Molecular and clinicopathologic impact of GNAS variants across solid tumors

The molecular drivers underlying mucinous tumor pathogenicity are poorly understood. GNAS mutations predic metastatic burden and treatment resistance in mucinous appendical adenocarcinoma. A study at Memorial Sloan Kettering Cancer Center (New York, NY) investigated the pan-cancer clinicopathologic relevance of GNAS variants. MSK-IMPACT sequencing revealed that mucinous tumors were enriched for oncogenic GNAS variants. GNAS was mutated in ≥ 1% of small bowel, cervical, colorectal, pancreatic, esophagogastric, hepatobiliary, and GI neuroeocrine cancers. GNAS-mutated tumors demonstrated an increased prevalence of peritoneal metastases (OR 1.7; p=0.006), worse response to first-line systemic therapy (OR 2.2; p=0.003), and shorter median progression-free survival (5.6 versus 7.0 months; p=0.047). In multivariable analysis, GNAS mutated status was independently prognostic of worse overall survival (HR 1.25; p=0.04). The authors conclude that across the assessed cancers, GNAS-mutated tumors exhibit an phenotype defined by mucinous tumor status, increased peritoneal metastasis, poor response to first-line therapy, and worse survival.