PDF(Pubmed)
Abstract：
NRAS wildtype melanoma accounts for approximately 80% of melanomas. Previous studies have shown that NRAS wildtype melanoma had higher response rates and better prognoses than NRAS-mutant patients following immunotherapy, while as major actors in tumor cells and tumor microenvironment (TME), the association between NOTCH family genes and response to immunotherapy in NRAS wildtype melanoma remains indistinct.
We aim to explore whether NOTCH family gene variation is associated with genomic factors in immune checkpoint inhibitor (ICI) response in NRAS wildtype melanoma and with clinical results in these patients.
This research used genomic data of 265 NRAS wildtype ICI-pretreatment samples from five ICI-treated melanoma cohorts to analyze the relationship between NOTCH family gene mutation and the efficacy of ICI therapy.
NRAS wildtype melanomas with NOTCH4-Mut were identified to be associated with prolonged overall survival (OS) in both the discovery (HR: 0.30, 95% CI: 0.11-0.83, P = 0.01) and validation cohorts(HR: 0.21, 95% CI: 0.07-0.68, P = 0.003). Moreover, NOTCH4-Mut melanoma had a superior clinical response in the discovery cohort (ORR, 40.0% vs 13.11%, P = 0.057) and validation cohort (ORR, 68.75% vs 30.07%, P = 0.004). Further exploration found that NOTCH4-Mut tumors had higher tumor mutation burden (TMB) and tumor neoantigen burden (TNB) (P <0.05). NOTCH4-Mut tumors had a significantly increased mutation in the DNA damage response (DDR) pathway. Gene set enrichment analysis revealed NOTCH4-Mut tumor enhanced anti-tumor immunity.
NOTCH4 mutation may promote tumor immunity and serve as a biomarker to predict good immune response in NRAS wildtype melanoma and guide immunotherapeutic responsiveness.
We aim to explore whether NOTCH family gene variation is associated with genomic factors in immune checkpoint inhibitor (ICI) response in NRAS wildtype melanoma and with clinical results in these patients.
This research used genomic data of 265 NRAS wildtype ICI-pretreatment samples from five ICI-treated melanoma cohorts to analyze the relationship between NOTCH family gene mutation and the efficacy of ICI therapy.
NRAS wildtype melanomas with NOTCH4-Mut were identified to be associated with prolonged overall survival (OS) in both the discovery (HR: 0.30, 95% CI: 0.11-0.83, P = 0.01) and validation cohorts(HR: 0.21, 95% CI: 0.07-0.68, P = 0.003). Moreover, NOTCH4-Mut melanoma had a superior clinical response in the discovery cohort (ORR, 40.0% vs 13.11%, P = 0.057) and validation cohort (ORR, 68.75% vs 30.07%, P = 0.004). Further exploration found that NOTCH4-Mut tumors had higher tumor mutation burden (TMB) and tumor neoantigen burden (TNB) (P <0.05). NOTCH4-Mut tumors had a significantly increased mutation in the DNA damage response (DDR) pathway. Gene set enrichment analysis revealed NOTCH4-Mut tumor enhanced anti-tumor immunity.
NOTCH4 mutation may promote tumor immunity and serve as a biomarker to predict good immune response in NRAS wildtype melanoma and guide immunotherapeutic responsiveness.
摘要：
NRAS野生型黑素瘤占黑素瘤的约80%。以前的研究表明，NRAS野生型黑色素瘤在免疫治疗后比NRAS突变患者有更高的反应率和更好的预后。作为肿瘤细胞和肿瘤微环境(TME)的主要参与者，在NRAS野生型黑色素瘤中,NOTCH家族基因与免疫治疗应答之间的关联仍不明确.
我们的目的是探索NOTCH家族基因变异是否与NRAS野生型黑色素瘤中免疫检查点抑制剂（ICI）反应中的基因组因子相关，以及这些患者的临床结果。
这项研究使用来自五个ICI治疗的黑色素瘤队列的265个NRAS野生型ICI预处理样本的基因组数据来分析NOTCH家族基因突变与ICI治疗疗效之间的关系。
在发现组（HR：0.30，95％CI：0.11-0.83，P=0.01）和验证组（HR：0.21，95％CI：0.07-0.68，P=0.003）中，NRAS野生型黑色素瘤与延长的总生存期（OS）相关。此外，NOTCH4-Mut黑色素瘤在发现队列中具有优异的临床反应（ORR，40.0%vs13.11%，P=0.057)和验证队列(ORR，68.75%对30.07%，P=0.004)。进一步探索发现NOTCH4-Mut肿瘤具有较高的肿瘤突变负荷(TMB)和肿瘤新抗原负荷(TNB)(P<0.05)。NOTCH4-Mut肿瘤在DNA损伤应答(DDR)途径中具有显著增加的突变。基因集富集分析显示NOTCH4-Mut肿瘤增强了抗肿瘤免疫力。
NOTCH4突变可促进肿瘤免疫，并作为生物标志物预测NRAS野生型黑色素瘤的良好免疫应答和指导免疫治疗应答。
我们的目的是探索NOTCH家族基因变异是否与NRAS野生型黑色素瘤中免疫检查点抑制剂（ICI）反应中的基因组因子相关，以及这些患者的临床结果。
这项研究使用来自五个ICI治疗的黑色素瘤队列的265个NRAS野生型ICI预处理样本的基因组数据来分析NOTCH家族基因突变与ICI治疗疗效之间的关系。
在发现组（HR：0.30，95％CI：0.11-0.83，P=0.01）和验证组（HR：0.21，95％CI：0.07-0.68，P=0.003）中，NRAS野生型黑色素瘤与延长的总生存期（OS）相关。此外，NOTCH4-Mut黑色素瘤在发现队列中具有优异的临床反应（ORR，40.0%vs13.11%，P=0.057)和验证队列(ORR，68.75%对30.07%，P=0.004)。进一步探索发现NOTCH4-Mut肿瘤具有较高的肿瘤突变负荷(TMB)和肿瘤新抗原负荷(TNB)(P<0.05)。NOTCH4-Mut肿瘤在DNA损伤应答(DDR)途径中具有显著增加的突变。基因集富集分析显示NOTCH4-Mut肿瘤增强了抗肿瘤免疫力。
NOTCH4突变可促进肿瘤免疫，并作为生物标志物预测NRAS野生型黑色素瘤的良好免疫应答和指导免疫治疗应答。
