MicroRNA-based molecular classification of non-BRCA1/2 hereditary breast tumours.

摘要: Breast cancer continues to be the most common among women and second leading cause of deaths. Only about 5–10% all breast cases arise in families with various affected members throughout several generations that follow a pattern autosomal dominant inheritance, earlier age onset, and/or presenting bilateral/multiple tumours are considered hereditary cases. Germline mutations two high-susceptibility genes, BRCA1 BRCA2, can account for only ∼20–25% (Bradbury Olopade, 2007), along other rare intermediate-risk genes identified through re-sequencing studies candidate involved DNA damage repair pathway low-susceptibility alleles explain less than half cases. More 50% arising high-risk fulfil criteria syndrome unaccounted for, designated as non-BRCA1/2 or BRCAX (Rahman Stratton, 1998; Palacios et al, 2008; Stratton Rahman, Mavaddat 2010). These represent not big ‘black box' terms our understanding underlying biology these but also major problem genetic counselling management patients their families. Due difficulties acquisition fresh frozen tissue material, there have been handful aimed at characterising molecular signature by gene expression profiling (Hedenfalk 2003). Have demonstrated small series 19 heterogeneous mRNA profiles could sub-classified least subgroups different signature. Previous results from group (Fernandez-Ramires 2010) supported this notion identifying tumours, one groups showing ‘BRCA1-like' profile. Discovery miRNAs, short non-coding single-stranded RNA molecules negatively regulate inducing either translational repression degradation depending on level complementarity its target 3′UTR, has improved regulation. It miRNAs significant role biological processes, including differentiation development, metabolism, regulation cell proliferation apoptosis (Inui Deregulation miRNA extensively implicated pathogenesis tumour types (Croce, 2009; Lujambio Lowe, 2012). Further, is specific it more robust classification origin (Lu 2005). Specifically, cancer, number defined associated sporadic (Iorio 2005; Volinia 2006, 2012), subtypes (Blenkiron 2007; Fassan 2009) features such hormone receptor HER2 status, metastasis, progression (Mattie 2006; Tavazoie Lowery 2009). There longstanding expectation evolution may result pathological directly reflects aetiology tumours. Unfortunately, lived expectations primarily due technical logistic related material. Given very stable molecules, shown well preserved paraffin-embedded tissues present body fluids, they an ideal class biomarkers proven useful classification. Here we studied global large 66 FFPE using microarrays aim explore heterogeneity based signatures. We into four homogenous (BRCAX-A, -B, -C, -D) characterised signatures histopathological features. findings introduce new insight defining help search novel susceptibility pathways cancer.