Developing prognostic biomarkers for specific cancer types that accurately predict patient survival is increasingly important in clinical research and practice. Despite the enormous potential of prognostic signatures, proposed models have found limited implementations in routine clinical practice. Herein, we propose a generic, RNA sequencing platform independent, statistical framework named whole transcriptome signature for prognostic prediction to generate prognostic gene signatures. Using ovarian cancer and lung adenocarcinoma as examples, we provide evidence that our prognostic signatures overperform previous reported signatures, capture prognostic features not explained by clinical variables, and expose biologically relevant prognostic pathways, including those involved in the immune system and cell cycle. Our approach demonstrates a robust method for developing prognostic gene expression signatures. In conclusion, our statistical framework can be generally applied to all cancer types for prognostic prediction and might be extended to other human diseases. The proposed method is implemented as an R package (PanCancerSig) and is freely available on GitHub ( https://github.com/Cheng-Lab-GitHub/PanCancer_Signature ).