NF1-mutated melanoma tumors harbor distinct clinical and biological characteristics.
NF1-mutated melanoma tumors harbor distinct clinical and biological characteristics.
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DOI：
10.1002/1878-0261.12050
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发表时间：
2017-04
影响因子：
6.6
通讯作者：
Jönsson G
中科院分区：
文献类型：
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作者：
Cirenajwis H;Lauss M;Ekedahl H;Törngren T;Kvist A;Saal LH;Olsson H;Staaf J;Carneiro A;Ingvar C;Harbst K;Hayward NK;Jönsson G
一般而言，黑色素瘤可被认为是一种紫外线驱动的疾病，具有侵袭性转移过程和高突变负荷，只有少数肿瘤（肢端、粘膜和葡萄膜黑色素瘤）不是由阳光诱导的，并且具有较低的突变负荷。黑色素瘤中最常见的活化途径是丝裂原活化蛋白激酶（MAPK）途径。然而，突变分层的预后意义尚不清楚，需要进一步研究。在这里，我们通过计算机模拟将来自162个黑色素瘤的突变数据与来自三项已发表研究的突变数据进行了靶向深度测序。根据BRAF、RAS、NF 1突变或三重野生型状态对870例患者的肿瘤进行分组，并与肿瘤和患者特征相关。我们发现NF 1突变亚型具有更高的突变负荷和最强的UV突变特征。搜索共发生的突变基因揭示了RAS病基因PTPN 11和RASA 2，以及另一个含有RAS结构域的基因RASSF 2，在调整突变负荷后富集在NF 1亚型中。我们发现，NF 1突变型肿瘤的比例较大，来自男性，诊断时年龄较大。重要的是，我们发现黑色素瘤的死亡风险增加（疾病特异性生存期，DSS; HR，1.9; 95% CI，1.21-3.10; P = 0.046）和较差的总生存期（OS; HR，2.0; 95% CI，1.28-2.98; P = 0.01），在校正年龄、性别和病变类型后仍具有显著性（分别为DSS P = 0.03，OS P = 0.06）。黑色素瘤基因组亚型显示不同的生物学和临床特征。在NF 1亚型中观察到的不良结果突出了需要改进该组的表征。
In general, melanoma can be considered as a UV‐driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen‐activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies. Tumors from 870 patients were grouped according to BRAF,RAS,NF1 mutation or triple‐wild‐type status and correlated with tumor and patient characteristics. We found that the NF1‐mutated subtype had a higher mutational burden and strongest UV mutation signature. Searching for co‐occurring mutated genes revealed the RASopathy genes PTPN11 and RASA2, as well as another RAS domain‐containing gene RASSF2 enriched in the NF1 subtype after adjustment for mutational burden. We found that a larger proportion of the NF1‐mutant tumors were from males and with older age at diagnosis. Importantly, we found an increased risk of death from melanoma (disease‐specific survival, DSS; HR, 1.9; 95% CI, 1.21–3.10; P = 0.046) and poor overall survival (OS; HR, 2.0; 95% CI, 1.28–2.98; P = 0.01) in the NF1 subtype, which remained significant after adjustment for age, gender, and lesion type (DSS P = 0.03, OS P = 0.06, respectively). Melanoma genomic subtypes display different biological and clinical characteristics. The poor outcome observed in the NF1 subtype highlights the need for improved characterization of this group.
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影响因子：
30.8
作者：
Krauthammer M;Kong Y;Bacchiocchi A;Evans P;Pornputtapong N;Wu C;McCusker JP;Ma S;Cheng E;Straub R;Serin M;Bosenberg M;Ariyan S;Narayan D;Sznol M;Kluger HM;Mane S;Schlessinger J;Lifton RP;Halaban R
通讯作者：
Halaban R
影响因子：
30.8
作者：
Krauthammer, Michael;Kong, Yong;Ha, Byung Hak;Evans, Perry;Bacchiocchi, Antonella;McCusker, James P.;Cheng, Elaine;Davis, Matthew J.;Goh, Gerald;Choi, Murim;Ariyan, Stephan;Narayan, Deepak;Dutton-Regester, Ken;Capatana, Ana;Holman, Edna C.;Bosenberg, Marcus;Sznol, Mario;Kluger, Harriet M.;Brash, Douglas E.;Stern, David F.;Materin, Miguel A.;Lo, Roger S.;Mane, Shrikant;Ma, Shuangge;Kidd, Kenneth K.;Hayward, Nicholas K.;Lifton, Richard P.;Schlessinger, Joseph;Boggon, Titus J.;Halaban, Ruth
通讯作者：
Halaban, Ruth
影响因子：
8
作者：
Joensson, G.;Dahl, C.;Borg, A.
通讯作者：
Borg, A.
影响因子：
11.2
作者：
Nissan MH;Pratilas CA;Jones AM;Ramirez R;Won H;Liu C;Tiwari S;Kong L;Hanrahan AJ;Yao Z;Merghoub T;Ribas A;Chapman PB;Yaeger R;Taylor BS;Schultz N;Berger MF;Rosen N;Solit DB
通讯作者：
Solit DB
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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