In this model, SPINK1-regulated pathways would include all upstream etiologic factors associated with recurrent trypsinogen activation (e.g. PRSS1 and CFTR mutations) while SPINK1-independent pathways would include factors that drive PSC to produce fibrosis through mechanisms that are generally independent of recurrent trypsinogen activation (e.g. autoimmune pancreatitis, toxins, pancreatic cancer). This evidence concerns the gene SPINK1 and familial pancreatic carcinoma.