title: Evolutionary pathways in BRCA1-associated breast tumors.
abstract: BRCA1-associated breast tumors display loss of BRCA1 and frequent somatic mutations of PTEN and TP53. Here we describe the analysis of BRCA1, PTEN, and p53 at the single cell level in 55 BRCA1-associated breast tumors and computational methods to predict the relative temporal order of somatic events, on the basis of the frequency of cells with single or combined alterations. Although there is no obligatory order of events, we found that loss of PTEN is the most common first event and is associated with basal-like subtype, whereas in the majority of luminal tumors, mutation of TP53 occurs first and mutant PIK3CA is rarely detected. We also observed intratumor heterogeneity for the loss of wild-type BRCA1 and increased cell proliferation and centrosome amplification in the normal breast epithelium of BRCA1 mutation carriers. Our results have important implications for the design of chemopreventive and therapeutic interventions in this high-risk patient population.
authors.affiliation: Departments of Medical Oncology, Brigham and Women's Hospital, USA.
authors.forename: Filipe C
authors.initials: FC
authors.lastname: Martins
authors.forename: Subhajyoti
authors.initials: S
authors.lastname: De
authors.forename: Vanessa
authors.initials: V
authors.lastname: Almendro
authors.forename: Mithat
authors.initials: M
authors.lastname: Gönen
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Park
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Blum
authors.forename: William
authors.initials: W
authors.lastname: Herlihy
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Ethington
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Schnitt
authors.forename: Nadine
authors.initials: N
authors.lastname: Tung
authors.forename: Judy E
authors.initials: JE
authors.lastname: Garber
authors.forename: Katharina
authors.initials: K
authors.lastname: Fetten
authors.forename: Franziska
authors.initials: F
authors.lastname: Michor
authors.forename: Kornelia
authors.initials: K
authors.lastname: Polyak
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human