Abstract
A disintegrin and metalloproteinase domain-containing protein 9 (ADAM9) functions as a membranous bridge, forming cell-cell and cell-matrix connections that regulate tumor aggressiveness in various cancer types, including prostate cancer (PCa). Elevated ADAM9 levels in PCa were identified as a prognostic marker for biochemical recurrence (BCR) in patients who had undergone a radical prostatectomy (RP). However, impacts of genetic variants of ADAM9 on clinicopathological development and BCR remain unclear. Herein, we recruited 702 patients with PCa to evaluate associations of single-nucleotide polymorphisms (SNPs) of ADAM9 with the risk of BCR and clinicopathological development. We genotyped four loci of ADAM9 SNPs located in the promoter and intron regions using a TaqMan allelic discrimination assay, including rs10105311 (C/T), rs7006414 (T/C), rs6474526 (T/G), and rs78451751 (T/C) in 702 Taiwanese PCa patients. Our results showed that the risk of postoperative BCR was 1.508-fold higher in patients carrying the T/C genotype in ADAM9 rs7006414 compared to those with the homozygous T/T genotype, a phenomenon more pronounced in younger PCa patients (aged ≤ 65 years). Furthermore, patients with at least one polymorphic G allele in ADAM9 rs6474526 had a 2.016-fold increased risk of developing an advanced clinical primary tumor stage, particularly in a subpopulation without BCR. Clinical observations from the Genotype-Tissue Expression (GTEx) database showed increased ADAM9 expression in whole blood tissues among individuals carrying the polymorphic C allele of rs7006414 and the G allele of rs6474526. Additionally, data from The Cancer Genome Atlas indicated that elevated ADAM9 levels were observed in PCa tissues compared to corresponding matched normal tissues. Our findings suggest that the rs7006414 and rs6474526 genetic variants of ADAM9 may influence ADAM9 expression and are associated with BCR and clinicopathological development in PCa patients after an RP.