Genetic Variations in the M6A Modification Pathway as Potential Predictors of Imatinib Secondary Resistance in Gastrointestinal Stromal Tumors

<b>Background/Objectives:</b> Imatinib mesylate (IM) is the first-line therapy for gastrointestinal stromal tumor (GIST). Emerging evidence suggests that genes involved in m6A modification, autophagy, and DNA damage repair pathways might contribute to IM secondary resistance and result in substantial inter-patient variability in treatment outcomes. However, influence of the genetic variations in these genes on IM-treated GIST remains unclear. <b>Methods:</b> A total of 172 GIST patients treated with IM in Sun Yat-sen University Cancer Center from 2014 to 2018 were enrolled. A 6-month landmark analysis was applied to specifically investigate secondary resistance, restricting the cohort to patients alive and progression-free at 6 months. Tag single-nucleotide polymorphisms (SNPs) in 54 evidence-based candidate genes involved in m6A modification, autophagy, and DNA damage repair pathways were selected and genotyped. Associations between SNPs and progression-free survival (PFS) were assessed using univariate Cox regression and Kaplan-Meier analyses with time zero reset to the 6-month landmark. Identified SNPs were further analyzed in multivariable Cox models adjusted for demographic and clinical factors. <b>Results:</b> During a median follow-up of 53.62 months (range, 7.60-129.77) as of October 2023, 39 progression events occurred. Univariate analyses identified 12 SNPs located in 9 genes associated with PFS. After adjustment for demographic and clinical covariates, 10 SNPs remained associated with PFS. Of these, seven variants were located in m6A pathway genes (<i>ALKBH5</i>, <i>METTL3</i>, <i>YTHDC2</i>, and <i>ZC3H13</i>), four of which were associated with shorter PFS (e.g., <i>YTHDC2</i> rs1833678 T > C, HR = 2.87, 95% CI: 1.18-7.03, <i>p</i> = 0.021) and three with longer PFS (e.g., <i>METTL3</i> rs1263793 A > G, HR = 0.40, 95% CI: 0.20-0.83, <i>p</i> = 0.014) of progression. A cumulative genetic risk score based on the identified m6A SNPs was associated with PFS (<i>p</i> < 0.001). Additionally, one SNP in autophagy and two in DNA damage repair pathways also remained associated with PFS after adjustment. <b>Conclusions:</b> Genetic polymorphisms in the m6A modification genes, along with variants in autophagy and DNA damage repair pathways, were associated with PFS in IM-treated patients who had achieved initial disease control. The cumulative risk score based on m6A pathway variants showed a strong association with PFS. These findings provide preliminary, hypothesis-generating evidence that genetic variations may contribute to inter-patient variability in outcomes and warrant further investigation as potential biomarkers in IM-treated GIST.