Paul Johannet, Somer Abdelfattah, Callahan Wilde, Shrey Patel, Henry Walch, Benoit Rousseau, Guillem Argiles, Oliver Artz, Miteshkumar Patel, Andrea Arfe, Andrea Cercek, Rona Yaeger, Karuna Ganesh, Nikolaus Schultz, Luis A Diaz, Michael B Foote
{"title":"Molecular and Clinicopathologic Impact of GNAS Variants Across Solid Tumors.","authors":"Paul Johannet, Somer Abdelfattah, Callahan Wilde, Shrey Patel, Henry Walch, Benoit Rousseau, Guillem Argiles, Oliver Artz, Miteshkumar Patel, Andrea Arfe, Andrea Cercek, Rona Yaeger, Karuna Ganesh, Nikolaus Schultz, Luis A Diaz, Michael B Foote","doi":"10.1200/JCO.24.00186","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>The molecular drivers underlying mucinous tumor pathogenicity are poorly understood. <i>GNAS</i> mutations predict metastatic burden and treatment resistance in mucinous appendiceal adenocarcinoma. We investigated the pan-cancer clinicopathologic relevance of <i>GNAS</i> variants.</p><p><strong>Methods: </strong>We assessed 58,043 patients with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT)-sequenced solid tumors to identify oncogenic variants, including <i>GNAS</i>, associated with mucinous tumor phenotype. We then performed comprehensive molecular analyses to compare <i>GNAS-</i>mutant (mut) and wild-type tumors across cancers. Gene expression patterns associated with <i>GNAS-</i>mut tumors were assessed in a The Cancer Genome Atlas cohort. Associations between <i>GNAS</i> 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.</p><p><strong>Results: </strong>Mucinous tumors were enriched for oncogenic <i>GNAS</i> variants. <i>GNAS</i> was mutated in >1% of small bowel, cervical, colorectal, pancreatic, esophagogastric, hepatobiliary, and GI neuroendocrine cancers. Across these cancers, <i>GNAS-</i>mut tumors exhibited a generally conserved C-to-T mutation-high, aneuploidy-low molecular profile with co-occurring prevalent <i>KRAS</i> variants (65% of GNAS-mut tumors) and fewer <i>TP53</i> alterations. <i>GNAS-</i>mut tumors exhibited recurrently comutated alternative tumor suppressors (<i>RBM10</i>, <i>INPPL1</i>) and upregulation of MAPK and cell surface modulators. <i>GNAS-</i>mut tumors demonstrate an increased prevalence of peritoneal metastases (odds ratio [OR], 1.7 [95% CI, 1.1 to 2.5]; <i>P =</i> .006), worse response to first-line systemic therapy (OR, 2.2 [95% CI, 1.3 to 3.8]; <i>P =</i> .003), and shorter PFS (median, 5.6 <i>v</i> 7.0 months; <i>P =</i> .047). In a multivariable analysis, <i>GNAS</i> mutated status was independently prognostic of worse OS (hazard ratio, 1.25 [95% CI, 1.01 to 1.56]; adjusted <i>P =</i> .04).</p><p><strong>Conclusion: </strong>Across the assessed cancers, <i>GNAS-</i>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.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"3847-3857"},"PeriodicalIF":42.1000,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540749/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Clinical Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1200/JCO.24.00186","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/9 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Purpose: The 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.
Methods: We 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.
Results: Mucinous 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).
Conclusion: Across 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.
期刊介绍:
The Journal of Clinical Oncology serves its readers as the single most credible, authoritative resource for disseminating significant clinical oncology research. In print and in electronic format, JCO strives to publish the highest quality articles dedicated to clinical research. Original Reports remain the focus of JCO, but this scientific communication is enhanced by appropriately selected Editorials, Commentaries, Reviews, and other work that relate to the care of patients with cancer.