Integrated genomic and molecular characterization of cervical cancer.
Integrated genomic and molecular characterization of cervical cancer.
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DOI：
10.1038/nature21386
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发表时间：
2017-03-16
期刊：
影响因子：
64.8
通讯作者：
Washington University in St Louis
中科院分区：
文献类型：
--
作者：
Cancer Genome Atlas Research Network;Albert Einstein College of Medicine;Analytical Biological Services;Barretos Cancer Hospital;Baylor College of Medicine;Beckman Research Institute of City of Hope;Buck Institute for Research on Aging;Canada's Michael Smith Genome Sciences Centre;Harvard Medical School;Helen F. Graham Cancer Center &Research Institute at Christiana Care Health Services;HudsonAlpha Institute for Biotechnology;ILSbio, LLC;Indiana University School of Medicine;Institute of Human Virology;Institute for Systems Biology;International Genomics Consortium;Leidos Biomedical;Massachusetts General Hospital;McDonnell Genome Institute at Washington University;Medical College of Wisconsin;Medical University of South Carolina;Memorial Sloan Kettering Cancer Center;Montefiore Medical Center;NantOmics;National Cancer Institute;National Hospital, Abuja, Nigeria;National Human Genome Research Institute;National Institute of Environmental Health Sciences;National Institute on Deafness &Other Communication Disorders;Ontario Tumour Bank, London Health Sciences Centre;Ontario Tumour Bank, Ontario Institute for Cancer Research;Ontario Tumour Bank, The Ottawa Hospital;Oregon Health &Science University;Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center;SRA International;St Joseph's Candler Health System;Eli &Edythe L. Broad Institute of Massachusetts Institute of Technology &Harvard University;Research Institute at Nationwide Children's Hospital;Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University;University of Bergen;University of Texas MD Anderson Cancer Center;University of Abuja Teaching Hospital;University of Alabama at Birmingham;University of California, Irvine;University of California Santa Cruz;University of Kansas Medical Center;University of Lausanne;University of New Mexico Health Sciences Center;University of North Carolina at Chapel Hill;University of Oklahoma Health Sciences Center;University of Pittsburgh;University of São Paulo, Ribeir ão Preto Medical School;University of Southern California;University of Washington;University of Wisconsin School of Medicine &Public Health;Van Andel Research Institute;Washington University in St Louis
宫颈癌仍然是世界范围内癌症相关死亡的主要原因之一。本文报道了228例原发性宫颈癌的广泛分子特征，这是迄今为止最大规模的宫颈癌综合基因组研究。我们观察到惊人的APOBEC突变模式，并确定SHKBP 1，ERBB 3，CASP 8，HLA-A和TGFBR 2作为宫颈癌中新的显著突变基因。我们还发现了免疫靶点CD 274/PD-L1和PDCD 1 LG 2/PD-L2以及与拉帕替尼应答相关的BCAR 4 lncRNA的新扩增。在所有HPV 18相关病例和76%的HPV 16相关病例中观察到HPV整合，并与结构畸变和靶基因表达增加相关。我们发现了一组独特的子宫颈样宫颈癌，主要由HPV阴性肿瘤组成，具有高频率的KRAS，ARID 1A和PTEN突变。178个样本的综合聚类确定了角蛋白-低鳞状、角蛋白-高鳞状和腺癌富集亚组。这些分子分析揭示了宫颈癌新的潜在治疗靶点。
Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Reported here is an extensive molecular characterization of 228 primary cervical cancers, the largest comprehensive genomic study of cervical cancer to date. We observed striking APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A, and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered novel amplifications in immune targets CD274/PD-L1 and PDCD1LG2/PD-L2, and the BCAR4 lncRNA that has been associated with response to lapatinib. HPV integration was observed in all HPV18-related cases and 76% of HPV16-related cases, and was associated with structural aberrations and increased target gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumors with high frequencies of KRAS, ARID1A, and PTEN mutations. Integrative clustering of 178 samples identified Keratin-low Squamous, Keratin-high Squamous, and Adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers.