title: Gene signature model for breast cancer risk prediction for women with sclerosing adenosis.
abstract: Benign breast disease (BBD) is diagnosed in 1-2 million women/year in the US, and while these patients are known to be at substantially increased risk for subsequent development of breast cancer, existing models for risk assessment perform poorly at the individual level. Here, we describe a DNA-microarray-based transcriptional model for breast cancer risk prediction for patients with sclerosing adenosis (SA), which represent ¼ of all BBD patients. A training set was developed from 86 patients diagnosed with SA, of which 27 subsequently developed cancer within 10 years (cases) and 59 remained cancer-free at 10 years (controls). An diagonal linear discriminate analysis-prediction model for prediction of cancer within 10 years (SA TTC10) was generated from transcriptional profiles of FFPE biopsy-derived RNA. This model was tested on a separate validation case-control set composed of 65 SA patients. The SA TTC10 gene signature model, composed of 35 gene features, achieved a clear and significant separation between case and control with receiver operating characteristic area under the curve of 0.913 in the training set and 0.836 in the validation set. Our results provide the first demonstration that benign breast tissue contains transcriptional alterations that indicate risk of breast cancer development, demonstrating that essential precursor biomarkers of malignancy are present many years prior to cancer development. Furthermore, the SA TTC10 gene signature model, which can be assessed on FFPE biopsies, constitutes a novel prognostic biomarker for patients with SA.
authors.affiliation: Department of Surgery, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Degnim
authors.forename: Aziza
authors.initials: A
authors.lastname: Nassar
authors.forename: Melody
authors.initials: M
authors.lastname: Stallings-Mann
authors.forename: S
authors.initials: S
authors.lastname: Keith Anderson
authors.forename: Ann L
authors.initials: AL
authors.lastname: Oberg
authors.forename: Robert A
authors.initials: RA
authors.lastname: Vierkant
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Frank
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.forename: Stacey J
authors.initials: SJ
authors.lastname: Winham
authors.forename: Marlene H
authors.initials: MH
authors.lastname: Frost
authors.forename: Lynn C
authors.initials: LC
authors.lastname: Hartmann
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Visscher
authors.forename: Derek C
authors.initials: DC
authors.lastname: Radisky
mesh_terms: D000328:Adult; D001706:Biopsy; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005348:Fibrocystic Breast Disease / Q000150:complications / Q000235:genetics*; D020869:Gene Expression Profiling; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D008875:Middle Aged; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012372:ROC Curve; D015203:Reproducibility of Results; D018570:Risk Assessment / Q000379:methods