CD40 has no DD either, in contrast to FAS (and other TNF receptor superfamily members, such as TNFR and TRAIL), raising the possibility that, in CD154 and IL-21-stimulated B cells, caspase 8 was activated by a receptor-independent apoptosis process, e.g., through a macromolecular complex nucleated by the auto-aggregation of DD- and DED-containing adaptor FADD followed by pro-caspase 8 recruitment and self-activation, as occurring in cancer cells (57). This evidence concerns the gene CASP8 and cancer.