Connecting gene expression subtypes of colorectal cancer (CRC) with cell lines and drug resistance.

Konference: 2013 49th ASCO Annual Meeting - účast ČR

Kategorie: Gastrointestinální nádory; Kolorektální karcinom

Téma: Gastrointestinal (Colorectal) Cancer

Číslo abstraktu: e14544

Autoři: Mgr. Eva Budinská, Ph.D.; Jenny Wilding; Ing. Vlad Calin Popovici; Dr. Edoardo Missiaglia; MD Arnaud Roth, CC; Prof. Fred Bosman; Mauro Delorenzi; Walter Bodmer; Sabine Tejpar, MD

Plný text abstraktu(odkaz vede na stránky ASCO)

Abstrakt byl publikován rovněž v Supplementu časopisu
J Clin Oncol 31, 2013 (suppl; abstr e14544)


Background: We identified CRC gene expression subtypes (ASCO 2012, #3511), which associate with established parameters of outcome as well as relevant biological motifs. We now substantiate their biological and potentially clinical significance by linking them with cell line data and drug sensitivity, primarily attempting to identify models for the poor prognosis subtypes Mesenchymal and CIMP-H like (characterized by EMT/stroma and immune-associated gene modules, respectively). Methods: We analyzed gene expression profiles of 35 publicly available cell lines with sensitivity data for 82 drug compounds, and our 94 cell lines with data on sensitivity for 7 compounds and colony morphology. As in vitro, stromal and immune-associated genes loose their relevance, we trained a new classifier based on genes expressed in both systems, which identifies the subtypes in both tissue and cell cultures. Cell line subtypes were validated by comparing their enrichment for molecular markers with that of our CRC subtypes. Drug sensitivity was assessed by linking original subtypes with 92 drug response signatures (MsigDB) via gene set enrichment analysis, and by screening drug sensitivity of cell line panels against our subtypes (Kruskal-Wallis test). Results: Of the cell lines 70% could be assigned to a subtype with a probability as high as 0.95. The cell line subtypes were significantly associated with their KRAS, BRAF and MSI status and corresponded to our CRC subtypes. Interestingly, the cell lines which in matrigel created a network of undifferentiated cells were assigned to the Mesenchymal subtype. Drug response studies revealed potential sensitivity of subtypes to multiple compounds, in addition to what could be predicted based on their mutational profile (e.g. sensitivity of the CIMP-H subtype to Dasatinib, p<0.01). Conclusions: Our data support the biological and potentially clinical significance of the CRC subtypes in their association with cell line models, including results of drug sensitivity analysis. Our subtypes might not only have prognostic value but might also be predictive for response to drugs. Subtyping cell lines further substantiates their significance as relevant model for functional studies.

Datum přednesení příspěvku: 31. 5. 2013