Inactivating Mutation in the Prostaglandin Transporter Gene, SLCO2A1, Associated with Familial Digital Clubbing, Colon Neoplasia, and NSAID Resistance
| العنوان: | Inactivating Mutation in the Prostaglandin Transporter Gene, SLCO2A1, Associated with Familial Digital Clubbing, Colon Neoplasia, and NSAID Resistance |
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| المؤلفون: | Lakshmeswari Ravi, Neil Molyneaux, Sanford D. Markowitz, Susan Lewis, Georgia L. Wiesner, Kishore Guda, Andrew J. Dannenberg, Ginger L. Milne, Joseph Willis, Stephen P. Fink, Courtney G. Montgomery, Shulin Na Zhang |
| المصدر: | Cancer Prevention Research. 7:805-812 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Adult, Male, Heterozygote, Cancer Research, medicine.medical_specialty, Osteoarthropathy, Primary Hypertrophic, Colon Adenoma, Colorectal cancer, Nonsense mutation, Drug Resistance, Organic Anion Transporters, Prostaglandin, Biology, Dinoprostone, Article, Prostaglandin E2 Metabolite, chemistry.chemical_compound, Internal medicine, medicine, Humans, Exome, Genetic Predisposition to Disease, Alleles, SLCO2A1, PROSTAGLANDIN TRANSPORTER, Anti-Inflammatory Agents, Non-Steroidal, Digital Clubbing, Genetic Variation, Sequence Analysis, DNA, Middle Aged, medicine.disease, digestive system diseases, Pedigree, Phenotype, Endocrinology, Oncology, chemistry, Colonic Neoplasms, Mutation, Prostaglandins, biology.protein, Female, Algorithms |
| الوصف: | HPGDand SLCO2A1 genes encode components of the prostaglandin catabolic pathway, with HPGD encoding the degradative enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and SLCO2A1 encoding the prostaglandin transporter PGT that brings substrate to 15-PGDH. HPGD-null mice show increased prostaglandin E2 (PGE2), marked susceptibility to developing colon tumors, and resistance to colon tumor prevention by nonsteroidal anti-inflammatory drugs (NSAID). 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 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 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. Cancer Prev Res; 7(8); 805–12. ©2014 AACR. |
| تدمد: | 1940-6215 1940-6207 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::74560eb0770b659e6a0f129696122687 https://doi.org/10.1158/1940-6207.capr-14-0108 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....74560eb0770b659e6a0f129696122687 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19406215 19406207 |
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