Molecular and Clinicopathologic Impact of GNAS Variants Across Solid Tumors

PURPOSE The molecular drivers underlying mucinous tumor pathogenicity are poorly understood. GNAS mutations predict metastatic burden and treatment resistance in mucinous appendiceal adenocarcinoma. We investigated the pan-cancer clinicopathologic relevance of GNAS variants. METHODS We assessed 58,043 patients with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT)–sequenced solid tumors to identify oncogenic variants, including GNAS , associated with mucinous tumor phenotype. We then performed comprehensive molecular analyses to compare GNAS- mutant (mut) and wild-type tumors across cancers. Gene expression patterns associated with GNAS- mut tumors were assessed in a The Cancer Genome Atlas cohort. Associations between GNAS variant status and peritoneal metastasis, first-line systemic therapy response, progression-free survival (PFS), and overall survival (OS) were determined using a propensity-matched subcohort of patients with metastatic disease. RESULTS Mucinous tumors were enriched for oncogenic GNAS variants. GNAS was mutated in >1% of small bowel, cervical, colorectal, pancreatic, esophagogastric, hepatobiliary, and GI neuroendocrine cancers. Across these cancers, GNAS- mut tumors exhibited a generally conserved C-to-T mutation-high, aneuploidy-low molecular profile with co-occurring prevalent KRAS variants (65% of GNAS-mut tumors) and fewer TP53 alterations. GNAS- mut tumors exhibited recurrently comutated alternative tumor suppressors ( RBM10 , INPPL1 ) and upregulation of MAPK and cell surface modulators. GNAS- mut tumors demonstrate an increased prevalence of peritoneal metastases (odds ratio OR, 1.7 95% CI, 1.1 to 2.5; P = .006), worse response to first-line systemic therapy (OR, 2.2 95% CI, 1.3 to 3.8; P = .003), and shorter PFS (median, 5.6 v 7.0 months; P = .047). In a multivariable analysis, GNAS mutated status was independently prognostic of worse OS (hazard ratio, 1.25 95% CI, 1.01 to 1.56; adjusted P = .04). CONCLUSION Across the assessed cancers, GNAS- mut tumors exhibit a conserved molecular and clinical phenotype defined by mucinous tumor status, increased peritoneal metastasis, poor response to first-line systemic therapy, and worse survival.