Association of colorectal cancer intrinsic subtypes with prognosis, chemotherapy response, deficient mismatch repair, and epithelial to mesenchymal transition (EMT).

Abstract

3530 Background: Unbiased genome-wide analyses of gene expression patterns have been successfully used for molecular classification of breast cancer into subtypes that have clear relevance for prognosis and treatment. A similar classification is still missing for colorectal cancer (CRC). Methods: Using full genome expression data of 188 stage I-IV CRC patients, an unsupervised clustering revealed three major subtypes (A-, B-, C-type). A molecular subtype classification was developed and validated in 543 stage II and III patients. The subtypes were analyzed for correlation to clinical information, mutations in the kinome, known molecular markers status and chemotherapy response. In addition, subtypes were determined on 173 samples from The Cancer Genome Atlas (TCGA) colon dataset with Agilent genome expression data. Results: C-type patients have the worst outcome, a mesenchymal phenotype, and show no benefit from adjuvant chemotherapy treatment. Patients having A- or B-type tumors have a better clinical outcome, a more proliferative and epithelial phenotype and benefit from adjuvant chemotherapy. A- and C-type groups are enriched for tumors having oncogenic BRAF mutations and a deficient DNA mismatch repair system. B-type tumors showed a low overall kinome mutation frequency (1.6%), while both A- and C-type patients harbor a higher mutation frequency (respectively 4.2 and 6.2%), in agreement with their mismatch repair deficiency. Finally, CRC subtyping was confirmed in the colon TCGA dataset with 26 samples classified as A-type, 110 as B-type and 37 as C-type. In agreement with the different aggressiveness of the subtypes, A-type tumors were less prevalent in stage IV while C-type were less prevalent in stage I CRC. Conclusions: The heterogeneity of the intrinsic subtypes is largely based on three biological hallmarks of the tumor: an epithelial-to-mesenchymal transition, deficiency in mismatch repair genes that result in a high mutation frequency associated with MSI, and cellular proliferation. These subtypes are clinically relevant, as they differ in their underlying biology and might require different treatment strategies.