GNAS变异对实体瘤的分子和临床病理影响

粘液性肿瘤的致病分子机制尚不明确。GNAS突变可预测粘液性阑尾腺癌的转移负荷和治疗耐药性。我们研究了GNAS变异在泛癌种中的临床病理相关性。

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. 

我们对58,043名接受过Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT)测序的实体肿瘤患者进行了评估，以识别与粘液性肿瘤表型相关的致癌变异，包括GNAS。随后，我们进行了全面的分子分析，比较了不同癌症中的GNAS突变型（mut）和野生型肿瘤。我们还在The Cancer Genome Atlas队列中评估了与GNAS突变型肿瘤相关的基因表达模式。我们使用具有转移性疾病患者的倾向性匹配子队列，确定了GNAS变异状态与腹膜转移、一线全身治疗反应、无进展生存期（PFS）和总体生存期（OS）之间的关系。

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). 

粘液性肿瘤富含致癌GNAS变异。GNAS在1%以上的小肠、宫颈、结直肠、胰腺、食管胃、肝胆和胃肠神经内分泌癌中发生突变。在这些癌症中，GNAS-mut肿瘤通常表现出保守的C到T突变高、非整倍体低的分子特征，同时出现普遍的KRAS变异（占GNAS-mut肿瘤的65%）和较少的TP53变异。GNAS-mut肿瘤表现出反复突变的替代肿瘤抑制因子（RBM10、INPPL1）以及MAPK和细胞表面调节剂的上调。GNAS-mut肿瘤显示出腹膜转移的患病率增加（比值比[OR]，1.7 [95% CI，1.1至2.5]; P = .006），对一线全身治疗的反应更差（OR，2.2 [95% CI，1.3至3.8]; P = .003），以及更短的PFS（中位数，5.6个月对比7.0个月；P = .047）。在多变量分析中，GNAS突变状态独立预测了更差的OS（风险比，1.25 [95% CI，1.01至1.56];调整后P = .04）。

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.

在评估的癌症中，GNAS-mut肿瘤表现出保守的分子和临床表型。其特征是粘液性肿瘤状态、腹膜转移增加、对一线全身治疗反应不佳以及较差的生存期。