Molecular and Clinicopathologic Impact of GNAS Variants Across Solid Tumors
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View abstract on PubMed
Summary
This summary is machine-generated.GNAS mutations are linked to mucinous tumors across various cancers. These GNAS-mutant tumors show increased metastasis, poor treatment response, and worse survival outcomes, highlighting their clinical significance.
Area Of Science
- Oncology
- Molecular Biology
- Genetics
Background
- The molecular underpinnings of mucinous tumor development remain largely unknown.
- GNAS mutations have been associated with metastatic burden and treatment resistance in mucinous appendiceal adenocarcinoma.
Purpose Of The Study
- To investigate the pan-cancer clinicopathologic relevance of GNAS variants.
- To identify oncogenic GNAS variants associated with the mucinous tumor phenotype across various solid tumors.
Main Methods
- Analysis of 58,043 patients' solid tumors sequenced by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT).
- Comprehensive molecular analyses comparing GNAS-mutant and wild-type tumors.
- Assessment of gene expression patterns in The Cancer Genome Atlas cohort.
- Propensity-matched subcohort analysis for metastatic disease to evaluate GNAS variant status associations with peritoneal metastasis, therapy response, progression-free survival (PFS), and overall survival (OS).
Main Results
- Mucinous tumors showed enrichment for oncogenic GNAS variants, found in over 1% of small bowel, cervical, colorectal, pancreatic, esophagogastric, hepatobiliary, and GI neuroendocrine cancers.
- GNAS-mutant tumors displayed a conserved molecular profile (C-to-T mutation-high, aneuploidy-low) with frequent KRAS co-mutations and fewer TP53 alterations.
- GNAS-mutant tumors were associated with increased peritoneal metastases (OR 1.7), worse first-line systemic therapy response (OR 2.2), shorter PFS (median 5.6 vs. 7.0 months), and independently predicted worse OS (HR 1.25).
Conclusions
- GNAS-mutant tumors across various cancers share a conserved phenotype characterized by mucinous histology.
- This phenotype includes increased peritoneal metastasis, diminished response to first-line systemic therapy, and poorer survival outcomes.
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