ACSM5 c.1273 C> A Polymorphism Promotes Malignant Progression of Lung Adenocarcinoma in Xuanwei Region

Lung adenocarcinoma (LUAD) is highly prevalent in Xuanwei region, Yunnan, China, but little is known about the genetic basis of this regional cancer. In our study, by performing the transcriptome sequencing and exome sequencing of Xuanwei LUAD and expression quantitative trait loci (eQTL) analysis, ACSM5 c.1273 C> A variant was identified as the top polymorphism affecting the highest number of downstream genes in Xuanwei LUAD. While initial exome data suggested tumor-specific enrichment, expanded validation revealed comparable occurrence of this variant in tumors (15.0%, 6/40) and matched normal tissues (12.5%, 5/40; P = 0.745). Notably, ACSM5 expression was significantly downregulated in tumors versus adjacent tissues. Functional studies in A549 (non-Xuanwei) and JT (Xuanwei) LUAD cells demonstrated that wild-type ACSM5 overexpression suppressed proliferation, colony formation, migration, invasion, and tumorigenesis while inducing apoptosis and G0/G1 arrest. Critically, the ACSM5 c.1273 C> A polymorphism substantially attenuated these tumor-suppressive effects. Mechanistically, ACSM5 inactivated the PI3K/AKT pathway, whereas the c.1273 C> A variant reactivated this oncogenic signaling. In summary, the ACSM5 c.1273 C> A polymorphism promotes LUAD progression by impairing tumor suppression in Xuanwei LUAD, providing a novel promising target for LUAD treatment.