title: Cyclin D1 expression analysis in familial breast cancers may discriminate BRCAX from BRCA2-linked cases.
abstract: Most familial breast cancers arise in patients who tested negative for germline mutations in BRCA1 and BRCA2 genes (also referred to as BRCAX cases). Several studies aimed to define histopathological and molecular profiles characteristic of BRCA1, BRCA2 and BRCAX tumors have been performed. Major pathological and immunohistochemical differences have been reported in BRCA1 cancers compared to the other two groups, whereas less difference has been observed between BRCA2 and BRCAX cases. The aim of this study was to investigate the ability of selected tumor markers to discriminate BRCAX breast cancers from cancers arising in carriers of mutations in BRCA genes, and their usefulness in selecting familial cases in whom testing for such mutations is more likely to result uninformative. We carried out a morphological and immunohistochemical analysis on 22 BRCA1, 16 BRCA2 and 33 BRCAX familial breast cancers. Age at first diagnosis, histological type and grade, and immunostaining for estrogen receptor (ER), progesterone receptor (PR), p53, HER2/Neu, E-cadherin and cyclin D1 were investigated. The occurrence of somatic mutations of the TP53 gene was also verified. BRCA1 tumors resulted clearly distinguishable from BRCAX cases, occurring at a younger age, being more frequently of higher grade, negative for ER, PR and cyclin D1 expression and positive for p53 alterations. The predictive value of age at diagnosis, histological grade and PR expression was confirmed in a multivariable analysis. When comparing BRCA2 with BRCAX tumors, the only parameter that differed was cyclin D1, which was significantly overexpressed in BRCA2 cases both in the univariable and the multivariable analyses. If confirmed by further studies, our observations indicate that the investigation of cyclin D1 expression in familial breast cancer cases could be used, in conjunction with the analysis of other tumor markers preferentially associated with BRCA1 or BRCA2 tumors, to prioritize hereditary cases for mutation testing in BRCA genes.
authors.affiliation: Unit of Genetic Susceptibility to Cancer, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Colombo
authors.forename: Monica
authors.initials: M
authors.lastname: Giarola
authors.forename: Luigi
authors.initials: L
authors.lastname: Mariani
authors.forename: Carla B
authors.initials: CB
authors.lastname: Ripamonti
authors.forename: Virna
authors.initials: V
authors.lastname: De Benedetti
authors.forename: Michele
authors.initials: M
authors.lastname: Sardella
authors.forename: Marco
authors.initials: M
authors.lastname: Losa
authors.forename: Siranoush
authors.initials: S
authors.lastname: Manoukian
authors.forename: Bernard
authors.initials: B
authors.lastname: Peissel
authors.forename: Marco A
authors.initials: MA
authors.lastname: Pierotti
authors.forename: Silvana
authors.initials: S
authors.lastname: Pilotti
authors.forename: Paolo
authors.initials: P
authors.lastname: Radice
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D000328:Adult; D051017:Apoptosis Regulatory Proteins; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D024682:BRCA2 Protein / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism*; D003937:Diagnosis, Differential; D005192:Family Health; D005260:Female; D006801:Humans; D008875:Middle Aged
chemical_list: D051017:Apoptosis Regulatory Proteins; C118024:BLID protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor; D056741:Cyclin D; D016213:Cyclins