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

Abstract

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.

HomozygousSLCO2A1translation initiation codon mutation in a Pakistani family with recessive isolated congenital nail clubbing

“…The SLCO2A1 translational initiation codon mutation (p.M1V) reported here causes recessive ICNC with no abnormal phenotype in heterozygotes. In contrast, a heterozygous SLCO2A1 nonsense mutation (p.G104X) was reported in a family with autosomal dominant ICNC, colon neoplasia and non‐steroidal anti‐inflammatory drug resistance . A different heterozygous SLCO2A1 nonsense mutation (p.R252X) has been reported in a patient with sporadic ICNC, in an unaffected relative and also in patients with PDP .…”

“…Similarly, various loss‐of‐function and missense mutations in SLCO2A1 have also been reported both in families with autosomal recessive PHO and PDP . In addition, heterozygous SLCO2A1 loss‐of‐function mutations have been reported in a family with autosomal dominant ICNC and in a case of sporadic ICNC …”

Molecular cancer prevention: Current status and future directions

“…Observational data have already suggested that the benefit of aspirin may be dependent upon mutations in PIK3CA in individuals with a diagnosis of colon cancer; and familial data suggests that a mutation in SLCO2A1 , a member of the prostaglandin catabolic pathway, is associated with early colonic neoplasia and NSAID resistance. 119, 120 …”

Clinical, Biochemical, and Genetic Features of 41 Han Chinese Families With Primary Hypertrophic Osteoarthropathy, and Their Therapeutic Response to Etoricoxib: Results From a Six-Month Prospective Clinical Intervention

“…Because the skewed sex ratio and typical puberty onset are not observed in PHOAR1, it suggests a key role of sex hormones in PGT regulation. Additionally, previous studies scatteredly indicated the potential differences with respect to the clinical spectrum between PHOAR1 and PHOAR2 . However, systematic analyses were absent.…”