Molecular characteristics and prognostic impact of
GNAS
mutations in colorectal cancer: An international collaborative study between United States and Japan.
Authors: Arrondo Elisabeth , Iida Naoko , Hashimoto Tadayoshi , Ozaki Hiroshi , Shibuki Taro , Imai Mitsuho , Fujisawa Takao , Nakamura Yoshiaki , Bando Hideaki , Kopetz Scott , Shen John Paul Y.C. , Yoshino Takayuki 
Published: January 2025

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Background:
GNAS
(Guanine nucleotide-binding protein, alpha stimulating) encodes the alpha subunit of the stimulatory G protein, and gain of function mutations in this gene have been previously identified, especially those located at the R201 codon. Although
GNAS
R201C/H
has been associated with mucinous histology and poor response to chemotherapy in appendiceal cancer, the impact of
GNAS
mutations in colorectal cancer (CRC) remains unclear.
Methods:
We conducted a comparative, integrative analysis of
GNAS
mutations in CRC using two cohorts: MD Anderson Cancer Center (MDA) across all stages (N=5,249) and the GALAXY study involving only resectable disease (UMIN000039205, N=2,599). We assessed the correlation between
GNAS
pathogenic mutations and microsatellite stability, CRC sidedness, co-mutations, and survival outcomes. The Chi-squared test was used for categorical variables, and the log-rank test for overall survival (OS) and disease-free survival (DFS).
Results:
In the MDA and GALAXY cohorts,
GNAS
mutations were identified in 107 (2.0%) and 61 (2.4%) patients, respectively. Prevalence of
GNAS
mutations was higher in right sided tumors (MDA: 3.8% vs. 1.3%, GALAXY: 6.2% vs 2.8%, p<0.01 for both cohorts) and microsatellite instability-high (MSI-H) tumors (MDA: 6.5% vs. 1.8%, GALAXY: 16.5% vs. 1.4%, p<0.01 for both cohorts). There was not an association of
GNAS
mutations with stage in either cohort.
GNAS
was significantly enriched for co-mutation with
KRAS
in the MDA cohort (OR=3.26, P<0.01), similar to prior observations in appendix cancer, but was not significantly associated with
KRAS
mutations in the GALAXY cohort (OR=1.35, P=0.3).
GNAS
mutations were mutually exclusive with
TP53
in both cohorts (MDA: OR=0.58, P=0.026; GALAXY: OR=0.21, P<0.01). With regards to survival, in the MDA cohort,
GNAS
mutant tumors had a trend towards worse OS in the overall population (20 mo vs. 33 mo, HR=1.27, 95% CI=0.61-1, P=0.085). The survival impact of
GNAS
mutations was greatest in metastatic patients (Stage IV: 19 mo vs. 38 mo, HR=1.49, 95% CI=0.47-0.94, P=0.021 vs. Stage I-III: HR=1.35, 95% CI=0.46-1.2, P=0.22). The GALAXY cohort showed no significant association between
GNAS
mutations and DFS (HR=1.05, 95% CI=0.6-1.8, P=0.9). In both cohorts,
GNAS
mutations had a worse prognosis in left-sided CRC (MDA: HR for OS = 1.45, P = 0.091; GALAXY: HR for DFS=2.15, P=0.09) with no significant effect observed in right-sided CRC (MDA: HR for OS=0.91, P=0.68; GALAXY: HR for DFS=0.65, P=0.3).
Conclusions:
Our findings highlighted the intricate role of
GNAS
mutations in CRC, demonstrating its higher prevalence in MSI-H and right-sided colon, significant association with
KRAS
mutations, and divergent prognostic impacts based on tumor sidedness. Further research is needed to elucidate the mechanisms behind the worsened survival in left-sided
GNAS-
mutated CRC.