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Background  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. 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/Significance  Although 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.

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