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BMC Cancer. 2018 Jan 18;18(1):85. doi: 10.1186/s12885-017-3977-y.

Somatic evolutionary timings of driver mutations.

Author information

1
Institute for Genomics and Evolutionary Medicine, Sudhir Kumar, SERC 602A, 1925 N. 12th Street, Philadelphia, PA, 19122, USA.
2
Department of Biology, Temple University, Philadelphia, PA, 19122, USA.
3
Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, 06510, USA.
4
Department of Ecology and Evolutionary Biology, Yale University, New Haven, Connecticut, 06511, USA.
5
Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, 06511, USA.
6
Institute for Genomics and Evolutionary Medicine, Sudhir Kumar, SERC 602A, 1925 N. 12th Street, Philadelphia, PA, 19122, USA. s.kumar@temple.edu.
7
Department of Biology, Temple University, Philadelphia, PA, 19122, USA. s.kumar@temple.edu.
8
Center for Genomic Medicine and Research, King Abdulaziz University, Jeddah, Saudi Arabia. s.kumar@temple.edu.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

Driver mutation; Private mutation; Somatic mutation; Ubiquitous mutation

PMID:
29347918
PMCID:
PMC5774140
DOI:
10.1186/s12885-017-3977-y
[Indexed for MEDLINE]
Free PMC Article

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