| 1. |
- Nik-Zainal, Serena, et al.
(author)
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Mutational Processes Molding the Genomes of 21 Breast Cancers
- 2012
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In: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 149:5, s. 979-993
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Journal article (peer-reviewed)abstract
- 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.
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| 2. |
- Nik-Zainal, Serena, et al.
(author)
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The Life History of 21 Breast Cancers
- 2012
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In: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 149:5
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Journal article (peer-reviewed)abstract
- Cancer evolves dynamically as clonal expansions supersede one another driven by shifting selective pressures, mutational processes, and disrupted cancer genes. These processes mark the genome, such that a cancer's life history is encrypted in the somatic mutations present. We developed algorithms to decipher this narrative and applied them to 21 breast cancers. Mutational processes evolve across a cancer's lifespan, with many emerging late but contributing extensive genetic variation. Subclonal diversification is prominent, and most mutations are found in just a fraction of tumor cells. Every tumor has a dominant subclonal lineage, representing more than 50% of tumor cells. Minimal expansion of these subclones occurs until many hundreds to thousands of mutations have accumulated, implying the existence of long-lived, quiescent cell lineages capable of substantial proliferation upon acquisition of enabling genomic changes. Expansion of the dominant subclone to an appreciable mass may therefore represent the final rate-limiting step in a breast cancer's development, triggering diagnosis.
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| 30. |
- Edlund, Karolina, et al.
(author)
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Data-driven unbiased curation of the TP53 tumor suppressor gene mutation database and validation by ultradeep sequencing of human tumors
- 2012
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:24, s. 9551-9556
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Journal article (peer-reviewed)abstract
- Cancer mutation databases are expected to play central roles in personalized medicine by providing targets for drug development and biomarkers to tailor treatments to each patient. The accuracy of reported mutations is a critical issue that is commonly overlooked, which leads to mutation databases that include a sizable number of spurious mutations, either sequencing errors or passenger mutations. Here we report an analysis of the latest version of the TP53 mutation database, including 34,453 mutations. By using several data-driven methods on multiple independent quality criteria, we obtained a quality score for each report contributing to the database. This score can now be used to filter for high-confidence mutations and reports within the database. Sequencing the entire TP53 gene from various types of cancer using next-generation sequencing with ultradeep coverage validated our approach for curation. In summary, 9.7% of all collected studies, mostly comprising numerous tumors with multiple infrequent TP53 mutations, should be excluded when analyzing TP53 mutations. Thus, by combining statistical and experimental analyses, we provide a curated mutation database for TP53 mutations and a framework for mutation database analysis.
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| 31. |
- Aad, G., et al.
(author)
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- 2014
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Journal article (peer-reviewed)
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| 32. |
- Aad, G., et al.
(author)
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- 2012
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swepub:Mat__t (peer-reviewed)
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| 33. |
- Aad, G., et al.
(author)
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- 2014
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In: Physical Review C (Nuclear Physics). - 0556-2813 .- 1089-490X. ; 90:4
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Journal article (peer-reviewed)
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| 34. |
- Aad, G., et al.
(author)
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- 2013
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Journal article (peer-reviewed)
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| 35. |
- Aad, G., et al.
(author)
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- 2013
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In: New Journal of Physics. - : IOP Publishing. - 1367-2630. ; 15
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Journal article (peer-reviewed)
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| 36. |
- Aad, G., et al.
(author)
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- 2014
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In: The European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6052. ; 74:8
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Journal article (peer-reviewed)
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| 37. |
- Aad, G., et al.
(author)
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- 2012
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swepub:Mat__t (peer-reviewed)
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| 38. |
- Aad, G., et al.
(author)
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- 2012
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swepub:Mat__t (peer-reviewed)
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| 39. |
- Aad, G., et al.
(author)
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- 2012
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swepub:Mat__t (peer-reviewed)
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| 40. |
- Aad, G., et al.
(author)
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- 2013
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Journal article (peer-reviewed)
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| 41. |
- Aad, G., et al.
(author)
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- 2012
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swepub:Mat__t (peer-reviewed)
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| 42. |
- Aad, G., et al.
(author)
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- 2013
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In: The European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6052. ; 73:1
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Journal article (peer-reviewed)
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| 43. |
- Aad, G., et al.
(author)
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- 2013
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Journal article (peer-reviewed)
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| 44. |
- Aad, G., et al.
(author)
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- 2013
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Journal article (peer-reviewed)
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| 45. |
- Aad, G., et al.
(author)
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- 2014
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Journal article (peer-reviewed)
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| 46. |
- Aad, G., et al.
(author)
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- 2013
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Journal article (peer-reviewed)
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| 47. |
- Aad, G., et al.
(author)
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- 2013
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Journal article (peer-reviewed)
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| 48. |
- Aad, G., et al.
(author)
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- 2012
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swepub:Mat__t (peer-reviewed)
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| 49. |
- Aad, G., et al.
(author)
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- 2012
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Journal article (peer-reviewed)
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| 50. |
- Aad, G., et al.
(author)
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- 2013
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Journal article (peer-reviewed)
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