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.
%0 Journal Article
%1 nikzainal2012mutational
%A Nik-Zainal, S
%A Alexandrov, L B
%A Wedge, D C
%A Van Loo, P
%A Greenman, C D
%A Raine, K
%A Jones, D
%A Hinton, J
%A Marshall, J
%A Stebbings, L A
%A Menzies, A
%A Martin, S
%A Leung, K
%A Chen, L
%A Leroy, C
%A Ramakrishna, M
%A Rance, R
%A Lau, K W
%A Mudie, L J
%A Varela, I
%A McBride, D J
%A Bignell, G R
%A Cooke, S L
%A Shlien, A
%A Gamble, J
%A Whitmore, I
%A Maddison, M
%A Tarpey, P S
%A Davies, H R
%A Papaemmanuil, E
%A Stephens, P J
%A McLaren, S
%A Butler, A P
%A Teague, J W
%A Jönsson, G
%A Garber, J E
%A Silver, D
%A Miron, P
%A Fatima, A
%A Boyault, S
%A Langerod, A
%A Tutt, A
%A Martens, J W
%A Aparicio, S A
%A Borg, \AA
%A Salomon, A V
%A Thomas, G
%A Borresen-Dale, A L
%A Richardson, A L
%A Neuberger, M S
%A Futreal, P A
%A Campbell, P J
%A Stratton, M R
%A Breast Cancer Working Group of the International Cancer Genome Consortium,
%D 2012
%J Cell
%K cancer context-dependent-mutation methods mutation_motif nonnegative_matrix_factorization
%N 5
%P 979-993
%R 10.1016/j.cell.2012.04.024
%T Mutational processes molding the genomes of 21 breast cancers
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3414841/
%V 149
%X 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.
@article{nikzainal2012mutational,
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.},
added-at = {2017-05-31T07:01:29.000+0200},
author = {Nik-Zainal, S and Alexandrov, L B and Wedge, D C and Van Loo, P and Greenman, C D and Raine, K and Jones, D and Hinton, J and Marshall, J and Stebbings, L A and Menzies, A and Martin, S and Leung, K and Chen, L and Leroy, C and Ramakrishna, M and Rance, R and Lau, K W and Mudie, L J and Varela, I and McBride, D J and Bignell, G R and Cooke, S L and Shlien, A and Gamble, J and Whitmore, I and Maddison, M and Tarpey, P S and Davies, H R and Papaemmanuil, E and Stephens, P J and McLaren, S and Butler, A P and Teague, J W and J{\"o}nsson, G and Garber, J E and Silver, D and Miron, P and Fatima, A and Boyault, S and Langerod, A and Tutt, A and Martens, J W and Aparicio, S A and Borg, {\AA} and Salomon, A V and Thomas, G and Borresen-Dale, A L and Richardson, A L and Neuberger, M S and Futreal, P A and Campbell, P J and Stratton, M R and {Breast Cancer Working Group of the International Cancer Genome Consortium}},
biburl = {https://www.bibsonomy.org/bibtex/25e1ae4596cee278e25b5616a35105d4a/peter.ralph},
doi = {10.1016/j.cell.2012.04.024},
interhash = {f63d0b3f1a4669ac80e3d48ffbc98699},
intrahash = {5e1ae4596cee278e25b5616a35105d4a},
journal = {Cell},
keywords = {cancer context-dependent-mutation methods mutation_motif nonnegative_matrix_factorization},
month = may,
number = 5,
pages = {979-993},
pmid = {22608084},
timestamp = {2017-05-31T07:01:29.000+0200},
title = {Mutational processes molding the genomes of 21 breast cancers},
url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3414841/},
volume = 149,
year = 2012
}