Inactivating Mutation in the Prostaglandin Transporter Gene, SLCO2A1, Associated with Familial Digital Clubbing, Colon Neoplasia, and NSAID Resistance

HPGD and SLCO2A1 genes encode components of the prostaglandin catabolic pathway, HPGD encoding the degradative enzyme 15-PGDH, and SLCO2A1 encoding the prostaglandin transporter PGT that brings substrate to 15-PGDH. HPGD null mice show increased PGE2, marked susceptibility to developing colon tumors, and resistance to colon tumor prevention by NSAIDs. But in humans, HPGD and SLCO2A1 mutations have only been associated with familial digital clubbing. We here characterize a family with digital clubbing and early onset colon neoplasia. Whole exome sequencing identified a heterozygous nonsense mutation (G104X) in the SLCO2A1 gene segregating in three males with digital clubbing. Two of these males further demonstrated notably early onset colon neoplasia, one with an early onset colon cancer and another with an early onset sessile serrated colon adenoma. Two females also carried the mutation, and both these women developed sessile serrated colon adenomas without any digital clubbing. Males with clubbing also showed marked elevations in the levels of urinary prostaglandin E2 metabolite, PGE-M; whereas, female mutation carriers were in the normal range. Furthermore, in the male proband urinary PGE-M remained markedly elevated during NSAID treatment with either celecoxib or sulindac. Thus, in this human kindred, a null SLCO2A1 allele mimics the phenotype of the related HPGD null mouse, with increased prostaglandin levels that cannot be normalized by NSAID therapy, plus with increased colon neoplasia. The development of early onset colon neoplasia in male and female human SLCO2A1 mutation carriers suggests that disordered prostaglandin catabolism can mediate inherited susceptibility to colon neoplasia in man.