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.