{"entity":{"id":"paper-shah-tnbc-clonal-evolution-nature-2012","kind":"paper","name":"The clonal and mutational evolution spectrum of primary triple-negative breast cancers","aka":[],"tldr":"Sequencing 104 triple-negative breast cancers at diagnosis showed they range from tumours with a handful of mutations to tumours with hundreds, that only about a third of mutations are even expressed, and that TP53, PIK3CA and PTEN are the changes present in most of the tumour's cells.","summary":"104 primary TNBCs were profiled by exome and RNA sequencing with deep re-sequencing of 2,414 somatic mutations to measure clonal frequency. The cancers showed a wide, continuous spectrum of genomic evolution; about 36% of mutations were expressed. Basal TNBC showed more variation in clonal frequencies than non-basal TNBC. TP53, PIK3CA and PTEN mutations were clonally dominant compared with other genes, though in some tumours their frequencies were incompatible with founder status; mutations in cytoskeletal, cell-shape and motility genes occurred at lower clonal frequency, suggesting later acquisition.\n\nThe cohort is deposited as brca_bccrc (British Columbia, Nature 2012) on cBioPortal.","asOf":"2026-09-24","links":[{"label":"Shah et al., Nature 2012: clonal and mutational evolution spectrum of 104 primary TNBCs","url":"https://doi.org/10.1038/nature10933"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/22495314/"}],"tags":[],"related":[],"cancers":["tnbc"],"sections":[],"technologies":[],"targets":["tp53","pik3ca","pten"],"drugs":[],"companies":[],"institutions":[],"pathways":["clonal-evolution"],"terms":["ngs"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2012,"doi":"10.1038/nature10933","pmid":"22495314","authors":"Shah SP, Roth A, Goya R, et al.","paperType":"translational","findings":["Coding mutation counts ranged from a handful to hundreds per tumour; about 36% of mutations were expressed.","TP53, PIK3CA and PTEN were clonally dominant; basal TNBC showed wider clonal variation than non-basal.","Cytoskeletal and motility gene mutations were subclonal, consistent with later acquisition."],"whatItMeans":"The first TNBC-specific genome paper established that the disease has no shared driver beyond TP53 and that each tumour is a clonal mixture, the reason single-target drugs have struggled and ctDNA tracking needs patient-specific variants.","caveats":["104 tumours from one Canadian centre; exome depth of the era.","Clonal frequencies were estimated from bulk tissue without single-cell confirmation."],"changedPractice":false,"participants":104},"route":"/key-papers/paper-shah-tnbc-clonal-evolution-nature-2012/","neighbours":{"cancer":[{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"}],"target":[{"id":"pik3ca","kind":"target","name":"PIK3CA / PI3K-alpha","route":"/targets/pik3ca/"},{"id":"pten","kind":"target","name":"PTEN","route":"/targets/pten/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"pathway":[{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"}],"term":[{"id":"ngs","kind":"term","name":"Next-generation sequencing (NGS)","route":"/terms/ngs/"}],"journal":[{"id":"nature","kind":"journal","name":"Nature","route":"/journals/nature/"}]}}