Cancer gene profiling in non-small cell lung cancers reveals activating mutations in JAK2 and JAK3 with therapeutic implications.
Cancer gene profiling in non-small cell lung cancers reveals activating mutations in JAK2 and JAK3 with therapeutic implications.
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DOI：
10.1186/s13073-017-0478-1
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发表时间：
2017-10-30
期刊：
影响因子：
12.3
通讯作者：
Ye F
中科院分区：
文献类型：
--
作者：
Li SD;Ma M;Li H;Waluszko A;Sidorenko T;Schadt EE;Zhang DY;Chen R;Ye F
下一代癌症基因测序（NGS）被广泛应用于个性化癌症治疗和识别新的致癌突变。我们使用Ion AmpliSeq™Cancer Hotspot panel v2检测对932例非小细胞肺癌（nsclc）临床病例进行了靶向NGS。65%的有靶向治疗选择的病例中发现了可操作的突变，包括26%的国家综合癌症网络（NCCN）指导基因突变的患者。最值得注意的是，我们在1%（9/932）的非小细胞肺癌中发现JAK2 p.V617F体细胞突变，这是骨髓增殖性肿瘤的标志。对癌细胞系药物基因组学数据的分析表明，在一组非小细胞肺癌细胞系中，高水平的JAK2表达与对选择性JAK2抑制剂的敏感性增加相关。TCGA基因组数据的进一步分析显示，在非小细胞肺癌临床样本中，由于遗传改变而导致的JAK2的增加或减少与PD-L1表达的显著升高或降低相关，这表明JAK2 p.V617F突变的激活可能赋予对JAK抑制剂和抗pd1免疫治疗的敏感性。鉴于最近发现JAK3突变上调PD-L1表达，我们还在6.7%（62/932）可能受益于抗pd1治疗的患者中检测到JAK3种系激活突变。综上所述，本研究证明了靶向NGS在非小细胞肺癌中的临床应用，并通过对癌症遗传学、基因组学和药物基因组学数据的综合分析，确定了JAK2和JAK3的激活突变，并推断了其临床意义。JAK2和JAK3突变作为靶向治疗JAK激酶或抗pd1免疫治疗的应答标记物的潜力值得进一步研究。本文的在线版本（doi:10.1186/ s130773 -017-0478-1）包含补充材料，可供授权用户使用。
Next-generation sequencing (NGS) of cancer gene panels are widely applied to enable personalized cancer therapy and to identify novel oncogenic mutations. We performed targeted NGS on 932 clinical cases of non-small-cell lung cancers (NSCLCs) using the Ion AmpliSeq™ Cancer Hotspot panel v2 assay. Actionable mutations were identified in 65% of the cases with available targeted therapeutic options, including 26% of the patients with mutations in National Comprehensive Cancer Network (NCCN) guideline genes. Most notably, we discovered JAK2 p.V617F somatic mutation, a hallmark of myeloproliferative neoplasms, in 1% (9/932) of the NSCLCs. Analysis of cancer cell line pharmacogenomic data showed that a high level of JAK2 expression in a panel of NSCLC cell lines is correlated with increased sensitivity to a selective JAK2 inhibitor. Further analysis of TCGA genomic data revealed JAK2 gain or loss due to genetic alterations in NSCLC clinical samples are associated with significantly elevated or reduced PD-L1 expression, suggesting that the activating JAK2 p.V617F mutation could confer sensitivity to both JAK inhibitors and anti-PD1 immunotherapy. We also detected JAK3 germline activating mutations in 6.7% (62/932) of the patients who may benefit from anti-PD1 treatment, in light of recent findings that JAK3 mutations upregulate PD-L1 expression. Taken together, this study demonstrated the clinical utility of targeted NGS with a focused hotspot cancer gene panel in NSCLCs and identified activating mutations in JAK2 and JAK3 with clinical implications inferred through integrative analysis of cancer genetic, genomic, and pharmacogenomic data. The potential of JAK2 and JAK3 mutations as response markers for the targeted therapy against JAK kinases or anti-PD1 immunotherapy warrants further investigation. The online version of this article (doi:10.1186/s13073-017-0478-1) contains supplementary material, which is available to authorized users.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
影响因子：
32.4
作者：
Chen E;Staudt LM;Green AR
通讯作者：
Green AR
影响因子：
51.1
作者：
Drilon, Alexander;Rekhtman, Natasha;Arcila, Maria;Wang, Lu;Ni, Andy;Albano, Melanie;Van Voorthuysen, Martine;Somwar, Romel;Smith, Roger S.;Montecalvo, Joseph;Plodkowski, Andrew;Ginsberg, Michelle S.;Riely, Gregory J.;Rudin, Charles M.;Ladanyi, Marc;Kris, Mark G.
通讯作者：
Kris, Mark G.
影响因子：
28.2
作者：
Drilon A;Wang L;Hasanovic A;Suehara Y;Lipson D;Stephens P;Ross J;Miller V;Ginsberg M;Zakowski MF;Kris MG;Ladanyi M;Rizvi N
通讯作者：
Rizvi N