Two common polymorphic variants of OATP4A1 as potential risk factors for colorectal cancer

Abstract

Genetic variations in the organic-anion-transporting polypeptide (OATP)-encoding solute carrier of organic anions (SLCO) genes can promote cancer development and progression. The overexpression of solute carrier organic anion transporter family member 4A1 (OATP4A1), a transporter for steroid hormones, prostaglandins, and bile acids, has been previously associated with tumor recurrence and progression in colorectal cancer (CRC). Therefore, the present study aimed to investigate the association between 2 frequent single nucleotide polymorphisms (SNPs) in SLCO4A1 (rs34419428, R70Q; rs1047099G, V78I) and CRC predisposition. Following restriction fragment length polymorphism-PCR analysis in 178 patients with CRC [Union for International Cancer Control (UICC) stage I/II] and 65 healthy controls, no significant difference was observed in allele frequency and the number of heterozygous/homozygous individuals between the groups. Notably, the R70Q minor allele was identified to be associated with the V78I minor allele in the genome. Comparing of the individual genotypes of CRC patients to clinical data, including sex, UICC-stage and relapse revealed no increased risk for CRC. In addition, the OATP4A1 immunoreactivity assay in paraffin-embedded CRC and adjacent non-tumorous mucosa sections, examined using quantitative microscopy image analysis, did not reveal any association with these polymorphisms. No significant differences were observed in the expression levels, localization, and sodium fluorescein transport capacity among the OATP4A1 variants, which was studied using functional assays in Sf9-insect and A431 tumor cells overexpressing the 2 single and a double mutant OATP4A1 SNP variants. These results suggested that the 2 most frequent polymorphisms located in the first intracellular loop of OATP4A1 do not associate with CRC predisposition and tumor recurrence. They are unlikely to affect the outcome of CRC in patients.

Effects of the SLCO1B1 A388G single nucleotide polymorphism on the development, clinical parameters, treatment, and survival of multiple myeloma cases in a Polish population

“…Falkowski et al have shown that the A388G variant genotypes of SLCO1B1 were not associated with colorectal cancer (CRC); similar results were obtained by Özhan et al in colorectal cancer [21,42]. In another study on two common polymorphisms of OATP4A1, no association between CRC predisposition and tumor recurrence was found [38]. Noci et al showed that A388G is associated with overall survival for patients with metastatic CRC treated with irinotecan.…”

Effects of the SLCO1B1 A388G single nucleotide polymorphism on the development, clinical parameters and survival of multiple myeloma cases in a Polish population

“…Falkowski et al have shown that the A388G variant genotypes of SLCO1B1 were not associated with colorectal cancer (CRC); similar results were obtained by Özhan et al in colorectal cancer 24,42 . In another study on two common polymorphisms of OATP4A1, no association with CRC predisposition and tumor recurrence was found 41 .…”

“…Furthermore, expression levels of these in ux transporters may play a crucial role in chemoresistance mechanisms 26 . Patients with OATP polymorphisms have been found to have altered pharmacokinetics due to their impact on absorption, distribution, and excretion of anticancer drugs, thus cancer outcomes 15,23,24,41 .…”

SLCO4A1 expression is associated with activated inflammatory pathways in high-grade serous ovarian cancer

“…Sanger sequencing revealed that the heterozygous mutation g.323G>A (p.Val78Ile), previously described in colon cancer and healthy control patients, was present in 2 out of 7 investigated cell lines. This SNP, which is located in the first intracellular loop of the protein distant to the binding site of drugs, was previously shown to have no effect either on the expression levels nor on the uptake of the OATP surrogate substrate sodium-fluorescein ( Buxhofer-Ausch et al, 2020 ).…”