{"entity":{"id":"paper-bareche-tnbc-multiomic-heterogeneity-ann-oncol-2018","kind":"paper","name":"Unravelling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis","aka":[],"tldr":"Applying the Lehmann subtypes to 550 triple-negative tumours from the two biggest breast cancer genome projects showed each subtype has its own mutations: BL1 is TP53-mutant and unstable, LAR carries PIK3CA in more than half, the immunomodulatory type does best and LAR worst.","summary":"Copy-number, somatic mutation and gene expression data from METABRIC (355) and TCGA (195) gave 550 TNBC samples classified with the TNBCtype tool; 485 were stably classified (BL1 25%, IM 25%, M 21%, LAR 16%, MSL 13%) and 447 had sequencing. TP53 (81%), MUC16 (21%) and PIK3CA (20%) were the most mutated genes. IM was associated with better prognosis (HR 0.68, 95% CI 0.46 to 0.99) and LAR with worse (HR 1.47, 1.0 to 2.14). BL1 was the most genomically unstable subtype with TP53 mutation in 92% and copy-number deletion of BRCA2, MDM2, PTEN, RB1 and TP53. LAR carried a higher mutational burden with PIK3CA (55%), KMT2C (19%), CDH1 (13%), NF1 (13%) and AKT1 (13%) mutations and was 75% HER2-enriched by PAM50. MYC (64%), PIK3CA (51%) and CDK6 (39%) were the most gained or amplified genes. IM showed high expression of PD1, PDL1 and CTLA4. By PAM50, 76% of TNBCs were basal-like, 15% HER2-enriched, 5% normal-like and 2% luminal.","asOf":"2026-09-24","links":[{"label":"Bareche et al., Ann Oncol 2018: integrative multiomic analysis of 550 TNBCs from METABRIC and TCGA","url":"https://doi.org/10.1093/annonc/mdy024"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29365031/"},{"label":"cBioPortal study brca_metabric (METABRIC, Nature 2012 and Nat Commun 2016; 320 triple-negative samples, 299 on the 173-gene panel)","url":"https://www.cbioportal.org/study/summary?id=brca_metabric"},{"label":"cBioPortal study brca_tcga_pub (TCGA, Nature 2012; 825 samples, 123 recorded ER-, PR- and HER2-negative, 84 of them exome-sequenced)","url":"https://www.cbioportal.org/study/summary?id=brca_tcga_pub"}],"tags":[],"related":[],"cancers":["tnbc"],"sections":[],"technologies":[],"targets":["tp53","pik3ca","akt","pten","rb1","androgen-receptor","kmt2c","nf1"],"drugs":[],"companies":[],"institutions":["institut-jules-bordet"],"pathways":["myc","pi3k-akt-mtor","pd1-checkpoint"],"terms":["pam50"],"trials":[],"people":["martine-piccart"],"bottlenecks":[],"keyPapers":[],"journals":["annals-of-oncology"],"dependsOn":[],"notes":[],"journal":"Annals of Oncology","year":2018,"doi":"10.1093/annonc/mdy024","pmid":"29365031","authors":"Bareche Y, Venet D, Ignatiadis M, et al.","paperType":"translational","findings":["Stable subtypes among 485: BL1 25%, IM 25%, M 21%, LAR 16%, MSL 13%; BL2 did not reproduce.","TP53 81%, MUC16 21%, PIK3CA 20% overall; TP53 92% in BL1; PIK3CA 55%, AKT1 13%, CDH1 13%, KMT2C 19%, NF1 13% in LAR.","IM better (HR 0.68) and LAR worse (HR 1.47) prognosis; MYC gained or amplified in 64%; PAM50 basal-like 76%."],"whatItMeans":"This is the sourced bridge between expression subtype and mutation: it tells a clinician that a LAR tumour is the one to sequence for PIK3CA and AKT1, and that immunomodulatory biology is a favourable prognostic group before any immunotherapy.","caveats":["Retrospective re-analysis of METABRIC (173-gene panel) and TCGA; sequencing depth and gene coverage differ.","Subtype assignment used the online TNBCtype tool; 65 samples were unclassifiable."],"changedPractice":false,"participants":550},"route":"/key-papers/paper-bareche-tnbc-multiomic-heterogeneity-ann-oncol-2018/","neighbours":{"cancer":[{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"}],"target":[{"id":"akt","kind":"target","name":"AKT","route":"/targets/akt/"},{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"},{"id":"kmt2c","kind":"target","name":"KMT2C","route":"/targets/kmt2c/"},{"id":"nf1","kind":"target","name":"NF1 (neurofibromin)","route":"/targets/nf1/"},{"id":"pik3ca","kind":"target","name":"PIK3CA / PI3K-alpha","route":"/targets/pik3ca/"},{"id":"pten","kind":"target","name":"PTEN","route":"/targets/pten/"},{"id":"rb1","kind":"target","name":"RB1","route":"/targets/rb1/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"institution":[{"id":"institut-jules-bordet","kind":"institution","name":"Institut Jules Bordet","route":"/institutions/institut-jules-bordet/"}],"pathway":[{"id":"myc","kind":"pathway","name":"MYC","route":"/pathways/myc/"},{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"},{"id":"pi3k-akt-mtor","kind":"pathway","name":"PI3K / AKT / mTOR","route":"/pathways/pi3k-akt-mtor/"}],"term":[{"id":"pam50","kind":"term","name":"PAM50 / intrinsic subtypes","route":"/terms/pam50/"}],"person":[{"id":"martine-piccart","kind":"person","name":"Martine Piccart","route":"/people/martine-piccart/"}],"journal":[{"id":"annals-of-oncology","kind":"journal","name":"Annals of Oncology","route":"/journals/annals-of-oncology/"}],"biomarker":[{"id":"akt1-e17k","kind":"biomarker","name":"AKT1 E17K mutation","route":"/biomarkers/akt1-e17k/"},{"id":"pik3ca-hotspot-mutation","kind":"biomarker","name":"PIK3CA mutation","route":"/biomarkers/pik3ca-hotspot-mutation/"}]}}