Molecular and Clinicopathologic Impact of GNAS Variants Across Solid Tumors.

IF 42.1 1区 医学 Q1 ONCOLOGY Journal of Clinical Oncology Pub Date : 2024-11-10 Epub Date: 2024-08-09 DOI:10.1200/JCO.24.00186
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
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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.

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实体瘤中 GNAS 变异的分子和临床病理学影响
目的:人们对粘液性肿瘤致病性的分子驱动因素知之甚少。GNAS突变可预测粘液性阑尾腺癌的转移负荷和耐药性。我们研究了 GNAS 变异的泛癌症临床病理学相关性:我们评估了58043名患有纪念斯隆-凯特琳癌症行动靶点整合突变分析(IMPACT)序列实体瘤的患者,以确定与粘液性肿瘤表型相关的致癌变异,包括GNAS。然后,我们进行了全面的分子分析,以比较不同癌症中的GNAS突变体(mut)和野生型肿瘤。在癌症基因组图谱队列中评估了与 GNAS 突变肿瘤相关的基因表达模式。利用倾向匹配的转移性疾病患者亚队列确定了GNAS变异状态与腹膜转移、一线系统治疗反应、无进展生存期(PFS)和总生存期(OS)之间的关系:结果:黏液性肿瘤富含致癌GNAS变体。在小肠癌、宫颈癌、结直肠癌、胰腺癌、食管胃癌、肝胆癌和消化道神经内分泌癌中,GNAS突变率大于1%。在这些癌症中,GNAS突变肿瘤表现出普遍一致的C-T突变高、非整倍体低的分子特征,同时伴有普遍的KRAS变异(65%的GNAS突变肿瘤)和较少的TP53改变。GNAS突变肿瘤表现出反复发生的替代性肿瘤抑制因子(RBM10、INPPL1)组合,以及MAPK和细胞表面调节因子的上调。GNAS突变肿瘤显示腹膜转移的发生率增加(几率比 [OR],1.7 [95% CI,1.1 至 2.5];P = .006),对一线系统治疗的反应较差(OR,2.2 [95% CI,1.3 至 3.8];P = .003),PFS较短(中位数,5.6 对 7.0 个月;P = .047)。在多变量分析中,GNAS突变状态是较差OS的独立预后因素(危险比为1.25 [95% CI, 1.01 to 1.56];调整后P = .04):结论:在所有被评估的癌症中,GNAS突变肿瘤表现出一致的分子和临床表型,即粘液瘤状态、腹膜转移增加、对一线系统治疗反应差和生存率降低。
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来源期刊
Journal of Clinical Oncology
Journal of Clinical Oncology 医学-肿瘤学
CiteScore
41.20
自引率
2.20%
发文量
8215
审稿时长
2 months
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.
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