De Novo Mutation in Non-Tyrosine Kinase Domain of ROS1 as a Potential Predictor of Immune Checkpoint Inhibitors in Melanoma.
De Novo Mutation in Non-Tyrosine Kinase Domain of ROS1 as a Potential Predictor of Immune Checkpoint Inhibitors in Melanoma.
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ROS1非酪氨酸激酶结构域的从头突变作为黑色素瘤免疫检查点抑制剂的潜在预测因子
DOI：
10.3389/fonc.2021.666145
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发表时间：
2021
影响因子：
4.7
通讯作者：
Bai X
中科院分区：
文献类型：
--
作者：
Ma SC;Zhu HB;Wang J;Zhang YP;Guo XJ;Long LL;Guo ZQ;Wu DH;Dong ZY;Bai X
目的尽管c-ros癌基因1（ROS 1）重排的肿瘤，特别是非小细胞肺癌（NSCLC）的靶向治疗取得了成功，但ROS 1基因的新突变的临床意义尚不清楚。我们试图阐明ROS 1突变对黑色素瘤免疫检查点抑制剂（ICI）治疗的预测作用。方法癌症基因组图谱（n = 10967）]和纪念斯隆凯特琳癌症中心[MSK（n = 10，945）]数据集以及接受ICI的两个黑色素瘤临床队列[CA 209 -038（n = 73）和MEL-IPI（n = 110）]，以探索患病率、预后影响，以及ROS 1突变在黑色素瘤中的免疫预测作用。总生存期（OS）被定义为主要结局。结果ROS 1基因突变的比例以黑色素瘤最高（约20%），占ROS 1基因突变病例的95%。值得注意的是，在MSK黑色素瘤人群中，ROS 1突变导致ICI的OS比野生型对应物更长[风险比（HR）0.47，95%置信区间（CI）0.30-0.74]，两个外部黑色素瘤队列（CA 209 -038：HR 0.42，95%CI 0.20-0.89; MEL-IPI：HR 0.55，95%CI 0.34-0.91），不影响患者预后。在ROS 1突变患者中观察到肿瘤突变负荷升高和DNA损伤修复富集，为ICI治疗的有利反应提供了解释。确切地说，ROS 1非蛋白酪氨酸激酶（PTK）结构域的突变，而不是PTK突变是负责免疫治疗特异性反应的ROS 1突变的黑色素瘤患者。结论ROS 1基因突变，尤其是非PTK基因突变，是黑色素瘤ICI治疗的潜在预测因子，与ROS 1基因重排在NSCLC靶向治疗中的作用不同。
Purpose Despite the success of targeted therapy in c-ros oncogene 1 (ROS1)-rearranged cancers, especially non-small cell lung cancer (NSCLC), the clinical significance of ROS1 de novo mutation has not yet been understood. We sought to elucidate the predictive effect of ROS1 mutation for immune checkpoint inhibitor (ICI) therapy in melanoma. Methods The Cancer Genome Atlas [TCGA (n = 10967)] and Memorial Sloan Kettering Cancer Center [MSK (n = 10,945)] datasets, as well as two clinical cohorts of melanoma received ICI [CA209-038 (n = 73) and MEL-IPI (n = 110)], were included to explore the prevalence, prognostic effect, and immunotherapeutic predictive effect of ROS1 mutation in melanoma. Overall survival (OS) was defined as the primary outcome. Results Overall, melanoma accounted for the highest proportion of ROS1 mutation (~20%) which made up the majority (~95%) of the ROS1-alterated cases. Remarkably, ROS1 mutation yielded longer OS from ICI than the wild-type counterpart in the MSK melanoma population [hazard ratio (HR) 0.47, 95% confidence interval (CI) 0.30–0.74], and two external melanoma cohorts (CA209-038: HR 0.42, 95% CI 0.20–0.89; MEL-IPI: HR 0.55, 95% CI 0.34–0.91), without affecting the prognosis of patients. Elevated tumor mutational burden and enrichment of DNA damage repair was observed in ROS1 mutated patients, providing an explanation for the favorable responses to ICI therapy. Precisely, ROS1 mutation in non-protein tyrosine kinase (PTK) domain but not PTK mutation was responsible for the immunotherapy-specific responses of the ROS1 mutated patients in melanoma. Conclusions Collectively, ROS1 mutation, specifically the non-PTK mutation, is a potential predictor of ICI therapy in melanoma, which is distinct from the well-established role of ROS1 rearrangement for targeted therapy in NSCLC.
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影响因子：
64.5
作者：
Litchfield K;Reading JL;Puttick C;Thakkar K;Abbosh C;Bentham R;Watkins TBK;Rosenthal R;Biswas D;Rowan A;Lim E;Al Bakir M;Turati V;Guerra-Assunção JA;Conde L;Furness AJS;Saini SK;Hadrup SR;Herrero J;Lee SH;Van Loo P;Enver T;Larkin J;Hellmann MD;Turajlic S;Quezada SA;McGranahan N;Swanton C
通讯作者：
Swanton C
原发性和转移性病灶谱的综合评估指导非小细胞肺癌的抗 PD-L1 治疗：两项随机研究的结果
影响因子：
7.2
作者：
Ma SC;Tang XR;Long LL;Bai X;Zhou JG;Duan ZJ;Wang J;Fu QJ;Zhu HB;Guo XJ;Zhang YP;Guo ZQ;Wu DH;Dong ZY
通讯作者：
Dong ZY
影响因子：
28.2
作者：
Skoulidis F;Goldberg ME;Greenawalt DM;Hellmann MD;Awad MM;Gainor JF;Schrock AB;Hartmaier RJ;Trabucco SE;Gay L;Ali SM;Elvin JA;Singal G;Ross JS;Fabrizio D;Szabo PM;Chang H;Sasson A;Srinivasan S;Kirov S;Szustakowski J;Vitazka P;Edwards R;Bufill JA;Sharma N;Ou SI;Peled N;Spigel DR;Rizvi H;Aguilar EJ;Carter BW;Erasmus J;Halpenny DF;Plodkowski AJ;Long NM;Nishino M;Denning WL;Galan-Cobo A;Hamdi H;Hirz T;Tong P;Wang J;Rodriguez-Canales J;Villalobos PA;Parra ER;Kalhor N;Sholl LM;Sauter JL;Jungbluth AA;Mino-Kenudson M;Azimi R;Elamin YY;Zhang J;Leonardi GC;Jiang F;Wong KK;Lee JJ;Papadimitrakopoulou VA;Wistuba II;Miller VA;Frampton GM;Wolchok JD;Shaw AT;Jänne PA;Stephens PJ;Rudin CM;Geese WJ;Albacker LA;Heymach JV
通讯作者：
Heymach JV
影响因子：
11.5
作者：
Dong, Zhong-Yi;Zhong, Wen-Zhao;Wu, Yi-Long
通讯作者：
Wu, Yi-Long
DOI：
10.1126/science.aad0095
发表时间：
2015-10-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Van Allen EM;Miao D;Schilling B;Shukla SA;Blank C;Zimmer L;Sucker A;Hillen U;Foppen MHG;Goldinger SM;Utikal J;Hassel JC;Weide B;Kaehler KC;Loquai C;Mohr P;Gutzmer R;Dummer R;Gabriel S;Wu CJ;Schadendorf D;Garraway LA
通讯作者：
Garraway LA