Comparative and Histology-Aware Bioinformatic Characterization of FAM171A1 and FAM171A2 in Sarcoma: Expression, Prognostic, and Immune Associations

Background/Objectives: Sarcomas represent a diverse group of mesenchymal malignancies characterized by unique histological, molecular, and immune features. FAM171A1 and FAM171A2, although related members of the FAM171 family, exhibit significant differences in their current biological characterization, with their relevance to sarcoma largely unexplored. This study conducted a comparative characterization of FAM171A1 and FAM171A2 using a comprehensive bioinformatic approach. Methods: This approach integrated data from TCGA/GTEx, GEPIA3, the Human Protein Atlas (HPA), TIMER/TIMER3, GeneMANIA, TargetScan, and ENCORI, alongside two independent Gene Expression Omnibus (GEO) cohorts with paired normal tissues. Systematic evaluations were performed on gene expression, histology-specific patterns, overall survival, immune infiltration, functional association networks, and predicted miRNA-related relationships. Results: Both genes demonstrated higher expression in the pooled SARC cohort compared to the normal-reference dataset, with significant expression heterogeneity observed across major histological subtypes. In independent cohorts with paired normal tissue, FAM171A2 upregulation was reproduced in a matched liposarcoma cohort (15 patients), whereas FAM171A1 upregulation was not. Higher expression of both genes correlated with poorer overall survival, and these associations remained significant in histology-stratified multivariable Cox models after adjusting for available clinical covariates. Exploratory subtype-specific analyses suggested an association with overall survival in undifferentiated pleomorphic sarcoma; however, this finding was based on a small subgroup with wide confidence intervals and requires independent validation. Immune analyses indicated histology-dependent and gene-specific patterns of immune-cell association, suggesting non-uniform immune relationships across sarcoma subtypes. GeneMANIA identified database-supported functional associations, while TargetScan and ENCORI identified candidate miRNA-related relationships; these findings are considered hypothesis-generating rather than mechanistic evidence. Conclusions: Overall, FAM171A1 and FAM171A2 display distinct, histology-dependent expression, survival, and immune-associated patterns in sarcoma. These findings represent prognostic associations rather than established prognostic biomarkers; they prioritize both genes for further investigation but do not establish functional, mechanistic, or therapeutic roles. Independent clinical validation and targeted experimental studies are necessary to ascertain their biological and potential prognostic relevance.