Mutational Processes Molding the Genomes of 21 Breast Cancers

By S. Nik-Zainal, Ludmil B. Alexandrov, David C. Wedge, P. V. Loo, Christopher D. Greenman, K. Raine, David Jones, Jonathan Hinton, J. Marshall, L. Stebbings and 43 more. Cell, 2012

1,882 citations recorded by the source corpus.

Summary All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed “kataegis,” was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed. PaperClip

Subfields: Cancer Research, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/ff33abac07ac7c248ba0b83892db385a6bdcda28

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Citations in the corpus

Comprehensive Molecular Characterization of Urothelial Bladder Carcinoma (2014, neutral): “Graham Cancer Center at Christiana Care - Christine Czerwinski(17), Lori Huelsenbeck-Dill(17), Mary Iacocca(17), Nicholas Petrelli(17), Brenda Rabeno(17), Pat Swanson(17), International Genomics Consortium - Troy Shelton(18), Erin Curley(18), Johanna Gardner(18), David Mallery(18), Robert Penny(18),”
SomaticSignatures: inferring mutational signatures from single-nucleotide variants (2014, methodology): “SomaticSignatures is a flexible and efficient tool for inferring characteristics of mutational mechanisms, based on the methodology developed by Nik-Zainal et al. (2012). It integrates with Bioconductor tools for processing and annotating genomic variants.”
Pan-cancer analysis of whole genomes (2020, neutral): “6a), as previously described 50,51 .”
Landscape of somatic mutations in 560 breast cancer whole genome sequences (2016, positive): “Most cancers with these mutations showed many base substitutions of mutational signatures 2 and 13 that have been attributed to activity of APOBEC DNA-editing proteins that target the TCN sequence motif.”
Landscape of somatic mutations and clonal evolution in mantle cell lymphoma (2013, background): “Interestingly, WHSC1-mutated MCL showed a highly significant overexpression of the gene signature up-regulated in PCM with the t(4;14) translocation overexpressing WHSC1 (17).”
HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational-signatures (2017, background): “Previously, base-substitution signature 3 was shown to distinguish germline BRCA1 / BRCA2 -null cancers from sporadic cancers in a small subset of breast cancers 29,30 and was subsequently extended to pancreatic 32,33 , ovarian 34 and stomach 35 cancers.”
The repertoire of mutational signatures in human cancer (2018, neutral): “Two, which are found in multiple types of cancer, were similar to SBS2 and SBS13 (which have been attributed to APOBEC enzyme activity) and represent foci of katae-gis 3,32,46 .”
A Living Biobank of Breast Cancer Organoids Captures Disease Heterogeneity. (2018, neutral): “Driver as well as passenger mutations arise through diverse mutational processes resulting in distinct mutational signatures, at least 12 of which are found in BC (Alexandrov et al., 2013; Nik-Zainal et al., 2012, 2016).”