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The clonal and mutational evolution spectrum of primary triple negative breast cancers

Primary triple negative breast cancers (TNBC) represent approximately 16% of all breast cancers and are a tumour type defined by exclusion,for which comprehensive landscapes of somatic mutation have not been determined. Here we show in 104 early TNBC cases, that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some exhibiting only a handful of somatic aberrations in a few pathways, whereas others contain hundreds of somatic events and multiple pathways implicated. Integration with matched whole transcriptome sequence data revealed that only 36% of mutations are expressed. By examining single nucleotide variant (SNV) allelic abundance derived from deep re-sequencing (median > 20,000 fold) measurements in 2414 somatic mutations, we determine for the first time in an epithelial tumour, the relative abundance of clonal genotypes among cases in the population. We show that TNBC vary widely and continuously in their clonal frequencies at the time of diagnosis, with basal subtype TNBC exhibiting more variation than non-basal TNBC. Although p53 and somatic mutations appear clonally dominant compared with other pathways, in some tumours their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal and cell shape/motility proteins occurred at lower clonal frequencies, suggesting they occurred later during tumour progression. Taken together our results show that future attempts to dissect the biology and therapeutic responses of TNBC will require the determination of individual tumour clonal genotypes.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001000113 Illumina Genome Analyzer IIx 108
EGAD00001000115 ABI_SOLID 32
EGAD00001000132 Illumina Genome Analyzer IIx 80
EGAD00010000148 Affymetrix_GenomeWide_SNP6.34 104
Publications Citations
The clonal and mutational evolution spectrum of primary triple-negative breast cancers.
Nature 486: 2012 395-399
1211
Integrative analysis of genome-wide loss of heterozygosity and monoallelic expression at nucleotide resolution reveals disrupted pathways in triple-negative breast cancer.
Genome Res 22: 2012 1995-2007
151
CLImAT: accurate detection of copy number alteration and loss of heterozygosity in impure and aneuploid tumor samples using whole-genome sequencing data.
Bioinformatics 30: 2014 2576-2583
23
Diverse, Biologically Relevant, and Targetable Gene Rearrangements in Triple-Negative Breast Cancer and Other Malignancies.
Cancer Res 76: 2016 4850-4860
25
CloneCNA: detecting subclonal somatic copy number alterations in heterogeneous tumor samples from whole-exome sequencing data.
BMC Bioinformatics 17: 2016 310
12
Anaconda: AN automated pipeline for somatic COpy Number variation Detection and Annotation from tumor exome sequencing data.
BMC Bioinformatics 18: 2017 436
3
Detection of copy number variants and loss of heterozygosity from impure tumor samples using whole exome sequencing data.
Oncol Lett 16: 2018 4713-4720
2
ABL kinases regulate translation in HER2+ cells through Y-box-binding protein 1 to facilitate colonization of the brain.
Cell Rep 40: 2022 111268
3