely unknown which oncogenic mutations modulate differentiation patterns during colon cancer progression and which constraints exist in the tumor to balance stem cell traits, proliferation and differentiation.…”

The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

“…Colorectal tumours can be classified in up to six unique subtypes with diverse clinical features according to the genes they express [8][9][10][11][12] .…”

“…Expression profiles were therefore used to assign each cell line to a molecular subtype [8][9][10][11][12] by the Nearest Template Prediction (NTP) algorithm, which also estimates the classification false discovery rate (FDR) 23 . Each of the five classifiers was able to assign (FDRo0.2) the large majority of the cell lines to a subtype.…”

“…Transcriptional profiling has been recently used to identify distinct CRC subtypes [8][9][10][11][12] . The subtypes are associated with biological and clinical features such as cell of origin, MSI, prognosis and response to treatments.…”