Kataegis Expression Signature in Breast Cancer Is Associated with Late Onset, Better Prognosis, and Higher HER2 Levels

D’Antonio, Matteo; Tamayo, Pablo; Mesirov, Jill P.; Frazer, Kelly A.

doi:10.1016/j.celrep.2016.06.026

Cited by 40 publications

(66 citation statements)

References 46 publications

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“…Multiple studies have reported hypermutated genomic regions in several cancer types (Nik-Zainal et al 2012;Alexandrov et al 2013a;D'Antonio et al 2016). These genomic regions referred to as "Kataegis," presumed to be the result of aberrant activity of apolipoprotein B mRNA editing enzyme, catalytic polypeptidelike (APOBEC) cytidine deaminases, tend to be enriched in C > T and C > G substitutions occurring within TpCpN trinucleotide contexts (Lada et al 2012 Table S1; D' Antonio et al 2016).…”

Section: Visualizationmentioning

confidence: 99%

Maftools: efficient and comprehensive analysis of somatic variants in cancer

et al. 2018

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Numerous large-scale genomic studies of matched tumor-normal samples have established the somatic landscapes of most cancer types. However, the downstream analysis of data from somatic mutations entails a number of computational and statistical approaches, requiring usage of independent software and numerous tools. Here, we describe an R Bioconductor package, Maftools, which offers a multitude of analysis and visualization modules that are commonly used in cancer genomic studies, including driver gene identification, pathway, signature, enrichment, and association analyses. Maftools only requires somatic variants in Mutation Annotation Format (MAF) and is independent of larger alignment files. With the implementation of well-established statistical and computational methods, Maftools facilitates data-driven research and comparative analysis to discover novel results from publicly available data sets. In the present study, using three of the well-annotated cohorts from The Cancer Genome Atlas (TCGA), we describe the application of Maftools to reproduce known results. More importantly, we show that Maftools can also be used to uncover novel findings through integrative analysis.

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Section: Visualizationmentioning

confidence: 99%

Maftools: efficient and comprehensive analysis of somatic variants in cancer

et al. 2018

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“…Kataegis status, identified through an expression signature, has recently been shown to be associated with late onset, better prognosis and higher HER2 levels in breast cancer 45 . To further investigate the prognostic role of kataegis, a Cox regression was fit for overall survival between kataegic and kataegis-free patients, adjusting for age and sex for each cancer type (Supplementary Figure 18, Supplementary Table 11).…”

Section: Kataegismentioning

confidence: 99%

The Origins and Consequences of Localized and Global Somatic Hypermutation

Yousif

et al. 2018

Preprint

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Cancer is a disease of the genome, but the dramatic inter-patient variability in mutation number is poorly understood. Tumours of the same type can differ by orders of magnitude in their mutation rate. To understand potential drivers and consequences of the underlying heterogeneity in mutation rate across tumours, we evaluated both local and global measures of mutation density: both single-stranded and double-stranded DNA breaks in 2,460 tumours of 38 cancer types. We find that SCNAs in thousands of genes are associated with elevated rates of point-mutations, while similarly point-mutation patterns in dozens of genes are associated with specific patterns of DNA double-stranded breaks. These candidate drivers of mutation density are enriched for known cancer drivers, and preferentially occur early in tumour evolution, appearing clonally in all cells of a tumour. To supplement this understanding of global mutation density, we developed and validated a tool called SeqKat to identify localized "rainstorms" of point-mutations (kataegis). We show that rates of kataegis differ by four orders of magnitude across tumour types, with malignant lymphomas showing the highest. Tumours with TP53 mutations were 2.6-times more likely to harbour a kataegic event than those without, and 239 SCNAs were associated with elevated rates of kataegis, including loss of the tumour-suppressor CDKN2A. We identify novel subtypes of kataegic events not associated with aberrant APOBEC activity, and find that these are localized to specific cellular regions, enriched for MYC-target genes. Kataegic events were associated with patient survival in some, but not all tumour types, highlighting a combination of global and tumour-type specific effects. Taken together, we reveal a landscape of genes driving localized and tumour-specific hyper-mutation, and reveal novel mutational processes at play in specific tumour types.

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“…Chromoplexy is another catastrophic event characterized by chains of translocations resulting from punctuated bursts of interchromosomal SVs and CNAs (Baca et al 2013). Additional mutational processes include localized hypermutation involving small-scale alterations (sSNVs and indels) as in the case of kataegis, which is attributable to cytosine deam-ination catalyzed by AID/APOBEC proteins (Lada et al 2012;D'Antonio et al 2016). Impaired DNA mismatch repair (MMR) leading to microsatellite instability can also increase the rate of sSNVs and indels.…”

Section: Big Bang Tumor Growth and Clonal Evolutionmentioning

confidence: 99%

Big Bang Tumor Growth and Clonal Evolution

Sun

Curtis

2017

Cold Spring Harb Perspect Med

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The advent and application of next-generation sequencing (NGS) technologies to tumor genomes has reinvigorated efforts to understand clonal evolution. Although tumor progression has traditionally been viewed as a gradual stepwise process, recent studies suggest that evolutionary rates in tumors can be variable with periods of punctuated mutational bursts and relative stasis. For example, Big Bang dynamics have been reported, wherein after transformation, growth occurs in the absence of stringent selection, consistent with effectively neutral evolution. Although first noted in colorectal tumors, effective neutrality may be relatively common. Additionally, punctuated evolution resulting from mutational bursts and cataclysmic genomic alterations have been described. In this review, we contrast these findings with the conventional gradualist view of clonal evolution and describe potential clinical and therapeutic implications of different evolutionary modes and tempos.

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Kataegis Expression Signature in Breast Cancer Is Associated with Late Onset, Better Prognosis, and Higher HER2 Levels

Cited by 40 publications

References 46 publications

Maftools: efficient and comprehensive analysis of somatic variants in cancer

Maftools: efficient and comprehensive analysis of somatic variants in cancer

The Origins and Consequences of Localized and Global Somatic Hypermutation

Big Bang Tumor Growth and Clonal Evolution

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