Development and validation of a novel radiosensitivity signature in human breast cancer
Menée sur des lignées cellulaires de cancer du sein, cette étude identifie une signature, basée sur l'expression de 51 gènes, en association avec la sensibilité des cellules cancéreuses à une irradiation
Purpose: An unmet clinical need in breast cancer management is the accurate identification of patients who will benefit from adjuvant radiation therapy (RT). We hypothesized that integration of post-radiation clonogenic survival data with gene expression data across breast cancer cell (BCC) lines would generate a radiation sensitivity signature (RSS) and identify patients with tumors refractive to conventional therapy.
Experimental Design: Using clonogenic survival assays, we identified the surviving fraction (SF-2Gy) after radiation across a range of BCC lines. Intrinsic radiosensitivity was correlated to gene expression using Spearman's correlation. Functional analysis was performed in vitro, and enriched biological concepts were identified. The RSS was generated using a Random Forest model and was refined, cross-validated, and independently validated in additional breast cancer datasets.
Results: Clonogenic survival identifies a range of radiosensitivity in human BCC lines (SF-2Gy 77%-17%) with no significant correlation to the intrinsic BC subtypes. 147 genes were correlated with radiosensitivity. Functional analysis of RSS genes identifies previously unreported radioresistance-associated genes. RSS was trained, cross-validated, and further refined to 51 genes which were enriched for concepts involving cell-cycle arrest and DNA damage response. RSS was validated in an independent dataset and was the most significant factor in predicting local recurrence on multivariate analysis, outperfoming all clincally used clinicopathologic features.
Conclusions: We derive a human BC-specific RSS with biologic relevance and validate this signature for prediction of locoregional recurrence. By identifying patients with tumors refractory to standard radiation this signature has the potential to allow for personalization of radiotherapy.
Clinical Cancer Research , résumé, 2015