Genetic Variability in the IGF-1 Axis Modulates Cancer-Associated Cachexia and Prognosis

Cancer-associated cachexia (CAC) is a multifactorial syndrome driven by a profound metabolic and inflammatory dysregulation. Due to the central role of the insulin growth factor 1 (IGF-1) pathway in regulating muscle mass, energy metabolism, and inflammation, this study evaluated the relevance of IGF-1 axis-related genetic variants to CAC onset and their impact on overall survival (OS) in a cohort of 140 cancer patients. Five single-nucleotide polymorphisms (SNPs) were evaluated, including IGF1 rs6220, insulin-like growth factor 1 receptor (IGF1R) rs2016347 and rs2684788, growth hormone receptor (GHR) rs6873545 and insulin receptor substrate 1 (IRS1) rs1801278. The IGF1 rs6220 GG and GHR rs6873545 CC genotypes were associated with increased CAC risk in male patients. Younger patients (< 63 years) with the rs6873545 CC genotype also had a higher prevalence of CAC. For pre-CAC and CAC patients, subgroup analyses on patients’ OS were conducted. Among older patients and those with high prognostic nutritional index (PNI; > 44.2), the IGF1 rs6220 G allele was associated with longer OS. Conversely, the IGF1R rs2016347 G allele and rs2684788 T allele were linked to poorer OS across multiple pre-CAC and CAC subgroups. The effects of GHR rs6873545 varied across subgroups, suggesting context-dependent activity. This study highlights the functional heterogeneity of IGF-1 axis-related genetic variants as predictors of CAC development and patient survival. Further validation in larger cohorts is warranted.