Integrative analysis of genome-wide loss of heterozygosity and monoallelic expression at nucleotide resolution reveals disrupted pathways in triple-negative breast cancer.
Integrative analysis of genome-wide loss of heterozygosity and monoallelic expression at nucleotide resolution reveals disrupted pathways in triple-negative breast cancer.
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核苷酸分辨率上杂合性丧失和单相表达的全基因组丧失的综合分析揭示了三阴性乳腺癌的途径中断。
DOI：
10.1101/gr.137570.112
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发表时间：
2012-10
期刊：
影响因子：
7
通讯作者：
Shah SP
中科院分区：
文献类型：
--
作者：
Ha G;Roth A;Lai D;Bashashati A;Ding J;Goya R;Giuliany R;Rosner J;Oloumi A;Shumansky K;Chin SF;Turashvili G;Hirst M;Caldas C;Marra MA;Aparicio S;Shah SP
杂合性缺失（洛）和拷贝数改变（CNA）在肿瘤的体细胞基因组中占有重要地位。因此，癌症基因组中的核型畸变已被广泛研究，以发现新的癌基因和肿瘤抑制基因。测序技术的进步使得能够在单碱基对分辨率下经济有效地检测肿瘤基因组和转录组突变事件;然而，在这种情况下预测洛缺失节段性区域的计算方法尚未完全探索。因此，尚未在癌症中进行与洛杂合性缺失相关的单等位基因表达模式的全转录组、核苷酸水平分辨率分析。我们开发了一种从配对的肿瘤/正常序列数据推断洛缺失的新方法，并将其应用于23个三阴性乳腺癌（TNBC）基因组的队列。在广泛的基准实验之后，我们描述了TNBC中洛的核苷酸分辨率景观，并使用RNA-seq衍生的等位基因特异性表达测量来评估洛对这些肿瘤的转录组的后续影响。我们发现，大多数三阴性乳腺癌转录组中的单等位基因表达可以通过洛缺失的基因组区域来解释，并建立了单等位基因表达的上限，这可以通过其他肿瘤特异性修饰（如表观遗传学或突变）来解释。与洛缺失相关的单等位基因表达揭示了洛缺失对TNBC细胞周期、同源重组和肌动蛋白-细胞骨架功能的影响。最后，我们展示了如何推断的洛可以用来解释等位基因频率的体细胞突变和假设的时间顺序的突变在这些肿瘤的进化史。
Loss of heterozygosity (LOH) and copy number alteration (CNA) feature prominently in the somatic genomic landscape of tumors. As such, karyotypic aberrations in cancer genomes have been studied extensively to discover novel oncogenes and tumor-suppressor genes. Advances in sequencing technology have enabled the cost-effective detection of tumor genome and transcriptome mutation events at single-base-pair resolution; however, computational methods for predicting segmental regions of LOH in this context are not yet fully explored. Consequently, whole transcriptome, nucleotide-level resolution analysis of monoallelic expression patterns associated with LOH has not yet been undertaken in cancer. We developed a novel approach for inference of LOH from paired tumor/normal sequence data and applied it to a cohort of 23 triple-negative breast cancer (TNBC) genomes. Following extensive benchmarking experiments, we describe the nucleotide-resolution landscape of LOH in TNBC and assess the consequent effect of LOH on the transcriptomes of these tumors using RNA-seq-derived measurements of allele-specific expression. We show that the majority of monoallelic expression in the transcriptomes of triple-negative breast cancer can be explained by genomic regions of LOH and establish an upper bound for monoallelic expression that may be explained by other tumor-specific modifications such as epigenetics or mutations. Monoallelically expressed genes associated with LOH reveal that cell cycle, homologous recombination and actin-cytoskeletal functions are putatively disrupted by LOH in TNBC. Finally, we show how inference of LOH can be used to interpret allele frequencies of somatic mutations and postulate on temporal ordering of mutations in the evolutionary history of these tumors.
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DOI：
10.1093/bioinformatics/btr670
发表时间：
2012-02-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Boeva V;Popova T;Bleakley K;Chiche P;Cappo J;Schleiermacher G;Janoueix-Lerosey I;Delattre O;Barillot E
通讯作者：
Barillot E
影响因子：
64.8
作者：
Navin N;Kendall J;Troge J;Andrews P;Rodgers L;McIndoo J;Cook K;Stepansky A;Levy D;Esposito D;Muthuswamy L;Krasnitz A;McCombie WR;Hicks J;Wigler M
通讯作者：
Wigler M
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
影响因子：
64.5
作者：
Hou, Yong;Song, Luting;Wang, Jun
通讯作者：
Wang, Jun
影响因子：
46.9
作者：
Narva, Elisa;Autio, Reija;Lahesmaa, Riitta
通讯作者：
Lahesmaa, Riitta