Association of the P-Glycoprotein Transporter MDR1 C3435T Polymorphism with the Susceptibility to Renal Epithelial Tumors

Abstract

Abstract. Except for hereditary disease, genetic factors that contribute to the development of renal epithelial tumors are unknown. There is a possibility that the MDR1 encoded plasma membrane transporter P-glycoprotein (PGP) influences the risk of development of renal neoplasms. PGP is known to be involved in uptake, binding, transport, and distribution of xenobiotics. There is evidence that the MDR1 C3435T polymorphism drives expression and modulates disease risk. In an explorational case-control study, constitutional genotype frequencies were established at MDR1 C3435T of 537 healthy control subjects and compared with those of 212 patients with renal epithelial tumors. There were 179 clear cell renal cell carcinoma (CCRCC) and 33 tumors collectively assigned as non-CCRCC. In a second study, genotypes of another 150 healthy control subjects and 50 patients with three non-CCRCC types (26 papillary RCC, 11 chromophobe RCC, and 13 renal oncocytic adenoma) were compared. PCR-restriction fragment length polymorphism-based analysis of constitutional DNA, and statistical analysis were applied. PGP expression was analyzed by quantitative immunohistochemistry. The explorational study showed a significant association between T allele frequency and the occurrence of tumors (P ϭ 0.007). When tumors were histopathologically distinguished into frequent CCRCC and less frequent non-CCRCC, both patient groups contributed to this effect with a seemingly strong influence by the latter (P ϭ 0.0419). The second study established the T allele as a risk factor especially for non-CCRCC (P ϭ 0.0005) with the highest risk for homozygote TT allele carriers (P Ͻ 0.0001). Independently, MDR1C3435T genotype associated variations in PGP expression were shown in normal renal parenchyma with a 1.5-fold difference of median values (TT, 1.9; CC, 2.8; P ϭ 0.0065). The data provide evidence for PGP to influence the susceptibility to develop renal epithelial tumors by virtue of its MDR1 C3435T polymorphism and changes in expression. Especially T and TT carriers are at risk for developing non-CCRCC, i.e., papillary and chromophobe RCC as well as oncocytic adenomas.Renal epithelial tumors contribute approximately 3% to the overall cancer incidence and mortality. Renal cell carcinomas (RCC) compose clear cell RCC (CCRCC) in 75% to 80%, papillary (chromophilic) RCC in 10%, and chromophobe RCC in 5%. Others include granular cell carcinoma, spindle cell carcinoma, and duct Bellini and unclassified carcinomas (1). There are also benign oncocytic and papillary adenomas, which account for approximately 5% of all renal epithelial neoplasms. Although the molecular origins of these histologic subentities have been identified, i.e., mutations and hypermethylations of the VHL and RASSF1A tumor suppressor genes in CCRCC (2-5), mutations of the MET proto-oncogene in papillary RCC (6,7), and loci for hereditary chromophobe RCC and oncocytic adenoma on chromosome 17p11.2 (8), their cause and interindividual differences in susceptibility remain elusive.It is interes...

Functional Implications of Genetic Polymorphisms in the Multidrug Resistance Gene MDR1 (ABCB1)

“…Furthermore, patients with drug-resistant epilepsy were more likely to have the 3435CC genotype than the 3435TT genotype, pointing toward a more efficient barrier function in the capillary endothelial cells and around the epileptogenic focus in drug-resistant patients (60). At the intestinal and renal level, patients with ulcerative colitis and non-clear cell renal carcinoma had significantly increased frequencies of the 3435T allele, which again supports a role for P-glycoprotein in maintaining effective tissue barriers and protecting the body from potential environmental and metabolic toxins (61,62).…”

Ethnicity-Related Polymorphisms and Haplotypes in the Human ABCB1 Gene

“…Studies on the 3435C>T SNP show a correlation between allele frequency and risk of cancer development, as well as various responses to drug treatments. While no association has been observed between the TT genotype and the lung cancer phenotype [9,48], homozygous and heterozygous carriers of the T allele have been linked to a greater risk of developing nonclear cell renal cell carcinoma than individuals carrying the C allele [49]. Carriers of the TT genotype are more at risk of developing Acute Lymphoblastic Leukemia (ALL) than other individuals, whereas the CC genotype carriers exhibit a different prognosis [50].…”

Concise Review: Clinical Relevance of Drug–Drug and Herb–Drug Interactions Mediated by the ABC Transporter ABCB1 (MDR1, P-glycoprotein)

“…Moreover, genetic variation in ABCB1, by potentially altering the physiologic protective role of P-gp, has recently been assessed in the etiology of several human pathophysiological conditions. An increasing number of studies have associated certain SNPs in ABCB1 with susceptibility to diseases such as pharmacoresistant epilepsy, Parkinson's disease, inflammatory bowel diseases (ulcerative colitis and Crohn's disease), colorectal cancer, and renal carcinoma [22][23][24][25][26][27].…”