Association of the BCRP C421A polymorphism with nonpapillary renal cell carcinoma

Abstract

Breast cancer resistance protein (BCRP), the second member of the ATP-binding cassette membrane transporter family, has a single nucleotide polymorphism, C421A (resulting in Q141K), that is of functional importance. Our aim was to explore the relationship between this polymorphism of the BCRP gene and the risk of renal cell carcinoma (RCC) development. For a case-control study, DNA samples from 200 nonpapillary RCC patients and 200 healthy control subjects were analyzed using the TaqMan technique. The genotypic frequencies of the BCRP C421A polymorphism were compared between RCC patients and control subjects. The frequency of the C/C genotype was significantly higher in RCC patients than in control subjects (age-and gender-adjusted OR 5 1.96, 95% CI 1.32-2.93). No associations were observed between the BCRP C421A polymorphism and clinicopathologic or epidemiologic factors, including age, gender, tumor grade, stage, cigarette smoking, family history of cancer and body mass index. Carriers with the C/C genotype of the BCRP C421A polymorphism are at risk of developing nonpapillary RCC. These data suggest that BCRP is a candidate RCC susceptibility gene. ' 2005 Wiley-Liss, Inc.Key words: breast cancer resistance protein; single nucleotide polymorphism; renal cell carcinoma RCC is the most common malignancy of human adult kidneys and accounts for 2-3% of all cancers. Approximately 80% of all RCCs belong to the clear cell subtype, originating from the proximal epithelia.1 The prevalence of RCC is increasing, 2,3 probably for the following reasons: (i) an improved detection rate arising from the widespread use of noninvasive imaging procedures, such as ultrasonography, CT and MRI; (ii) prolongation of the life span in developed countries; and (iii) increases in environmental risk factors, especially exogenous carcinogens derived from various foods and industrial processes. Regarding the metabolism of such xenobiotics, genetically polymorphic enzymes such as cytochrome P-450, glutathione S-transferase and N-acetyltransferase have been reported to modulate renal cancer risk.4-6 Detection of high-risk groups based on the knowledge of cancer-susceptibility genes is clearly important for further improvement in the early diagnosis and prevention of RCC.Accumulating evidence has revealed that transporter molecules involved in the distribution, delivery and penetration of environmental agents into cellular and subcellular compartments may also play roles in the risk of renal cancer development.7,8 P-gp (MDR1/ABCB1), MRP2 (ABCC2) and BCRP (ABCG2) are members of the ABC transporter family, which function in the uptake, binding, transport and distribution of xenobiotics. P-gp is a plasma membrane transporter encoded by MDR1. Studies have shown that these proteins are expressed not only in cancer cells for effluxing multi-anticancer agents but also in the apical membrane of normal enterocytes, where they presumably act as ''gatekeepers'', controlling the oral availability of many substances. 9This hypothesis could be applicable t...

Investigation of the functional single-nucleotide polymorphisms in the BCRP transporter and susceptibility to colorectal cancer

“…An increased risk of DLBCL was associated with the 421A allele (P=0.042) and a worse survival was associated with the 34AA genotypes (hazard ratio, 3.69) in 156 DLBCL patients and 376 control subjects. In another study, a Japanese group found that the BCRP 421CC homozygotes were at a higher risk to develop non-papillary renal cell carcinoma (30). In the present study, BCRP 421C>A was significantly associated with the colorectal cancer risk (OR=16.12, 95% CI: 2.08-125.1), whereas distribution of the BCRP 34G>A genotypes did not significantly differ in the case and control groups (P=0.204).…”

“…The differential xenobiotic metabolism, which is due to variations in the transporter molecules, may affect the risk of certain types of cancers (26)(27)(28)(29)(30)(31). In certain studies, a possible role of transporter deficiencies was indicated in the susceptibility for colon carcinoma (14,18,32).…”

Genetic Polymorphisms Associated with a Prolonged Progression-Free Survival in Patients with Metastatic Renal Cell Cancer Treated with Sunitinib

“…In RCC, an increase in ABCB1 expression (33,34) and activity (35) has been reported, suggesting a contribution of ABCB1 to the resistance of RCC to some anticancer drugs. Although polymorphisms in ABCB1 and ABCG2 may be associated with the development of RCC (36,37), it is currently not known whether polymorphisms in ABCB1 and ABCG2 are associated with the expression and function of these transporters at the somatic level in renal cancer cells (38). Nevertheless, the role of efflux transporters in tumor cells may be limited for acquired resistance to sunitinib, which may develop after an initial response to sunitinib, as acquired resistance to sunitinib may be more related to physiological changes in the microenvironment of tumors, allowing reestablishment of angiogenesis during sunitinib treatment (16).…”

Identification and Functional Assessment ofBCRPPolymorphisms in a Korean Population

“…For example, the BCRP Q141K variant has been implicated in the altered pharmacokinetics of diflomotecan (Sparreboom et al, 2004). This BCRP polymorphism has also been associated with the susceptibility of renal carcinoma cells to drug treatments (Korenaga et al, 2005) and with the low expression of …”