Differential pathogenesis of lung adenocarcinoma subtypes involving sequence mutations, copy number, chromosomal instability, and methylation.
Differential pathogenesis of lung adenocarcinoma subtypes involving sequence mutations, copy number, chromosomal instability, and methylation.
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DOI：
10.1371/journal.pone.0036530
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Hayes DN
中科院分区：
文献类型：
--
作者：
Wilkerson MD;Yin X;Walter V;Zhao N;Cabanski CR;Hayward MC;Miller CR;Socinski MA;Parsons AM;Thorne LB;Haithcock BE;Veeramachaneni NK;Funkhouser WK;Randell SH;Bernard PS;Perou CM;Hayes DN
肺腺癌（LAD）在患者中具有极端的遗传变异，目前尚不清楚，限制了治疗开发和研究的进展。LAD内在分子亚型是自然发生的基因表达模式的有效分层，包含不同的功能途径和患者结果。患者可能发生了不同的突变和改变，导致不同的亚型。我们假设LAD分子亚型在患者肿瘤中与不同的突变和改变共同发生。使用统计方法和已发表的队列（n = 504）检测LAD分子亚型（细支气管、Magnoid和Squamoid）与基因突变和DNA拷贝数改变的相关性。一个新的验证队列（n = 116）进行了分析和询问，以确认亚型改变的关联。基因突变率（EGFR、KRAS、STK11、TP53）、染色体不稳定性、区域拷贝数和全基因组DNA甲基化在分子亚型肿瘤中存在显著差异。二级分析通过综合改变和患者预后来比较亚型。肿瘤具有与亚型相关的同一基因的综合改变，例如Magnoid的STK11突变、缺失和低表达，细支气管样细胞的EGFR突变、扩增和过表达。这些亚型还与具有并发突变基因的肿瘤相关，例如KRAS-STK11与Magnoid。患者总生存期、顺铂加长春瑞滨治疗反应和预测吉非替尼敏感性在不同亚型间存在显著差异。肺腺癌固有的分子亚型与截然不同的基因组改变和患者治疗反应同时发生。这些结果促进了对肺腺癌病因的理解，并为未来治疗反应的评估指定了患者亚组。
Lung adenocarcinoma (LAD) has extreme genetic variation among patients, which is currently not well understood, limiting progress in therapy development and research. LAD intrinsic molecular subtypes are a validated stratification of naturally-occurring gene expression patterns and encompass different functional pathways and patient outcomes. Patients may have incurred different mutations and alterations that led to the different subtypes. We hypothesized that the LAD molecular subtypes co-occur with distinct mutations and alterations in patient tumors. The LAD molecular subtypes (Bronchioid, Magnoid, and Squamoid) were tested for association with gene mutations and DNA copy number alterations using statistical methods and published cohorts (n = 504). A novel validation (n = 116) cohort was assayed and interrogated to confirm subtype-alteration associations. Gene mutation rates (EGFR, KRAS, STK11, TP53), chromosomal instability, regional copy number, and genomewide DNA methylation were significantly different among tumors of the molecular subtypes. Secondary analyses compared subtypes by integrated alterations and patient outcomes. Tumors having integrated alterations in the same gene associated with the subtypes, e.g. mutation, deletion and underexpression of STK11 with Magnoid, and mutation, amplification, and overexpression of EGFR with Bronchioid. The subtypes also associated with tumors having concurrent mutant genes, such as KRAS-STK11 with Magnoid. Patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes. The lung adenocarcinoma intrinsic molecular subtypes co-occur with grossly distinct genomic alterations and with patient therapy response. These results advance the understanding of lung adenocarcinoma etiology and nominate patient subgroups for future evaluation of treatment response.
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影响因子：
50.3
作者：
Carretero J;Shimamura T;Rikova K;Jackson AL;Wilkerson MD;Borgman CL;Buttarazzi MS;Sanofsky BA;McNamara KL;Brandstetter KA;Walton ZE;Gu TL;Silva JC;Crosby K;Shapiro GI;Maira SM;Ji H;Castrillon DH;Kim CF;García-Echeverría C;Bardeesy N;Sharpless NE;Hayes ND;Kim WY;Engelman JA;Wong KK
通讯作者：
Wong KK
影响因子：
8
作者：
Chitale, D.;Gong, Y.;Taylor, B. S.;Broderick, S.;Brennan, C.;Somwar, R.;Golas, B.;Wang, L.;Motoi, N.;Szoke, J.;Reinersman, J. M.;Major, J.;Sander, C.;Seshan, V. E.;Zakowski, M. F.;Rusch, V.;Pao, W.;Gerald, W.;Ladanyi, M.
通讯作者：
Ladanyi, M.
影响因子：
28.2
作者：
Kim ES;Herbst RS;Wistuba II;Lee JJ;Blumenschein GR Jr;Tsao A;Stewart DJ;Hicks ME;Erasmus J Jr;Gupta S;Alden CM;Liu S;Tang X;Khuri FR;Tran HT;Johnson BE;Heymach JV;Mao L;Fossella F;Kies MS;Papadimitrakopoulou V;Davis SE;Lippman SM;Hong WK
通讯作者：
Hong WK
影响因子：
82.9
作者：
Beer, DG;Kardia, SLR;Hanash, S
通讯作者：
Hanash, S
影响因子：
3.7
作者：
Bryant CM;Albertus DL;Kim S;Chen G;Brambilla C;Guedj M;Arima C;Travis WD;Yatabe Y;Takahashi T;Brambilla E;Beer DG
通讯作者：
Beer DG