title: Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition.
abstract: In most colorectal cancer (CRC) patients, outcome cannot be predicted because tumors with similar clinicopathological features can have differences in disease progression and treatment response. Therefore, a better understanding of the CRC biology is required to identify those patients who will benefit from chemotherapy and to find a more tailored therapy plan for other patients. Based on unsupervised classification of whole genome data from 188 stages I-IV CRC patients, a molecular classification was developed that consist of at least three major intrinsic subtypes (A-, B- and C-type). The subtypes were validated in 543 stages II and III patients and were associated with prognosis and benefit from chemotherapy. The heterogeneity of the intrinsic subtypes is largely based on three biological hallmarks of the tumor: epithelial-to-mesenchymal transition, deficiency in mismatch repair genes that result in high mutation frequency associated with microsatellite instability and cellular proliferation. A-type tumors, observed in 22% of the patients, have the best prognosis, have frequent BRAF mutations and a deficient DNA mismatch repair system. C-type patients (16%) have the worst outcome, a mesenchymal gene expression phenotype and show no benefit from adjuvant chemotherapy treatment. Both A-type and B-type tumors have a more proliferative and epithelial phenotype and B-types benefit from adjuvant chemotherapy. B-type tumors (62%) show a low overall mutation frequency consistent with the absence of DNA mismatch repair deficiency. Classification based on molecular subtypes made it possible to expand and improve CRC classification beyond standard molecular and immunohistochemical assessment and might help in the future to guide treatment in CRC patients.
authors.affiliation: Department of Research and Development, Agendia NV, Amsterdam, The Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: Roepman
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlicker
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: Ian
authors.initials: I
authors.lastname: Majewski
authors.forename: Sun
authors.initials: S
authors.lastname: Tian
authors.forename: Victor
authors.initials: V
authors.lastname: Moreno
authors.forename: Mireille H
authors.initials: MH
authors.lastname: Snel
authors.forename: Christine M
authors.initials: CM
authors.lastname: Chresta
authors.forename: Robert
authors.initials: R
authors.lastname: Rosenberg
authors.forename: Ulrich
authors.initials: U
authors.lastname: Nitsche
authors.forename: Teresa
authors.initials: T
authors.lastname: Macarulla
authors.forename: Gabriel
authors.initials: G
authors.lastname: Capella
authors.forename: Ramon
authors.initials: R
authors.lastname: Salazar
authors.forename: George
authors.initials: G
authors.lastname: Orphanides
authors.forename: Lodewyk F A
authors.initials: LF
authors.lastname: Wessels
authors.forename: Rene
authors.initials: R
authors.lastname: Bernards
authors.forename: Iris M
authors.initials: IM
authors.lastname: Simon
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D020137:Base Pair Mismatch; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008297:Male
chemical_list: D000970:Antineoplastic Agents
keywords: EMT; chemotherapy benefit; colorectal cancer; mismatch repair; molecular subtypes