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The clonal and mutational evolution spectrum of primary triple-negative breast cancers
- Source :
- Nature, vol 486, iss 7403, Breast Cancer Research : BCR
- Publication Year :
- 2012
- Publisher :
- eScholarship, University of California, 2012.
-
Abstract
- Primary triple negative breast cancers (TNBC) represent approximately 16% of all breast cancers1 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 TNBC2,3 exhibiting more variation than non-basal TNBC. Although p53 and PIK3CA/PTEN 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.
- Subjects :
- Genotype
DNA Copy Number Variations
Somatic cell
Evolution
General Science & Technology
Population
DNA Mutational Analysis
Breast Neoplasms
Biology
medicine.disease_cause
Article
Evolution, Molecular
Viewpoint
INDEL Mutation
Breast Cancer
medicine
PTEN
Humans
Point Mutation
Allele
Precision Medicine
education
Alleles
Cancer
Genetics
Mutation
education.field_of_study
Neoplastic
screening and diagnosis
Multidisciplinary
Sequence Analysis, RNA
Point mutation
Gene Expression Profiling
Reproducibility of Results
Molecular
High-Throughput Nucleotide Sequencing
Clone Cells
4.1 Discovery and preclinical testing of markers and technologies
Gene expression profiling
Gene Expression Regulation, Neoplastic
Detection
Gene Expression Regulation
biology.protein
Disease Progression
RNA
Female
Sequence Analysis
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Nature, vol 486, iss 7403, Breast Cancer Research : BCR
- Accession number :
- edsair.doi.dedup.....4bbcc35bb7ac9493fde0c36676387dda