Molecular and Clinicopathologic Impact of GNAS Variants Across Solid Tumors.

Abstract

The molecular drivers underlying mucinous tumor pathogenicity are poorly understood. <i>GNAS</i> mutations predict metastatic burden and treatment resistance in mucinous appendiceal adenocarcinoma. We investigated the pan-cancer clinicopathologic relevance of <i>GNAS</i> variants. 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 <i>GNAS</i>, associated with mucinous tumor phenotype. We then performed comprehensive molecular analyses to compare <i>GNAS-</i>mutant (mut) and wild-type tumors across cancers. Gene expression patterns associated with <i>GNAS-</i>mut tumors were assessed in a The Cancer Genome Atlas cohort. Associations between <i>GNAS</i> 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. Mucinous tumors were enriched for oncogenic <i>GNAS</i> variants. <i>GNAS</i> was mutated in >1% of small bowel, cervical, colorectal, pancreatic, esophagogastric, hepatobiliary, and GI neuroendocrine cancers. Across these cancers, <i>GNAS-</i>mut tumors exhibited a generally conserved C-to-T mutation-high, aneuploidy-low molecular profile with co-occurring prevalent <i>KRAS</i> variants (65% of GNAS-mut tumors) and fewer <i>TP53</i> alterations. <i>GNAS-</i>mut tumors exhibited recurrently comutated alternative tumor suppressors (<i>RBM10</i>, <i>INPPL1</i>) and upregulation of MAPK and cell surface modulators. <i>GNAS-</i>mut tumors demonstrate an increased prevalence of peritoneal metastases (odds ratio [OR], 1.7 [95% CI, 1.1 to 2.5]; <i>P =</i> .006), worse response to first-line systemic therapy (OR, 2.2 [95% CI, 1.3 to 3.8]; <i>P =</i> .003), and shorter PFS (median, 5.6 <i>v</i> 7.0 months; <i>P =</i> .047). In a multivariable analysis, <i>GNAS</i> mutated status was independently prognostic of worse OS (hazard ratio, 1.25 [95% CI, 1.01 to 1.56]; adjusted <i>P =</i> .04). Across the assessed cancers, <i>GNAS-</i>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.