Molecular subtyping of colorectal cancer to identify a mesenchymal tumor type that might benefit from TGF-beta pathway inhibition

• Published in: Journal of clinical oncology Vol. 32; no. 3_suppl; p. 456
• Main Authors: Salazar, Ramon, Roepman, Paul, Willems, Stefan M., Brunen, Diede, Kellner, Udo, Midgley, Rachel A, Bernards, Rene, Simon, Iris M.
• Format: Journal Article
• Language: English
• Published: 20.01.2014
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/jco.2014.32.3_suppl.456

Abstract only 456 Background: Currently, most colorectal cancer (CRC) patients receive chemotherapy treatment, even though many patients do not benefit. Therefore, a better understanding of the biology is required to identify those patients who will benefit from chemotherapy and to find a more tailored therapy plan for all other patients. Methods: A molecular subtype classification was developed using full genome expression data of 188 stage I-IV CRC patients and validated in 543 stage II and III patients. Subtypes were correlated to clinical factors, prognosis and treatment benefit (stage III). To determine whether TGF-β signaling is elevated in the tumors, 78 patient biopsies were analyzed for p-SMAD2/3 expression using immunohistochemistry. To analyze the effect of TGF-β activation, we studied the effects of MED12 suppression in SKCO-1 CRC cells under treatment with Cisplatin, Oxaliplatin or 5-FU. Results: We developed a diagnostic test that allows the classification of colorectal cancer tumors into different intrinsic molecular subtypes (A-, B-, C-type). The heterogeneity of these subtypes is largely based on 3 biological hallmarks of the tumor: an epithelial-to-mesenchymal transition, deficiency in mismatch repair genes resulting in a high mutation frequency associated with MSI, and cellular proliferation. Especially the C-type (~15% of CRC tumors) is of clinical interest, as C-type patients have the worst outcome, a mesenchymal phenotype and show no benefit from chemotherapy treatment in our patient set or a public dataset. The C-type subgroup has elevated TGF-β signaling, as shown by TGF-beta and TGF-beta receptor over-expression (TGFB1, p=0.0012; TGFBR1, p=0.0005) and increased phopho-SMAD2/3 staining in the tumor cells (1.9-fold, p=0.0002). In cell line experiments, we show that up-regulation of TGF-β signaling by MED12 knockdown resulted in resistance against chemotherapy by preventing apoptosis. Conclusions: The molecular subtypes differ largely in prognosis and response to chemotherapy. A treatment strategy combining standard drugs with agents suppressing TGF-β signaling might benefit C-type patients.