The 11q13-q14 locus is frequently amplified in human cancers, with a complex structure harbouring multiple potential oncogenic drivers. The EMSY gene has been proposed as a driver of the third core of the 11q13-q14 amplicon. This gene encodes a protein reported to be a BRCA2-binding partner, which when over-expressed would lead to impairment of BRCA2 functions and could constitute a mechanism for BRCA2 inactivation in non-hereditary breast and ovarian cancers. We hypothesized that if EMSY amplification abrogates BRCA2 functions, cells harbouring this aberration would be unable to elicit competent homologous recombination DNA repair and, therefore, may have increased sensitivity to genotoxic therapies and potent PARP inhibitors. Microarray-based comparative genomic hybridization of cell lines from distinct tumour sites, including breast, ovary, pancreas, oesophagus, lung and the oral cavity, led to the identification of 10 cell lines with EMSY amplification and 18 without. EMSY amplification was shown to correlate with EMSY mRNA levels, although not all cell lines harbouring EMSY amplification displayed EMSY mRNA or protein over-expression. RNA interference-mediated silencing of EMSY did not lead to a reduction in cell viability in tumour models harbouring EMSY amplification. Cell lines with and without EMSY amplification displayed a similar ability to elicit RAD51 foci in response to DNA damaging agents, and similar sensitivity to cisplatin and olaparib. Taken together, this suggests that EMSY is unlikely to be a driver of the 11q13-q14 amplicon and does not have a dominant role in modulating the response to agents targeting cells with defective homologous recombination.
The ten-eleven translocation 2 gene (TET2) encodes a member of the TET family of DNA methylcytosine oxidases that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) to initiate the demethylation of DNA within genomic CpG islands. Somatic loss-of-function mutations of TET2 are frequently observed in human myelodysplastic syndrome (MDS), which is a clonal malignancy characterized by dysplastic changes of developing blood cell progenitors, leading to ineffective hematopoiesis. We used genome-editing technology to disrupt the zebrafish Tet2 catalytic domain. T ET2 belongs to the TET (ten-eleven translocation) family of methylcytosine oxidases, which require 2-oxoglutarate, oxygen, and Fe(II) for their activity. TET2, like TET1 and TET3, modifies the methylation status of the genome, regulating the transcription of specific genes by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and then to 5-formylcytosine (5fC) and finally to 5-carboxylcytosine (5caC). Each of the last 3 products is recognized and excised by thymine DNA glycosylase (TDG), completing the removal of the 5-methyl group and regenerating unmodified cytosine (1). Hydroxylation of 5mC by the TET enzymes, returning cytosine to its unmethylated state, has been shown to be crucial to many aspects of embryonic development, including embryonic stem cell (ESC) renewal, epigenetic programming of zygotic cells, and meiosis of primordial germ cells (PGCs) (reviewed in references 2 and 3).A variety of alterations, including deletions and missense, nonsense, and frameshift mutations, inactivate the TET2 enzyme in different types of human myeloid malignancies, such as myelodysplastic syndromes (MDS) (25 to 35%) (4-7), myeloproliferative neoplasms (MPN) (2 to 20%) (8, 9), de novo acute myeloid leukemia (AML) (12 to 17%) (10-14), secondary AML (24 to 32%) (11,12), and chronic myelomonocytic leukemia (CMML) (50 to 60%) (5). In these diseases, TET2 gene alterations lead to a marked reduction in global levels of 5hmC (15). TET2 mutations have also been identified in the hematopoietic cells of otherwise healthy adults over 50 years of age who have "clonal skewing" of their bone marrow cells (16), indicating that TET2 mutations may represent one of the first mutations leading to clonal expansion and the eventual development of myeloid malignancies.The role of TET2 mutations in myeloid malignancies has been studied in a number of mouse models (17-20). The hematopoietic stem cells (HSCs) in these models have low 5hmC content and exhibit increased self-renewal ability and a competitive advantage over wild-type HSCs for repopulating hematopoietic lineages. Tet2 knockout mice are viable and fertile and appear to develop normally. However, as they age, Tet2-deficient mice are prone to develop myeloid malignancies, predominantly CMML, with 20 to 30% developing disease after 8 months of age, clearly suggesting that additional genetic lesions are needed to initiate myeloid malignancy.Thus, the essential role of TET2 in maintaining the normal growt...
Triple-negative breast cancers account for 12-17% of all invasive breast carcinomas and comprise a heterogeneous group of tumours, with varying histological features and clinical behaviours. Focal apocrine differentiation can be associated with a subset of these lesions. To establish whether morphological diversity is associated with divergent genetic aberrations the genomic profiles of microdissected, morphologically distinct components from an invasive ductal carcinoma of no special type with triple-negative phenotype and a region of apocrine differentiation were determined by high-resolution microarray-based comparative genomic hybridisation and validated by fluorescence in-situ hybridisation. Morphologically distinct components were found to harbour differing genetic aberrations, with the region of apocrine differentiation demonstrating genomic gains and losses on chromosome arms 9p and 9q, respectively, not present in non-apocrine areas. The results provide additional direct evidence of intra-tumour genetic heterogeneity in breast cancer and demonstrate that morphologically distinct regions can be associated with distinct genetic aberrations.
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