Subclonal diversification of primary breast cancer revealed by multiregion sequencing.
Subclonal diversification of primary breast cancer revealed by multiregion sequencing.
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DOI：
10.1038/nm.3886
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发表时间：
2015-07
期刊：
影响因子：
82.9
通讯作者：
Campbell PJ
中科院分区：
文献类型：
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作者：
Yates LR;Gerstung M;Knappskog S;Desmedt C;Gundem G;Van Loo P;Aas T;Alexandrov LB;Larsimont D;Davies H;Li Y;Ju YS;Ramakrishna M;Haugland HK;Lilleng PK;Nik-Zainal S;McLaren S;Butler A;Martin S;Glodzik D;Menzies A;Raine K;Hinton J;Jones D;Mudie LJ;Jiang B;Vincent D;Greene-Colozzi A;Adnet PY;Fatima A;Maetens M;Ignatiadis M;Stratton MR;Sotiriou C;Richardson AL;Lønning PE;Wedge DC;Campbell PJ
对癌症基因组进行测序可以使得能够针对驱动特定患者的肿瘤的潜在生物学异常来定制治疗剂。然而，基于测序的策略严重依赖于肿瘤的代表性取样。为了了解原发性乳腺癌的亚克隆结构，我们对来自50名患者的肿瘤（总共303个）的多个样本进行了全基因组和靶向测序。亚克隆多样化的程度各不相同的情况下，遵循空间格局。没有严格的时间顺序是明显的，点突变和重排影响最常见的乳腺癌基因，包括PIK 3CA，TP 53，PTEN，BRCA 2和MYC，发生在一些肿瘤的早期和晚期。在13/50的癌症中，潜在的靶向突变是亚克隆的。疾病进展的标志，如抵抗化疗和获得侵袭或转移的潜力，出现在可检测的亚克隆的前期病变。这些发现强调了在原发性乳腺癌临床试验中包括亚克隆结构和肿瘤演变分析的重要性。
Sequencing cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient’s tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole genome and targeted sequencing to multiple samples from each of 50 patients’ tumors (total 303). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and late in others. In 13/50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resisting chemotherapy and acquiring invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer.