Molecular and clinicopathologic impact of GNAS variants across solid tumors Journal Article
| Authors: | Johannet, P.; Abdelfattah, S.; Wilde, C.; Patel, S.; Walch, H.; Rousseau, B.; Argiles, G.; Artz, O.; Patel, M.; Arfe, A.; Cercek, A.; Yaeger, R.; Ganesh, K.; Schultz, N.; Diaz, L. A.; Foote, M. B. |
| Article Title: | Molecular and clinicopathologic impact of GNAS variants across solid tumors |
| Abstract: | PURPOSEThe molecular drivers underlying mucinous tumor pathogenicity are poorly understood. GNAS mutations predict metastatic burden and treatment resistance in mucinous appendiceal adenocarcinoma. We investigated the pan-cancer clinicopathologic relevance of GNAS variants.METHODSWe assessed 58,043 patients with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT)-sequenced solid tumors to identify oncogenic variants, including GNAS, associated with mucinous tumor phenotype. We then performed comprehensive molecular analyses to compare GNAS-mutant (mut) and wild-type tumors across cancers. Gene expression patterns associated with GNAS-mut tumors were assessed in a The Cancer Genome Atlas cohort. Associations between GNAS variant status and peritoneal metastasis, first-line systemic therapy response, progression-free survival (PFS), and overall survival (OS) were determined using a propensity-matched subcohort of patients with metastatic disease.RESULTSMucinous tumors were enriched for oncogenic GNAS variants. GNAS was mutated in >1% of small bowel, cervical, colorectal, pancreatic, esophagogastric, hepatobiliary, and GI neuroendocrine cancers. Across these cancers, GNAS-mut tumors exhibited a generally conserved C-to-T mutation-high, aneuploidy-low molecular profile with co-occurring prevalent KRAS variants (65% of GNAS-mut tumors) and fewer TP53 alterations. GNAS-mut tumors exhibited recurrently comutated alternative tumor suppressors (RBM10, INPPL1) and upregulation of MAPK and cell surface modulators. GNAS-mut tumors demonstrate an increased prevalence of peritoneal metastases (odds ratio [OR], 1.7 [95% CI, 1.1 to 2.5]; P =.006), worse response to first-line systemic therapy (OR, 2.2 [95% CI, 1.3 to 3.8]; P =.003), and shorter PFS (median, 5.6 v 7.0 months; P =.047). In a multivariable analysis, GNAS mutated status was independently prognostic of worse OS (hazard ratio, 1.25 [95% CI, 1.01 to 1.56]; adjusted P =.04).CONCLUSIONAcross the assessed cancers, GNAS-mut 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. © American Society of Clinical Oncology. |
| Keywords: | mitogen activated protein kinase; adult; cancer survival; controlled study; treatment response; aged; middle aged; unclassified drug; gene mutation; major clinical study; overall survival; genetics; mutation; mortality; liver cell carcinoma; systemic therapy; pancreas cancer; neoplasm; neoplasms; colorectal cancer; phenotype; progression free survival; antineoplastic metal complex; adenocarcinoma, mucinous; cohort analysis; pathology; protein p53; tumor marker; carcinogenesis; colon cancer; uterine cervix cancer; stomach cancer; bile duct carcinoma; upregulation; k ras protein; tumor suppressor protein; esophagus cancer; colloid carcinoma; peritoneum metastasis; guanine nucleotide binding protein; chromogranin; gallbladder cancer; fluoropyrimidine derivative; aneuploidy; small intestine cancer; pancreas islet cell tumor; clinical outcome; hepatobiliary system cancer; first-line treatment; chromogranins; cancer prognosis; humans; human; male; female; article; median survival time; differential gene expression; biomarkers, tumor; solid malignant neoplasm; molecular fingerprinting; stimulatory guanine nucleotide binding protein; gtp-binding protein alpha subunits, gs; gnas protein, human; small intestinal neuroendocrine tumor; colorectal neuroendocrine tumor; gastric neuroendocrine tumor; guanine nucleotide binding protein alpha stimulating activity polypeptide |
| Journal Title: | Journal of Clinical Oncology |
| Volume: | 42 |
| Issue: | 32 |
| ISSN: | 0732-183X |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2024-11-10 |
| Start Page: | 3847 |
| End Page: | 3857 |
| Language: | English |
| DOI: | 10.1200/jco.24.00186 |
| PUBMED: | 39121438 |
| PROVIDER: | scopus |
| PMCID: | PMC11540749 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Michael B. Foote -- Source: Scopus |
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