An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers

被引：898

作者：

Roberts, Steven A. ^{[1
]}

Lawrence, Michael S. ^{[2
]}

Klimczak, Leszek J. ^{[3
]}

Grimm, Sara A. ^{[3
]}

Fargo, David ^{[3
]}

Stojanov, Petar ^{[2
]}

Kiezun, Adam ^{[2
]}

Kryukov, Gregory V. ^{[2
,4
]}

Carter, Scott L. ^{[2
]}

Saksena, Gordon ^{[2
]}

Harris, Shawn ^{[5
]}

Shah, Ruchir R. ^{[5
]}

Resnick, Michael A. ^{[1
]}

Getz, Gad ^{[2
,6
,7
]}

Gordenin, Dmitry A.

机构：

[1] Natl Inst Environm Hlth Sci, Mol Genet Lab, Durham, NC USA

[2] Broad Inst MIT & Harvard, Cambridge, MA USA

[3] Natl Inst Environm Hlth Sci, Durham, NC USA

[4] Harvard Univ, Sch Med, Boston, MA 02115 USA

[5] SRA Int Inc, Durham, NC USA

[6] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA

[7] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

来源：

NATURE GENETICS | 2013年 / 45卷 / 09期

基金：

美国国家卫生研究院;

关键词：

HOMOLOGOUS RECOMBINATION; SOMATIC MUTATIONS; GENOMIC DNA; BREAST; REPLICATION; MECHANISMS; RECURRENT; DAMAGE; RETROTRANSPOSITION; EXPRESSION;

D O I：

10.1038/ng.2702

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Recent studies indicate that a subclass of APOBEC cytidine deaminases, which convert cytosine to uracil during RNA editing and retrovirus or retrotransposon restriction, may induce mutation clusters in human tumors. We show here that throughout cancer genomes APOBEC-mediated mutagenesis is pervasive and correlates with APOBEC mRNA levels. Mutation clusters in whole-genome and exome data sets conformed to the stringent criteria indicative of an APOBEC mutation pattern. Applying these criteria to 954,247 mutations in 2,680 exomes from 14 cancer types, mostly from The Cancer Genome Atlas (TCGA), showed a significant presence of the APOBEC mutation pattern in bladder, cervical, breast, head and neck, and lung cancers, reaching 68% of all mutations in some samples. Within breast cancer, the HER2-enriched subtype was clearly enriched for tumors with the APOBEC mutation pattern, suggesting that this type of mutagenesis is functionally linked with cancer development. The APOBEC mutation pattern also extended to cancer-associated genes, implying that ubiquitous APOBEC-mediated mutagenesis is carcinogenic.

引用

页码：970 / +

页数：8

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