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

Background: Cancer-associated cachexia (CAC) is a multifactorial syndrome driven by a profound metabolic and inflammatory dysregulation. Due to the central role of the insulin-like growth factor 1 (IGF-1) pathway in regulating muscle mass, energy metabolism, and inflammation, this study evaluated the relevance of five IGF-1 axis-related single-nucleotide polymorphisms (SNPs), namely IGF1 rs6220, insulin-like growth factor 1 receptor (IGF1R) rs2016347 and rs2684788, growth hormone receptor (GHR) rs6873545, and insulin receptor substrate 1 (IRS1) rs1801278. Methods: The impact of these variants on CAC onset and overall survival (OS) was assessed in a cohort of 140 cancer patients. Results: While overall-cohort analyses did not reach statistical significance, exploratory analyses suggested potential associations between the IGF1 rs6220 GG and GHR rs6873545 CC genotypes and increased CAC risk in male patients. A trend for higher CAC prevalence was also noted in younger patients (<63 years) with the rs6873545 CC genotype. For pre-CAC and CAC patients, exploratory subgroup analyses on patients' OS were conducted following no significant results in the overall cohort. 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. Conclusions: This study highlights the functional heterogeneity of IGF-1 axis-related genetic variants, indicating potential to serve as predictors of CAC. Given the exploratory nature of these findings, validation in larger cohorts is required to confirm the associations found.