Somatic evolutionary timings of driver mutations

Karen Gomez,Brianna S Spell,Sayaka Miura,Louise A Huuki,Sudhir Kumar,Jeffrey P Townsend

doi:10.1186/s12885-017-3977-y

Karen Gomez, Brianna S Spell + Show 4 more

Open Access

https://doi.org/10.1186/s12885-017-3977-y

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Abstract

BackgroundA 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.MethodsTo 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.ResultsWhile 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.ConclusionsThe 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.

Highlights

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
When cancer cell fraction (CCF) were estimated for driver mutations found in tumors from the Cancer Genome Atlas (TCGA), most driver mutations were present at high CCF, meaning most driver mutations were found in the majority of cells in a
Our analysis focused on single nucleotide variants (SNVs) and insertions and deletions that arose somatically in the tumors of individual patients

Summary

Introduction

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. Knowledge of the relative timing of driver mutations is essential for understanding cancer progression as a whole and for optimizing treatment for individual patients [1,2,3,4] For this reason, much attention has been paid to identifying the distribution and Mutations found in most cells of a tumor can be detected by estimating the fraction of cancer cells harboring a particular variant, or cancer cell fraction (CCF) [8]. Much attention has been paid to identifying the distribution and Mutations found in most cells of a tumor can be detected by estimating the fraction of cancer cells harboring a particular variant, or cancer cell fraction (CCF) [8] This approach has been utilized to analyze the extensive data available through the Cancer Genome Atlas (TCGA), a comprehensive database that contains genomic changes in hundreds of thousands of tumors (single tumor genome sequencing results) from 33 types of cancers [9]. When CCFs were estimated for driver mutations found in tumors from TCGA, most driver mutations were present at high CCF, meaning most driver mutations were found in the majority of cells in a

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