title: Relationship of immunohistochemistry, copy number aberrations and epigenetic disorders with BRCAness pattern in hereditary and sporadic breast cancer.
abstract: The study aims to identify the relevance of immunohistochemistry (IHC), copy number aberrations (CNA) and epigenetic disorders in BRCAness breast cancers (BCs). We studied 95 paraffin included BCs, of which 41 carried BRCA1/BRCA2 germline mutations and 54 were non hereditary (BRCAX/Sporadic). Samples were assessed for BRCA1ness and CNAs by Multiplex Ligation-dependent Probe Amplification (MLPA); promoter methylation (PM) was assessed by methylation-specific-MLPA and the expression of miR-4417, miR-423-3p, miR-590-5p and miR-187-3p by quantitative RT-PCR. IHC markers Ki67, ER, PR, HER2, CK5/6, EGFR and CK18 were detected with specific primary antibodies (DAKO, Denmark). BRCAness association with covariates was performed using multivariate binary logistic regression (stepwise backwards Wald option). BRCA1/2 mutational status (p = 0.027), large tumor size (p = 0.041) and advanced histological grade (p = 0.017) among clinic-pathological variables; ER (p < 0.001) among IHC markers; MYC (p < 0.001) among CNA; APC (p = 0.065), ATM (p = 0.014) and RASSF1 (p = 0.044) among PM; and miR-590-5p (p = 0.001), miR-4417 (p = 0.019) and miR-423 (p = 0.013) among microRNA expression, were the selected parameters significantly related with the BRCAness status. The logistic regression performed with all these parameters selected ER+ as linked with the lack of BRCAness (p = 0.001) and MYC CNA, APC PM and miR-590-5p expression with BRCAness (p = 0.014, 0.045 and 0.007, respectively). In conclusion, the parameters ER expression, APC PM, MYC CNA and miR-590-5p expression, allowed detection of most BRCAness BCs. The identification of BRCAness can help establish a personalized medicine addressed to predict the response to specific treatments.
authors.affiliation: Laboratory of Molecular Biology, Service of Clinical Analysis, University Hospital La Fe, Torre A 4ª planta, Avenida de Fernando Abril Martorell, no 106, 46026, Valencia, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Murria Estal
authors.affiliation: Laboratory of Molecular Biology, Service of Clinical Analysis, University Hospital La Fe, Torre A 4ª planta, Avenida de Fernando Abril Martorell, no 106, 46026, Valencia, Spain.
authors.forename: Sarai
authors.initials: S
authors.lastname: Palanca Suela
authors.affiliation: Laboratory of Molecular Biology, Service of Clinical Analysis, University Hospital La Fe, Torre A 4ª planta, Avenida de Fernando Abril Martorell, no 106, 46026, Valencia, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: de Juan Jiménez
authors.affiliation: Department of Pathology, University General Hospital, Alicante, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Alenda Gonzalez
authors.affiliation: Department of Pathology, University General Hospital, Alicante, Spain.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Egoavil Rojas
authors.affiliation: Laboratory of Molecular Biology, IVO, Valencia, Spain.
authors.forename: Zaida
authors.initials: Z
authors.lastname: García-Casado
authors.affiliation: Laboratory of Molecular Biology, IVO, Valencia, Spain.
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: López Guerrero
authors.affiliation: Department of Oncology, IVO, Valencia, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Juan Fita
authors.affiliation: Genetic Counseling Unit, Elche Hospital, Alicante, Spain.
authors.forename: Ana Beatriz
authors.initials: AB
authors.lastname: Sánchez Heras
authors.affiliation: Genetic Counseling Unit, University Hospital La Fe, Valencia, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Segura Huerta
authors.affiliation: Department of Oncology, University Hospital La Fe, Valencia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Santaballa Bertrán
authors.affiliation: Genetic Counseling Unit, Clinic University Hospital, Valencia, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Chirivella González
authors.affiliation: Laboratory of Molecular Biology, Service of Clinical Analysis, University Hospital La Fe, Torre A 4ª planta, Avenida de Fernando Abril Martorell, no 106, 46026, Valencia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Llop García
authors.affiliation: Laboratory of Molecular Biology, Service of Clinical Analysis, University Hospital La Fe, Torre A 4ª planta, Avenida de Fernando Abril Martorell, no 106, 46026, Valencia, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Pérez Simó
authors.affiliation: Laboratory of Molecular Biology, Service of Clinical Analysis, University Hospital La Fe, Torre A 4ª planta, Avenida de Fernando Abril Martorell, no 106, 46026, Valencia, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Barragán González
authors.affiliation: Laboratory of Molecular Biology, Service of Clinical Analysis, University Hospital La Fe, Torre A 4ª planta, Avenida de Fernando Abril Martorell, no 106, 46026, Valencia, Spain. bolufer_pas@gva.es.
authors.forename: Pascual
authors.initials: P
authors.lastname: Bolufer Gilabert
mesh_terms: D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D009154:Mutation
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor; D035683:MicroRNAs
keywords: BRCAness; Copy number aberrations; Immunohistochemical markers; Promoter methylation; microRNA expression