Genomic characterization of metastatic breast cancers
Top Cited Papers
- 22 May 2019
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 569 (7757), 560-564
- https://doi.org/10.1038/s41586-019-1056-z
Abstract
Metastasis is the main cause of death for patients with breast cancer. Many studies have characterized the genomic landscape of breast cancer during its early stages. However, there is evidence that genomic alterations are acquired during the evolution of cancers from their early to late stages, and that the genomic landscape of early cancers is not representative of that of lethal cancers1,2,3,4,5,6,7. Here we investigated the landscape of somatic alterations in 617 metastatic breast cancers. Nine driver genes (TP53, ESR1, GATA3, KMT2C, NCOR1, AKT1, NF1, RIC8A and RB1) were more frequently mutated in metastatic breast cancers that expressed hormone receptors (oestrogen and/or progesterone receptors; HR+) but did not have high levels of HER2 (HER2−; n = 381), when compared to early breast cancers from The Cancer Genome Atlas. In addition, 18 amplicons were more frequently observed in HR+/HER2− metastatic breast cancers. These cancers showed an increase in mutational signatures S2, S3, S10, S13 and S17. Among the gene alterations that were enriched in HR+/HER2− metastatic breast cancers, mutations in TP53, RB1 and NF1, together with S10, S13 and S17, were associated with poor outcome. Metastatic triple-negative breast cancers showed an increase in the frequency of somatic biallelic loss-of-function mutations in genes related to homologous recombination DNA repair, compared to early triple-negative breast cancers (7% versus 2%). Finally, metastatic breast cancers showed an increase in mutational burden and clonal diversity compared to early breast cancers. Thus, the genomic landscape of metastatic breast cancer is enriched in clinically relevant genomic alterations and is more complex than that of early breast cancer. The identification of genomic alterations associated with poor outcome will allow earlier and better selection of patients who require the use of treatments that are still in clinical trials. The genetic complexity observed in advanced breast cancer suggests that such treatments should be introduced as early as possible in the disease course.Keywords
This publication has 61 references indexed in Scilit:
- Signatures of mutational processes in human cancerNature, 2013
- Pyrvinium pamoate changes alternative splicing of the serotonin receptor 2C by influencing its RNA structureNucleic Acids Research, 2013
- Discovery and characterization of artifactual mutations in deep coverage targeted capture sequencing data due to oxidative DNA damage during sample preparationNucleic Acids Research, 2013
- Comprehensive molecular portraits of human breast tumoursNature, 2012
- Strelka: accurate somatic small-variant calling from sequenced tumor–normal sample pairsBioinformatics, 2012
- Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion SequencingThe New England Journal of Medicine, 2012
- The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing dataGenome Research, 2010
- Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short readsBioinformatics, 2009
- Fast and accurate short read alignment with Burrows–Wheeler transformBioinformatics, 2009
- Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancersNature, 2008