Landscape of genomic alterations in cervical carcinomas.
Landscape of genomic alterations in cervical carcinomas.
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DOI：
10.1038/nature12881
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发表时间：
2014-02-20
期刊：
影响因子：
64.8
通讯作者：
Meyerson M
中科院分区：
文献类型：
--
作者：
Ojesina AI;Lichtenstein L;Freeman SS;Pedamallu CS;Imaz-Rosshandler I;Pugh TJ;Cherniack AD;Ambrogio L;Cibulskis K;Bertelsen B;Romero-Cordoba S;Treviño V;Vazquez-Santillan K;Guadarrama AS;Wright AA;Rosenberg MW;Duke F;Kaplan B;Wang R;Nickerson E;Walline HM;Lawrence MS;Stewart C;Carter SL;McKenna A;Rodriguez-Sanchez IP;Espinosa-Castilla M;Woie K;Bjorge L;Wik E;Halle MK;Hoivik EA;Krakstad C;Gabiño NB;Gómez-Macías GS;Valdez-Chapa LD;Garza-Rodríguez ML;Maytorena G;Vazquez J;Rodea C;Cravioto A;Cortes ML;Greulich H;Crum CP;Neuberg DS;Hidalgo-Miranda A;Escareno CR;Akslen LA;Carey TE;Vintermyr OK;Gabriel SB;Barrera-Saldaña HA;Melendez-Zajgla J;Getz G;Salvesen HB;Meyerson M
子宫颈癌占全球女性癌症相关死亡的10-15%。高危型人乳头状瘤病毒（HPV）感染在宫颈癌中的病因学作用已得到充分证实。先前的研究已经涉及PIK 3CA、PTEN、TP 53、STK 11和KRAS中的体细胞突变以及宫颈癌发病机制中的几个拷贝数改变。在这里，我们报告了115例宫颈癌-正常配对样本的全外显子组测序分析，79例病例的转录组测序和14例肿瘤-正常配对的全基因组测序。79例原发性鳞状细胞癌中的新体细胞突变包括MAPK 1基因中的复发性E322 K置换（8%），HLA-B基因中的失活突变（9%），以及EP 300（16%），FBXW 7（15%），NFE 2L 2（4%），TP 53（5%）和ERBB 2（6%）突变。我们还在24例腺癌中观察到体细胞ELF 3（13%）和CBFB（8%）突变。鳞状细胞癌在Tp*C二核苷酸背景下的体细胞突变频率高于腺癌。与在相同位点没有病毒整合的肿瘤中相同基因的表达相比，在HPV整合位点的基因表达水平在具有HPV整合的肿瘤中显著更高。这些数据表明，宫颈癌中的几个复发性基因组改变，提出了新的战略，以打击这种疾病。
Cervical cancer is responsible for 10–15% of cancer-related deaths in women worldwide. The etiological role of infection with high-risk human papilloma viruses (HPV) in cervical carcinomas is well established. Previous studies have implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as several copy number alterations in the pathogenesis of cervical carcinomas. Here, we report whole exome sequencing analysis of 115 cervical carcinoma-normal paired samples, transcriptome sequencing of 79 cases and whole genome sequencing of 14 tumor-normal pairs. Novel somatic mutations in 79 primary squamous cell carcinomas include recurrent E322K substitutions in the MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in EP300 (16%), FBXW7 (15%), NFE2L2 (4%) TP53 (5%) and ERBB2 (6%). We also observed somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. Squamous cell carcinomas had higher frequencies of somatic mutations in the Tp*C dinucleotide context than adenocarcinomas. Gene expression levels at HPV integration sites were significantly higher in tumors with HPV integration compared with expression of the same genes in tumors without viral integration at the same site. These data demonstrate several recurrent genomic alterations in cervical carcinomas that suggest novel strategies to combat this disease.
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Le Gallo, Matthieu;O'Hara, Andrea J.;Rudd, Meghan L.;Urick, Mary Ellen;Hansen, Nancy F.;O'Neil, Nigel J.;Price, Jessica C.;Zhang, Suiyuan;England, Bryant M.;Godwin, Andrew K.;Sgroi, Dennis C.;Hieter, Philip;Mullikin, James C.;Merino, Maria J.;Bell, Daphne W.
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Bell, Daphne W.