GNAS

Overview

GNAS encodes the Gαs subunit of the heterotrimeric G protein; activating hotspot mutations are hallmark events in mucinous appendiceal and pancreatic neoplasms.

Alterations observed in the corpus

  • Defines the GNAS-mut predominant molecular subtype of mucinous appendiceal adenocarcinoma (MAAP) in the MSK cohort PMID:36493333.
  • GNAS-mut predominant tumors are chemotherapy-resistant: 6% first-line response rate vs 50% in RAS-mut predominant MAAP (P=.03) PMID:36493333.
  • GNAS-mut predominant patients had worse OS than RAS-mut predominant patients (P=.05), intermediate between RAS-mut and TP53-mut subtypes PMID:36493333.
  • GNAS R201 hotspot mutation found in 1 of 23 treatment-refractory somatotroph pituitary neuroendocrine tumors (PitNETs); absent in benign somatotrophs in the same cohort PMID:38758238.
  • In the MSK pdac_msk_2024 PDAC cohort (n = 2,336), GNAS was enriched in MAPK-WT tumors vs KRAS-mutant (16% vs 2%, P = 1.5 × 10⁻⁵) and in resectable IPMN-derived tumors (7.9%); co-occurred with germline ATM mutations PMID:39753968.
  • GNAS is among the most frequently mutated genes in pancreatic cystic neoplasms detected by whole-exome sequencing, particularly intraductal papillary mucinous neoplasms (IPMNs) PMID:22158988
  • Somatic mutation in 2/23 (9%) pancreatic acinar cell carcinomas, both at the codon 201 oncogenic hotspot, in whole-exome sequencing of a rare pancreatic tumor subtype PMID:24293293
  • Mutated in 6% of PDAC at hotspot codon 201 (R201C/R201H); all invasive cases derived from IPMN precursors; frequent co-mutation with KRAS PMID:25855536
  • Selectively mutated in mCRPC vs. primary prostate cancer (q<0.1); mutation observed exclusively in mCRPC PMID:26000489
  • Identified as a lineage-associated oncogene in the MET500 cohort of 500 metastatic solid tumors profiled by paired whole-exome and transcriptome sequencing; enrichment restricted to selected tumor types PMID:28783718

Cancer types (linked)

  • APAD — GNAS mutation status is one of three axes (GNAS/RAS/TP53) defining clinically distinct MAAP molecular lineages PMID:36493333.
  • PTAD (pituitary adenoma / PitNET) — GNAS R201 hotspot in 1 treatment-refractory somatotroph PitNET PMID:38758238.
  • PAAD — enriched in MAPK-WT and IPMN-derived PDAC subtypes; 16% in MAPK-WT vs 2% in KRAS-mutant tumors PMID:39753968.

Co-occurrence and mutual exclusivity

  • Defines a subtype largely distinct from RAS-mut/TP53-wt indolent MAAP and from TP53-mut predominant aneuploid MAAP PMID:36493333.
  • In PDAC, GNAS co-occurs with germline ATM mutations and is nearly exclusive to MAPK-WT tumors, a subtype also enriched for germline ATM (18% vs 1.4%, P = 2 × 10⁻⁶) PMID:39753968.

Therapeutic relevance

  • GNAS-mut predominant appendiceal adenocarcinomas appear unlikely to benefit from colorectal-style FOLFOX/FOLFIRI/FOLFIRINOX or capecitabine first-line regimens PMID:36493333.

Open questions

  • Mechanistic basis for GNAS-mut-associated chemoresistance in appendiceal tumors PMID:36493333.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:28783718

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