Evaluating the Molecular, Clinicopathologic Effects of GNAS Variants in Solid Tumors

In patients with mucinous appendiceal adenocarcinoma, GNAS mutations can estimate metastatic burden and treatment resistance. However, there is little research regarding the molecular drivers related to mucinous tumor pathogenicity.

A recent study from Paul Johannet, MD, and colleagues published in the Journal of Clinical Oncology sought to determine the effects of GNAS variants on pan-cancer clinicopathology.

Researchers reviewed the data of 58,043 patients with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets–sequenced solid tumors to determine the associations between oncogenic variants, such as GNAS, and mucinous tumor phenotype.

A propensity-matched subcohort of patients with metastatic disease was used to determine the connection between GNAS mutation variant status and peritoneal metastasis, first-line systemic therapy response, progression-free survival (PFS), and overall survival (OS).

In small bowel, cervical, colorectal, pancreatic, esophagogastric, hepatobiliary, and gastrointestinal neuroendocrine cancers, GNAS was mutated in less than 1% of samples. GNAS-mutated tumors also displayed C-to-T mutation-high, aneuploidy-low molecular profile with co-occurring prevalent KRAS variants and fewer TP53 alterations.

Tumors with GNAS mutations demonstrated recurrently co-mutated alternative tumor suppressors, including RBM10 and INPPL1, as well as upregulation of MAPK and cell surface modulators. Patients with these tumors also reported an increased rate of peritoneal metastases (odds ratio [OR], 1.7; 95% CI, 1.1-2.5; P=.006), worse response to first-line systemic therapy (OR, 2.2; 95% CI, 1.3-3.8; P=.003), and decreased PFS (P=.047).

Following a multivariate analysis, researchers discovered a connection between GNAS-mutated tumors and a decreased OS rate (95% CI, 1.01-1.56; P=.04).

“Across the assessed cancers, GNAS-mutated 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,” the investigators wrote.