Genomic Landscape of GNAQ and GNA11 Mutations in Metastatic Solid Tumors: A Real-World Data Analysis.

Authors

Minsuk Kwon, Yunjin Go, Ji Eun Shin, Sung Hee Lim, Jung Yong Hong, Se Hoon Park, Joon Oh Park, Young Suk Park, Kee-Taek Jang, Jeeyun Lee, Seung Tae Kim

Published in

JCO precision oncology. Volume 10. Issue 7. Pages e2600072. Epub Jul 06, 2026.

Abstract

Activating mutations in GNAQ and GNA11 are recognized oncogenic drivers in uveal melanoma (UM); however, their prevalence across various cancers and their genomic context remain inadequately characterized. This study aimed to elucidate the genomic landscape of these mutations across a range of metastatic solid tumors.
We conducted a pan-cancer analysis involving 5,416 patients with metastatic solid tumors who had undergone next-generation sequencing. Our evaluation encompassed mutational distribution, hotspot identification, tumor mutational burden (TMB), microsatellite instability (MSI), and coalterations.
Mutations in GNAQ (n = 10) or GNA11 (n = 16) were detected in 26 patients (0.48%). Aside from UM, these mutations were most frequently observed in colorectal cancer (38.5%), melanoma (15.4%), gastric cancer (11.5%), and neuroendocrine tumors (7.7%). A notable subset exhibited an immunogenic profile, with 42.3% classified as TMB-High (≥10 Mut/Mb) and 19.2% as MSI-High. This immunogenic subgroup was primarily associated with nonhotspot mutations (eg, p.Gln88His, p.Ala231Val), suggesting that these may represent bystander events in hypermutated tumors. Conversely, canonical hotspots (Q209, R183) were predominantly identified in TMB-Low/microsatellite stable tumors, such as UM. Notable coalterations included NOTCH3 (80%), FAT1 (70%), and TP53 (37.5%-40%). Exploratory survival analysis suggested favorable OS in the immunogenic subgroup, supported by cases with durable ICI benefit including a treatment-free remission exceeding 21 months.
This real-world analysis demonstrates that GNAQ and GNA11 mutations are not exclusive to UM, occurring across diverse solid tumors, particularly colorectal cancer. The strong association between nonhotspot mutations and high TMB/MSI status defines a distinct immunogenic subgroup, underscoring the need to differentiate canonical hotspot drivers from bystander mutations when selecting targeted pathway inhibitors versus immune checkpoint blockade.

PMID:
42407004
Bibliographic data and abstract were imported from PubMed on 07 Jul 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.