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.

Subtypes of familial breast tumours revealed by expression and copy number profiling

“…Columbo et al [20] reported that Cyclin D1 is overexpressed in BRCA2 versus BRCA1 tumours. In our tumour cohort, we found that CCND1 was more likely to be overexpressed in luminal rather than basal tumours, and, therefore, the high frequency of basal-like tumours within BRCA1 tumours probably accounts for this reported difference.…”

“…Despite their high grade, BRCA2 tumours are typically positive for hormone receptors and negative for HER2 and basal cytokeratins [6,47,64], although Atchley et al (2008) found that 23% were triple negative. Compared to BRCA1 and non-BRCA1/2 tumours, BRCA2 tumours have been found to be less frequently positive for p53 [64], and some studies have reported that these tumours over-express cyclin D1 [20,36,92]. A potential biomarker of BRCA2 tumours is high RAD51 cytoplasmic expression/low nuclear expression relative to other familial and sporadic breast tumours [38].…”

“…We evaluated the expression of a set of 16 genes previously associated with BRCA mutation or molecular subtype [7,9,20,21,24,44,45,53,56,62,75,84] (Table S3). Eleven of these genes, showed expression differences between mutation or molecular subtype (P \ 0.01) (Fig.…”

CCND1 and ZNF217 gene amplification is equally frequent in BRCA1 and BRCA2 associated and non-BRCA breast cancer

“…ER negativity is typical of tumors from BRCA1 mutation carriers. Although the rate of cyclin D1 positive cases is lower in BRCA1 tumors than in sporadic tumors, they still represent some 5 to 33% of all positive cases [7,20,24,25,36]. The aforementioned alternative pathways of cyclin D1 overexpression induction may be involved in these positive cases.…”

“…Most of these studies have exhibited significantly lower cyclin-D1 expression levels in BRCA1-mutation carriers than in sporadic tumors [1, 9,28]. The percentage of cyclin D1 expression ranges from 5 to 33% in BRCA1 tumors, from 27 to 57% in BRCA2 tumors and from 35 to 55% in non-BRCA tumors [7,16,24,25,26]. No difference in cyclin D1 expression was found in 157 hereditary breast cancers with BRCA2 germline mutations and 314 control tumors negative for the BRCA1 and BRCA2 mutations [8].…”