title: Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions.
abstract: The phosphatidylinositol-3-kinase pathway is one of the most commonly altered molecular pathways in invasive breast carcinoma, with phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) mutations in 25% of invasive carcinomas. Ductal carcinoma in situ (DCIS), benign papillomas, and small numbers of columnar cell lesions harbor an analogous spectrum of PIK3CA and AKT1 mutations, yet there is little data on usual ductal hyperplasia and atypical ductal and lobular neoplasias. We screened 192 formalin-fixed paraffin-embedded breast lesions from 75 patients for point mutations using a multiplexed panel encompassing 643 point mutations across 53 genes, including 58 PIK3CA substitutions. PIK3CA point mutations were identified in 31/62 (50%) proliferative lesions (usual ductal hyperplasia and columnar cell change), 10/14 (71%) atypical hyperplasias (atypical ductal hyperplasia and flat epithelial atypia), 7/16 (44%) lobular neoplasias (atypical lobular hyperplasia and lobular carcinoma in situ), 10/21 (48%) DCIS, and 13/37 (35%) invasive carcinomas. In genotyping multiple lesions of different stage from the same patient/specimen, we found considerable heterogeneity; most notably, in 12 specimens the proliferative lesion was PIK3CA mutant but the concurrent carcinoma was wild type. In 11 additional specimens, proliferative epithelium and cancer contained different point mutations. The frequently discordant genotypes of usual ductal hyperplasia/columnar cell change and concurrent carcinoma support a role for PIK3CA-activating point mutations in breast epithelial proliferation, perhaps more so than transformation. Further, these data suggest that proliferative breast lesions are heterogeneous and may represent non-obligate precursors of invasive carcinoma.
authors.affiliation: 1] Department of Pathology, Oregon Health & Science University, Portland, OR, USA [2] Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Daphne C
authors.initials: DC
authors.lastname: Ang
authors.affiliation: Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Warrick
authors.affiliation: Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Shilling
authors.affiliation: Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Beadling
authors.affiliation: 1] Department of Pathology, Oregon Health & Science University, Portland, OR, USA [2] Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Corless
authors.affiliation: 1] Department of Pathology, Oregon Health & Science University, Portland, OR, USA [2] Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Troxell
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics* / Q000473:pathology; D018275:Carcinoma, Lobular / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D009154:Mutation; D010212:Papilloma / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human