Revealing tumor heterogeneity of breast cancer by utilizing the linkage between somatic and germline mutations.
Revealing tumor heterogeneity of breast cancer by utilizing the linkage between somatic and germline mutations.
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利用体细胞和生殖细胞突变之间的联系揭示乳腺癌的肿瘤异质性。
DOI：
10.1093/bib/bby084
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发表时间：
2019-11-27
影响因子：
9.5
通讯作者：
Au KF
中科院分区：
文献类型：
--
作者：
Zou M;Jin R;Au KF
肿瘤内异质性与癌症进展和治疗耐药性相关，例如乳腺癌。虽然现有的研究肿瘤异质性的方法仅分析变异等位基因频率（VAF），但变异的基因型也为推断亚克隆提供了信息，可以通过长读长或双端读长来检测。我们开发了GenoClone，创新性地将VAF与变异体的基因型结合起来，因此在推断亚克隆数量、估计亚克隆比例以及鉴定亚克隆体细胞单核苷酸变异体组成方面表现出优越的性能。当 GenoClone 应用于 389 个 TCGA 乳腺癌样本时，它揭示了广泛的肿瘤内异质性。我们进一步发现一些体细胞突变与肿瘤进化的晚期相关，包括癌基因PIK3CA和肿瘤抑制基因TP53的突变。此外，从167个样本中鉴定出的52个亚克隆具有高度相似的体细胞突变，这些亚克隆被聚类成大小为24、14和14的三组。这有助于了解某些亚群人群中乳腺癌的发展情况以及人群水平的药物开发。此外，GenoClone 还鉴定了同一样品的不同等份中的肿瘤异质性。 GenoClone 的实施可在 http://www.healthcare.uiowa.edu/labs/au/GenoClone/ 上找到。
The intra-tumor heterogeneity is associated with cancer progression and therapeutic resistance, such as in breast cancer. While the existing methods for studying tumor heterogeneity only analyze variant allele frequency (VAF), the genotype of variant is also informative for inferring subclones, which can be detected by long reads or paired-end reads. We developed GenoClone to integrate VAF with the genotype of variant innovatively, so it showed superior performance of inferring the number of subclones, estimating the fractions of subclones and identifying somatic single-nucleotide variants composition of subclones. When GenoClone was applied to 389 TCGA breast cancer samples, it revealed extensive intra-tumor heterogeneity. We further found that a few somatic mutations were relevant to the late stage of tumor evolution, including the ones at the oncogene PIK3CA and the tumor suppress gene TP53. Moreover, 52 subclones that were identified from 167 samples shared high similarity of somatic mutations, which were clustered into three groups with the sizes of 24, 14 and 14. It is helpful for understanding the development of breast cancer in certain subgroups of people and the drug development for population level. Furthermore, GenoClone also identified the tumor heterogeneity in different aliquots of the same samples. The implementation of GenoClone is available at http://www.healthcare.uiowa.edu/labs/au/GenoClone/.
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影响因子：
64.8
作者：
Greaves, Mel;Maley, Carlo C.
通讯作者：
Maley, Carlo C.
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
单细胞基因组学生物信息学的当前挑战。
影响因子：
4.7
作者：
Ning L;Liu G;Li G;Hou Y;Tong Y;He J
通讯作者：
He J
影响因子：
3.6
作者：
Bachman, KE;Argani, P;Park, BH
通讯作者：
Park, BH
影响因子：
64.5
作者：
Nik-Zainal S;Van Loo P;Wedge DC;Alexandrov LB;Greenman CD;Lau KW;Raine K;Jones D;Marshall J;Ramakrishna M;Shlien A;Cooke SL;Hinton J;Menzies A;Stebbings LA;Leroy C;Jia M;Rance R;Mudie LJ;Gamble SJ;Stephens PJ;McLaren S;Tarpey PS;Papaemmanuil E;Davies HR;Varela I;McBride DJ;Bignell GR;Leung K;Butler AP;Teague JW;Martin S;Jönsson G;Mariani O;Boyault S;Miron P;Fatima A;Langerød A;Aparicio SA;Tutt A;Sieuwerts AM;Borg Å;Thomas G;Salomon AV;Richardson AL;Børresen-Dale AL;Futreal PA;Stratton MR;Campbell PJ;Breast Cancer Working Group of the International Cancer Genome Consortium
通讯作者：
Breast Cancer Working Group of the International Cancer Genome Consortium