Institute for Genomics and Evolutionary Medicine, Sudhir Kumar, SERC 602A, 1925 N. 12th Street, Philadelphia, PA, 19122, USA.
Department of Biology, Temple University, Philadelphia, PA, 19122, USA.
BMC Cancer. 2018 Jan 18;18(1):85. doi: 10.1186/s12885-017-3977-y.
A unified analysis of DNA sequences from hundreds of tumors concluded that the driver mutations primarily occur in the earliest stages of cancer formation, with relatively few driver mutation events detected in the late-arising subclones. However, emerging evidence from the sequencing of multiple tumors and tumor regions per individual suggests that late-arising subclones with additional driver mutations are underestimated in single-sample analyses.
To test whether driver mutations generally map to early tumor development, we examined multi-regional tumor sequencing data from 101 individuals reported in 11 published studies. Following previous studies, we annotated mutations as early-arising when all tumors/regions had those mutations (ubiquitous). We then inferred the fraction of mutations occurring early and compared it with late-arising mutations that were found in only single tumors/regions.
While a large fraction of driver mutations in tumors occurred relatively early in cancers, later driver mutations occurred at least as frequently as the early drivers in a substantial number of patients. This result was robust to many different approaches to annotate driver mutations. The relative frequency of early and late driver mutations varied among patients of the same cancer type and in different cancer types. We found that previous reports of the preponderance of early driver mutations were primarily informed by analysis of single tumor variant allele profiles, with which it is challenging to clearly distinguish between early and late drivers.
The origin and preponderance of new driver mutations are not limited to early stages of tumor evolution, with different tumors and regions showing distinct driver mutations and, consequently, distinct characteristics. Therefore, tumors with extensive intratumor heterogeneity appear to have many newly acquired drivers.
对数百个肿瘤的 DNA 序列进行的统一分析得出结论，驱动突变主要发生在癌症形成的早期阶段，在晚期出现的亚克隆中检测到的驱动突变事件相对较少。然而，从对个体的多个肿瘤和肿瘤区域进行测序中获得的新证据表明，在单样本分析中，具有额外驱动突变的晚期出现的亚克隆被低估了。
为了测试驱动突变是否通常映射到肿瘤的早期发展，我们检查了 11 项已发表研究中报告的 101 名个体的多区域肿瘤测序数据。按照先前的研究，当所有肿瘤/区域都具有这些突变（普遍存在）时，我们将突变注释为早期出现。然后，我们推断出早期发生的突变比例，并将其与仅在单个肿瘤/区域中发现的晚期出现的突变进行比较。
尽管肿瘤中的大量驱动突变发生在癌症的早期，但在相当多的患者中，晚期驱动突变的发生频率至少与早期驱动突变一样高。这一结果在许多不同的注释驱动突变的方法中都是稳健的。早期和晚期驱动突变的相对频率在同一癌症类型的患者和不同癌症类型的患者中有所不同。我们发现，先前关于早期驱动突变优势的报告主要是基于对单个肿瘤变异等位基因谱的分析，用这种方法很难清楚地区分早期和晚期驱动突变。
新驱动突变的起源和优势不仅限于肿瘤进化的早期阶段，不同的肿瘤和区域显示出不同的驱动突变，因此具有不同的特征。因此，具有广泛肿瘤内异质性的肿瘤似乎有许多新获得的驱动突变。
