Parsimonious Clone Tree Reconciliation in Cancer
Parsimonious Clone Tree Reconciliation in Cancer
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DOI：
10.4230/lipics.wabi.2021.9
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
P. Sashittal;Simone Zaccaria;M. El-Kebir
中科院分区：
文献类型：
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作者：
P. Sashittal;Simone Zaccaria;M. El-Kebir
每个肿瘤都是由异质克隆组成的，每个克隆对应于一个不同的细胞亚群，这些细胞亚群积累了不同类型的体细胞突变，从单核苷酸变异（snv）到拷贝数畸变（CNAs）。由于这种肿瘤内异质性的分析具有重要的临床应用，因此已经引入了几种计算方法来从DNA测序数据中识别克隆。然而，由于技术和方法的限制，目前的分析仅限于基于snv或CNAs识别肿瘤克隆，从而无法全面表征肿瘤的克隆组成。为了克服这些挑战，我们在考虑输入SNV和CNA比例的不确定性的同时，将SNV和CNA的克隆识别作为一个调和问题。因此，我们描述了这个问题的计算复杂性，并引入了一个混合整数线性规划公式来精确地求解它。在模拟数据中，我们表明可以可靠地识别肿瘤克隆，特别是当进一步考虑可以从输入snv和CNAs推断出的祖先关系时。在10例前列腺癌患者的49个肿瘤样本中，我们的和解方法提供了比以往研究更高分辨率的肿瘤进化视图。
Every tumor is composed of heterogeneous clones, each corresponding to a distinct subpopulation of cells that accumulated different types of somatic mutations, ranging from single-nucleotide variants (SNVs) to copy-number aberrations (CNAs). As the analysis of this intra-tumor heterogeneity has important clinical applications, several computational methods have been introduced to identify clones from DNA sequencing data. However, due to technological and methodological limitations, current analyses are restricted to identifying tumor clones only based on either SNVs or CNAs, preventing a comprehensive characterization of a tumor’s clonal composition. To overcome these challenges, we formulate the identification of clones in terms of both SNVs and CNAs as a reconciliation problem while accounting for uncertainty in the input SNV and CNA proportions. We thus characterize the computational complexity of this problem and we introduce a mixed integer linear programming formulation to solve it exactly. On simulated data, we show that tumor clones can be identified reliably, especially when further taking into account the ancestral relationships that can be inferred from the input SNVs and CNAs. On 49 tumor samples from 10 prostate cancer patients, our reconciliation approach provides a higher resolution view of tumor evolution than previous studies.