Gene expression profiling integrated into network modelling reveals heterogeneity in the mechanisms of BRCA1 tumorigenesis

Background: gene expression profiling has distinguished sporadic breast tumour classes with genetic and clinical differences. Less is known about the molecular classification of familial breast tumours, which are generally considered to be less heterogeneous. Here, we describe molecular signatures that define BRCA1 subclasses depending on the expression of the gene encoding for oestrogen receptor, ESR1. Methods: for this purpose, we have used the Oncochip v2, a cancer-related cDNA microarray to analyze 14 BRCA1-associated breast tumours. Results: signatures were found to be molecularly associated with different biological processes and transcriptional regulatory programs. The signature of ESR1-positive tumours was mainly linked to cell proliferation and regulated by ER, whereas the signature of ESR1-negative tumours was mainly linked to the immune response and possibly regulated by transcription factors of the REL/NFκB family. These signatures were then verified in an independent series of familial and sporadic breast tumours, which revealed a possible prognostic value for each subclass. Over-expression of immune response genes seems to be a common feature of ER-negative sporadic and familial breast cancer and may be associated with good prognosis. Interestingly, the ESR1-negative tumours were substratified into two groups presenting slight differences in the magnitude of the expression of immune response transcripts and REL/NFκB transcription factors, which could be dependent on the type of BRCA1 germline mutation. Conclusion: this study reveals the molecular complexity of BRCA1 breast tumours, which are found to display similarities to sporadic tumours, and suggests possible prognostic implications

Inhaled Corticosteroids and the Occurrence of Oral Candidiasis:A Prescription Sequence Symmetry Analysis

<p>The primary aim of the study was to gain insight into the relative risk of clinically relevant oral candidiasis following inhaled corticosteroid (ICS) initiation over time. A secondary aim was to analyse the influence of patient characteristics and co-medication on the occurrence of this adverse effect.</p><p>Drug prescription data from 1994 to 2011 were retrieved from the IADB.nl database. To study the influence of ICS use on occurrence of oral candidiasis, a prescription symmetry analysis was used, including patients using medication for oral candidiasis up to 1 year before or after ICS initiation. The relative risk was calculated by dividing the number of patients receiving medication for oral candidiasis after ICS initiation by the number of patients receiving the same medication before ICS initiation. Sub-analyses were conducted to compare the relative risks at several time points after ICS initiation and to account for therapy persistence by only including chronic users of ICS. A multivariate logistic regression model was used to identify predictive factors.</p><p>A total of 52,279 incident users of ICS therapy were identified, of which 1,081 received medication for oral candidiasis up to 1 year before or after ICS initiation. A total of 701 patients received medication for oral candidiasis after ICS initiation, while 361 received these medications in the reversed sequence, resulting in a sequence ratio (SR) of 1.94 (95 % CI 1.71-2.21). In the first 3 months after ICS initiation, the SR was 2.72 (95 % CI 2.19-3.38) and then decreased to 1.47 (95 % CI 1.11-1.95) 9-12 months after ICS initiation. Predictive factors were higher daily dose of ICS and concomitant use of oral corticosteroids.</p><p>This study found a significant and clinically relevant increased number of patients receiving medication for oral candidiasis in the first year after therapy initiation with ICS. Relative risk is highest in the first 3 months, but remains increased up to at least 1 year after ICS initiation. This study stresses the need for patient education and inhalation instruction.</p>