Gene dosage, expression, and ontology analysis identifies driver genes in the carcinogenesis and chemoradioresistance of cervical cancer.
Gene dosage, expression, and ontology analysis identifies driver genes in the carcinogenesis and chemoradioresistance of cervical cancer.
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DOI：
10.1371/journal.pgen.1000719
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发表时间：
2009-11
期刊：
影响因子：
4.5
通讯作者：
Lyng H
中科院分区：
文献类型：
--
作者：
Lando M;Holden M;Bergersen LC;Svendsrud DH;Stokke T;Sundfør K;Glad IK;Kristensen GB;Lyng H
对基因剂量、表达和本体（GO）数据进行综合分析，以发现宫颈癌发生和放化疗耐药性中的驱动基因。基因芯片技术产生的102个局部晚期宫颈癌的基因剂量和表达谱。还用Illumina表达方法分析了这些患者中的52例，以确认基因表达结果。41名患者的独立队列用于验证与临床结果相关的基因表达。统计分析确定了29例复发性增益和损失，3例损失（3p，13q，21q）与放化疗后的不良结局相关。从基因剂量谱评估的肿瘤内异质性对于这些改变是低的，表明它们在许多其他改变之前已经出现，并且可能是癌发生的早期事件。整合基因表达和GO数据的改变确定了受改变调节的基因，并揭示了受影响基因中显着过度表达的五个生物过程：细胞凋亡，代谢，大分子定位，翻译和转录。3p（RYBP，GBE 1）和13q（FAM 48A，MED 4）上的四个基因在基因剂量和表达水平上与结果相关，并且在独立队列中得到令人满意的验证。这些综合分析产生了24个遗传事件的57个候选驱动因子，包括负责化学放射抗性的新基因座。对遗传事件、驱动因子和生物过程之间的联系的进一步作图表明，每个单独的事件通过多个基因的协调控制来刺激致癌作用中的特定过程。本研究结果可能为早期和晚期宫颈癌提供新的治疗机会。基因获得和丢失，即基因剂量的变化，是人类癌症的常见异常。发现这些缺陷并了解其生物学意义可以改善治疗机会。本文报道了宫颈癌基因剂量改变的大规模筛查，并对基因的表达和功能进行了更广泛的探讨。我们集中在最常见的基因剂量改变和与放化疗后生存相关的改变，因为这些缺陷可能对疾病的发展至关重要。最值得注意的发现是发现了一系列生物学过程，这些过程是已知的癌症标志，与特定基因的获得和丢失有关。此外，新的基因座与放化疗耐药性独立于现有的临床标志物被发现，并描绘了相关的基因。我们的研究结果表明，基因剂量的改变在宫颈癌的发生和放化疗耐药性中起着致病作用，并确定了该疾病的候选生物标志物。
Integrative analysis of gene dosage, expression, and ontology (GO) data was performed to discover driver genes in the carcinogenesis and chemoradioresistance of cervical cancers. Gene dosage and expression profiles of 102 locally advanced cervical cancers were generated by microarray techniques. Fifty-two of these patients were also analyzed with the Illumina expression method to confirm the gene expression results. An independent cohort of 41 patients was used for validation of gene expressions associated with clinical outcome. Statistical analysis identified 29 recurrent gains and losses and 3 losses (on 3p, 13q, 21q) associated with poor outcome after chemoradiotherapy. The intratumor heterogeneity, assessed from the gene dosage profiles, was low for these alterations, showing that they had emerged prior to many other alterations and probably were early events in carcinogenesis. Integration of the alterations with gene expression and GO data identified genes that were regulated by the alterations and revealed five biological processes that were significantly overrepresented among the affected genes: apoptosis, metabolism, macromolecule localization, translation, and transcription. Four genes on 3p (RYBP, GBE1) and 13q (FAM48A, MED4) correlated with outcome at both the gene dosage and expression level and were satisfactorily validated in the independent cohort. These integrated analyses yielded 57 candidate drivers of 24 genetic events, including novel loci responsible for chemoradioresistance. Further mapping of the connections among genetic events, drivers, and biological processes suggested that each individual event stimulates specific processes in carcinogenesis through the coordinated control of multiple genes. The present results may provide novel therapeutic opportunities of both early and advanced stage cervical cancers. Genetic gains and losses, i.e. changes in gene dosages, are common abnormalities of human cancers. Discovering these defects and understanding the biological meaning can lead to improved therapeutic opportunities. This paper reports a large scale screening of gene dosage alterations in cervical cancer and gives a broader exploration of the expression and function of genes with gains or losses. We have focused on the most frequent gene dosage alterations and the alterations associated with survival after chemoradiotherapy, since these defects are likely to be of major importance for developing disease. The most notable finding was the discovery of a set of biological processes that are known hallmarks of cancer and were associated with gains and losses of specific genes. Moreover, novel loci associated with chemoradioresistance independent of existing clinical markers were found, and the genes involved were depicted. Our results indicated that gene dosage alterations play a causative role in the carcinogenesis and chemoradioresistance of cervical cancer and pinpointed candidate biomarkers of the disease.
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影响因子：
3
作者：
Beisvag V;Jünge FK;Bergum H;Jølsum L;Lydersen S;Günther CC;Ramampiaro H;Langaas M;Sandvik AK;Laegreid A
通讯作者：
Laegreid A
DOI：
10.1073/pnas.0710052104
发表时间：
2007-12-11
影响因子：
11.1
作者：
Beroukhim, Rameen;Getz, Gad;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
45.3
作者：
Fyles, A;Milosevic, M;Hill, RP
通讯作者：
Hill, RP
影响因子：
4.6
作者：
Birch, Ashley H.;Quinn, Michael C. J.;Tonin, Patricia N.
通讯作者：
Tonin, Patricia N.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y