Tandem-base mutations occur in mouse liver and adipose tissue preferentially as G:C to T:A transversions and accumulate with age

Doublet mutations in cancer are not well studied. We find that allelic somatic doublet mutations are present at high frequency in the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) domain in lung cancers. When doublets from the literature are added, a total of 96 doublets are available for analysis. The frequency of doublets overall is 6%, which is sevenfold greater than that observed in normal tissue in mouse. All characterized doublets are allelic, and silent mutations occur rarely. About half of all doublets contain one or two of 12 distinct missense mutations at five amino acids: E709, G719, S768, T790 and L861. The mutations at these five amino acids are seldom reported as singlets. Moreover, when the common L858 target is included, more than one-third of EGFR doublets are one of five specific missense pairs: G719/E709, G719/S768, G719/L861, L858/E709 and L858/T790. Structure suggests function: The data imply that most EGFR doublets are NOT consistent with a 'driver and passenger' mutation mechanism. EGFR doublets are highly skewed relative to singlets, consistent with functional selection of two individually suboptimal mutations that, in combination, have enhanced oncogenic potential.

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“…Tandem-base mutation (TBM) A mutation that results in base changes at adjacent nucleotides (Buettner et al, 1999;Hill et al, 2003).…”

Section: Terminology and Abbreviationsmentioning

confidence: 99%

EGFR somatic doublets in lung cancer are frequent and generally arise from a pair of driver mutations uncommonly seen as singlet mutations: one-third of doublets occur at five pairs of amino acids

et al. 2008

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“…Microindels were assembled from a collection of 6,016 Big Blue s lacI independent mutations that had been collected since 1994 [Nishino et al, 1995aBuettner et al, 1996aBuettner et al, ,b, 1997Buettner et al, , 1999Buettner et al, , 2000Moore et al, 1999;Kunishige et al, 2001;Hill et al, 2003Hill et al, , 2004aHill et al, ,b, 2005. All of the mice were housed in isolated airfiltered cages within a barrier facility according to a protocol approved by our institutional animal care and use committee.…”

Section: Sommer Laboratory Database Of Big Blue S Laci Mutationsmentioning

confidence: 99%

“…This assay has been used extensively since it was first introduced over 15 years ago. An extensive database of spontaneous mutations has been assembled in our laboratory, and 11 categories of mutation types have been studied extensively [Nishino et al, 1995aBuettner et al, 1996aBuettner et al, ,b, 1997Buettner et al, , 1999Buettner et al, , 2000Moore et al, 1999;Kunishige et al, 2001;Hill et al, 2003Hill et al, , 2004aHill et al, ,b, 2005. Our database of spontaneous mutations in somatic tissues permits detailed analyses of the features of microindels and pure microinsertions and pure microdeletions.…”

Section: Introductionmentioning

confidence: 99%

Preferential occurrence of 1-2 microindels

et al. 2005

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Communicated by Bruce GottliebMicroindels are unique, infrequent mutations that result in inserted and deleted sequences of different sizes (between one and 50 nucleotides) at the same nucleotide position. Little is known about the mutational mechanisms that are responsible for these mutations. From our database of 6,016 independent somatic mutational events in the lacI gene in Big Blue s mice, we assembled the 30 microindels (0.5%) for analysis. Microindels with one nucleotide inserted and two nucleotides deleted (1-2 microindels) accounted for seven (23%) of the microindels observed, with the remaining microindels distributed among 21 other combinations of insertion and deletion sizes. A preferential occurrence of 1-2 microindels (20%) was also observed in human germline transmitted mutations in the Human Gene Mutation Database (HGMD). An examination of the sequence flanking the mouse 1-2 microindels did not reveal obvious site specificity or associated secondary structure. A detailed examination of 1-2 microindels did not reveal the features typical of pure microinsertion and microdeletion events, but rather suggested a unique mutational mechanism. The 1 bp insertion in 1-2 microinsertions, and pure 1 bp insertions show distinct features. The mechanism for 1-2 microindels is not obviously a simple combination of pure microinsertion and microdeletion events. The dramatic enhancement of 1-2 microindels requires explanation. We speculate that certain error-prone polymerases may be responsible for the preferential occurrence of 1-2 microindels in both somatic tissues and germ cells. It is estimated that a human adult carries roughly 400 billion somatic 1-2 microindels with the potential to predispose to cancer. Hum Mutat 27(1), [55][56][57][58][59][60][61] 2006.

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“…In fact, the cloned plaque nature of the Big Blue assay allows detection of the presence of mutation showers, whereas these would be hard to detect in most other systems. The assay has been in use for Ͼ15 years, and an extensive database of 5,303 mutations exists for analysis of spontaneous mutations (5,6,16,18,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32).…”

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confidence: 99%

Evidence for mutation showers

Wang

González

Scaringe

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Mutants in the Big Blue transgenic mouse system show spontaneous clustered multiple mutations with unexpectedly high frequency, consistent with chronocoordinate events. We tested the prediction that the multiple mutations seen within the lacI mutation target sometimes occur in the context of chronocoordinate multiple mutations spanning multiple kilobases (mutation showers). Additional sequencing of mutants was performed in regions immediately flanking the lacI region (total of 10.7 kb). Nineteen additional mutations were found outside the lacI region (''ectomutations'') from 10 mutants containing two or more lacI mutations, whereas only one ectomutation was found in 130 mutants with a single mutation (P < 0.0001). The mutation showers had an average of approximately one mutation per 3 kb. Four mutants showed closely spaced double mutations in the new sequence, and analysis of the spacing between these mutations revealed significant clustering (P ‫؍‬ 0.0098). To determine the extent of the mutation showers, regions (8.5 kb total) remote from the lacI region (Ϸ16 -17 kb away) were sequenced. Only two additional ectomutations were found in these remote regions, consistent with mutation showers that generally do not extend more than Ϸ30 kb. We conclude that mutation showers exist and that they constitute at least 0.2% and possibly 1% or more of mutational events observed in this system. The existence of mutation showers has implications for oncogenesis and evolution, raising the possibilities of ''cancer in an instant'' and ''introns as sponges to reduce the deleterious impact of mutation showers.'' Big Blue mouse ͉ lacI transgene ͉ multiple mutations ͉ mutation clusters ͉ transient hypermutability

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Tandem-base mutations occur in mouse liver and adipose tissue preferentially as G:C to T:A transversions and accumulate with age

Cited by 29 publications

References 23 publications

EGFR somatic doublets in lung cancer are frequent and generally arise from a pair of driver mutations uncommonly seen as singlet mutations: one-third of doublets occur at five pairs of amino acids

EGFR somatic doublets in lung cancer are frequent and generally arise from a pair of driver mutations uncommonly seen as singlet mutations: one-third of doublets occur at five pairs of amino acids

Preferential occurrence of 1-2 microindels

Evidence for mutation showers

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