Epidemiology of Doublet/Multiplet Mutations in Lung Cancers: Evidence that a Subset Arises by Chronocoordinate Events

Zhenbin Chen,Amanda Ewart Toland,Jinong Feng,Steve S. Sommer,Carolyn H. Buzin

doi:10.1371/journal.pone.0003714

Abstract

BackgroundEvidence strongly suggests that spontaneous doublet mutations in normal mouse tissues generally arise from chronocoordinate events. These chronocoordinate mutations sometimes reflect “mutation showers”, which are multiple chronocoordinate mutations spanning many kilobases. However, little is known about mutagenesis of doublet and multiplet mutations (domuplets) in human cancer. Lung cancer accounts for about 25% of all cancer deaths. Herein, we analyze the epidemiology of domuplets in the EGFR and TP53 genes in lung cancer. The EGFR gene is an oncogene in which doublets are generally driver plus driver mutations, while the TP53 gene is a tumor suppressor gene with a more typical situation in which doublets derive from a driver and passenger mutation.Methodology/Principal Findings EGFR mutations identified by sequencing were collected from 66 published papers and our updated EGFR mutation database (www.egfr.org). TP53 mutations were collected from IARC version 12 (www-p53.iarc.fr). For EGFR and TP53 doublets, no clearly significant differences in race, ethnicity, gender and smoking status were observed. Doublets in the EGFR and TP53 genes in human lung cancer are elevated about eight- and three-fold, respectively, relative to spontaneous doublets in mouse (6% and 2.3% versus 0.7%).Conclusions/SignificanceAlthough no one characteristic is definitive, the aggregate properties of doublet and multiplet mutations in lung cancer are consistent with a subset derived from chronocoordinate events in the EGFR gene: i) the eight frameshift doublets (present in 0.5% of all patients with EGFR mutations) are clustered and produce a net in-frame change; ii) about 32% of doublets are very closely spaced (≤30 nt); and iii) multiplets contain two or more closely spaced mutations. TP53 mutations in lung cancer are very closely spaced (≤30 nt) in 33% of doublets, and multiplets generally contain two or more very closely spaced mutations. Work in model systems is necessary to confirm the significance of chronocoordinate events in lung and other cancers.

Highlights

Cancer is a heterogeneous, multi-step, complex genetic disease resulting from accumulated mutations
Mutation showers were found after analyses of intragenic doublet mutations revealed that they were clustered and chronocoordinate [9]
The results for the TP53 gene in lung cancer are similar with one exception

Summary

Introduction

Multi-step, complex genetic disease resulting from accumulated mutations. Cancers generally were considered to arise by the accumulation of an estimated 5–7 causative mutations [1,2]. The accumulation of mutations in certain cancers may reflect a mutator phenotype with globally random mutations [4,5,6]. Sequential selection offers another explanation [7,8]. Evidence strongly suggests that spontaneous doublet mutations in normal mouse tissues generally arise from chronocoordinate events. These chronocoordinate mutations sometimes reflect ‘‘mutation showers’’, which are multiple chronocoordinate mutations spanning many kilobases. The EGFR gene is an oncogene in which doublets are generally driver plus driver mutations, while the TP53 gene is a tumor suppressor gene with a more typical situation in which doublets derive from a driver and passenger mutation

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Conclusion