Data from Inactivating Mutation in the Prostaglandin Transporter Gene, <i>SLCO2A1</i>, Associated with Familial Digital Clubbing, Colon Neoplasia, and NSAID Resistance

Abstract

<div>Abstract<p><i>HPGD</i>and <i>SLCO2A1</i> genes encode components of the prostaglandin catabolic pathway, with <i>HPGD</i> encoding the degradative enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and <i>SLCO2A1</i> encoding the prostaglandin transporter PGT that brings substrate to 15-PGDH. <i>HPGD</i>-null mice show increased prostaglandin E<sub>2</sub> (PGE<sub>2</sub>), marked susceptibility to developing colon tumors, and resistance to colon tumor prevention by nonsteroidal anti-inflammatory drugs (NSAID). But in humans, <i>HPGD</i> and <i>SLCO2A1</i> 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 <i>SLCO2A1</i> gene segregating in 3 males with digital clubbing. Two of these males further demonstrated notably early-onset colon neoplasia, 1 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 E<sub>2</sub> 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 <i>SLCO2A1</i> 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 <i>SLCO2A1</i> mutation carriers suggests that disordered prostaglandin catabolism can mediate inherited susceptibility to colon neoplasia in man. <i>Cancer Prev Res; 7(8); 805–12. ©2014 AACR</i>.</p></div>