Intra-tumour genetic heterogeneity and poor chemoradiotherapy response in cervical cancer.
Intra-tumour genetic heterogeneity and poor chemoradiotherapy response in cervical cancer.
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DOI：
10.1038/sj.bjc.6605971
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发表时间：
2011-01-18
影响因子：
8.8
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中科院分区：
文献类型：
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肿瘤内遗传异质性在白血病和实体瘤中都有报道，并与CML和AML的耐药性发展有关。遗传异质性在实体瘤药物应答中的作用尚不清楚。为了研究肿瘤内遗传异质性和晚期宫颈癌的放化疗反应，我们分析了10例接受CTCR-CE 01临床研究治疗的病例。从治疗前、治疗第2周和第5周的子宫颈的四个象限采集用于分子分析的核心活检。对活检组织的细胞构成进行评分，并使用Agilent 180 k人类全基因组CGH阵列进行分析。我们比较了来自10名患者的69个核心的基因组图谱，以测试治疗第0周、第2周和第5周的遗传异质性和治疗效果。3例患者在治疗前有两个或更多不同的遗传亚群。每个肿瘤的亚群对放化疗的反应不同。在两种情况下，选择了一个单一的内在耐药亚群，持续在5周的放化疗后可检测的水平。系统发育分析重建了这些肿瘤发生过程中基因组重排的顺序，并证实了3q的增加和11 q的丢失是宫颈癌进展的早期事件。放化疗的选择效应导致晚期宫颈癌遗传亚群的动态变化，这可能解释疾病的持续性和随后的复发。因此，晚期宫颈癌的显著遗传异质性可能预示预后不良。
Intra-tumour genetic heterogeneity has been reported in both leukaemias and solid tumours and is implicated in the development of drug resistance in CML and AML. The role of genetic heterogeneity in drug response in solid tumours is unknown. To investigate intra-tumour genetic heterogeneity and chemoradiation response in advanced cervical cancer, we analysed 10 cases treated on the CTCR-CE01 clinical study. Core biopsies for molecular profiling were taken from four quadrants of the cervix pre-treatment, and weeks 2 and 5 of treatment. Biopsies were scored for cellularity and profiled using Agilent 180k human whole genome CGH arrays. We compared genomic profiles from 69 cores from 10 patients to test for genetic heterogeneity and treatment effects at weeks 0, 2 and 5 of treatment. Three patients had two or more distinct genetic subpopulations pre-treatment. Subpopulations within each tumour showed differential responses to chemoradiotherapy. In two cases, there was selection for a single intrinsically resistant subpopulation that persisted at detectable levels after 5 weeks of chemoradiotherapy. Phylogenetic analysis reconstructed the order in which genomic rearrangements occurred in the carcinogenesis of these tumours and confirmed gain of 3q and loss of 11q as early events in cervical cancer progression. Selection effects from chemoradiotherapy cause dynamic changes in genetic subpopulations in advanced cervical cancers, which may explain disease persistence and subsequent relapse. Significant genetic heterogeneity in advanced cervical cancers may therefore be predictive of poor outcome.
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影响因子：
8
作者：
Cooke, S. L.;Ng, C. K. Y.;Melnyk, N.;Garcia, M. J.;Hardcastle, T.;Temple, J.;Langdon, S.;Huntsman, D.;Brenton, J. D.
通讯作者：
Brenton, J. D.
影响因子：
4.5
作者：
Lando M;Holden M;Bergersen LC;Svendsrud DH;Stokke T;Sundfør K;Glad IK;Kristensen GB;Lyng H
通讯作者：
Lyng H
影响因子：
7
作者：
Navin, Nicholas;Krasnitz, Alexander;Wigler, Michael
通讯作者：
Wigler, Michael
影响因子：
2.1
作者：
Olshen, AB;Venkatraman, ES;Wigler, M
通讯作者：
Wigler, M
影响因子：
8.8
作者：
通讯作者：
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