For instance, genomic loss in the cancer cells of CDKN2A (encoding the cyclin-dependent kinase inhibitor p16INK4) and DPC4, encoding SMAD4, a central mediator of transforming growth factor (TGF)-β signaling, has been implicated in modifying the response to gemcitabine or 5-FU [14,15,16]. Here, SMAD4 is linked to cancer.