These biological and genetic features of cells and cancers with reduced FHIT expression, suggested that reduced FHIT expression might drive generation of a specific cancer-associated 'mutational signature' defined by Alexandrov et al [10] as Catalog of Somatic Mutations in Cancer (COSMIC; http://cancer.sanger.ac.uk/cosmic) [11] mutational signature 5. The gene discussed is FHIT; the disease is cancer.