BRCA mutations in the manifestation and treatment of ovarian cancer.

BRCA mutations in the manifestation and treatment of ovarian cancer.

Oncotarget. 2017 May 30;:

Authors: Pan Z, Xie X

Abstract
BRCA genes are important for the integrity and stability of genetic material and play key roles in repairing DNA breaks via high fidelity homologous recombination. BRCA mutations are known to predispose carriers to gynecological malignancies, accounting for a majority of hereditary OC cases. Known to be lethal, OC is difficult to detect and control. Testing for BRCA mutations is a key step in the risk assessment, prognosis, treatment and prevention of OC and current clinical guidelines recommend BRCA mutation testing for all OCs of epithelial origin. Studies have established that ovarian tumors harboring BRCA mutations have distinct molecular and histo-pathological features that can be exploited for effective, targeted treatment. Deficiencies in DNA repair pathways that arise as a result of BRCA mutations make them hypersensitive to DNA-damaging treatments such as platinum chemotherapy and PARP inhibitors. Different combinations of treatment regimens which have the potential to greatly improve prognosis and disease outcomes are currently being evaluated. However, the issue of developing resistance to these treatments remains unresolved. This review emphasizes unique features of BRCA mutated OC and outlines the lay of the land in terms of diagnosis and treatment, while aiming to unravel the challenges that are part of its management.

PMID: 28614062 [PubMed - as supplied by publisher]

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Germline Mutations in Triple-Negative Breast Cancer.

Related Articles

Germline Mutations in Triple-Negative Breast Cancer.

Breast Care (Basel). 2017 Mar;12(1):15-19

Authors: Hahnen E, Hauke J, Engel C, Neidhardt G, Rhiem K, Schmutzler RK

Abstract
Triple-negative breast cancer (TNBC) is associated with a poor prognosis and defines a subgroup of patients who do not benefit from endocrine or anti-HER2 therapy. Rather than being a biological entity, TNBC represents a heterogeneous disease, and further subtyping is necessary to establish targeted therapies. Germline mutational status may serve as a robust biomarker predicting therapy response, especially with respect to compounds challenging the DNA repair machinery. Patients with TNBC usually show an early onset of the disease, as well as a positive family history of breast and/or ovarian cancer in more than one third of all cases, which suggests that TNBC is closely associated with a hereditary disease cause. In unselected TNBC cases, the prevalence of pathogenic germline BRCA1/2 mutations is approximately twice as high as in breast cancer overall. Early age at diagnosis and positive family history are strong predictors for an increased BRCA1/2 mutation probability, which is up to 40% when both risk factors are considered. Apart from BRCA1/2, the rarely mutated breast cancer predisposition genes PALB2 and FANCM have been associated with TNBC. This review summarizes the role of germline mutational status in TNBC pathogenesis. Clinical trials addressing BRCA1/2 mutation carriers are discussed.

PMID: 28611536 [PubMed]

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In vitro downregulated hypoxia transcriptome is associated with poor prognosis in breast cancer

Abstract

Background

Hypoxia is a characteristic of breast tumours indicating poor prognosis. Based on the assumption that those genes which are up-regulated under hypoxia in cell-lines are expected to be predictors of poor prognosis in clinical data, many signatures of poor prognosis were identified. However, it was observed that cell line data do not always concur with clinical data, and therefore conclusions from cell line analysis should be considered with caution. As many transcriptomic cell-line datasets from hypoxia related contexts are available, integrative approaches which investigate these datasets collectively, while not ignoring clinical data, are required.

Results

We analyse sixteen heterogeneous breast cancer cell-line transcriptomic datasets in hypoxia-related conditions collectively by employing the unique capabilities of the method, UNCLES, which integrates clustering results from multiple datasets and can address questions that cannot be answered by existing methods. This has been demonstrated by comparison with the state-of-the-art iCluster method. From this collection of genome-wide datasets include 15,588 genes, UNCLES identified a relatively high number of genes (>1000 overall) which are consistently co-regulated over all of the datasets, and some of which are still poorly understood and represent new potential HIF targets, such as RSBN1 and KIAA0195. Two main, anti-correlated, clusters were identified; the first is enriched with MYC targets participating in growth and proliferation, while the other is enriched with HIF targets directly participating in the hypoxia response. Surprisingly, in six clinical datasets, some sub-clusters of growth genes are found consistently positively correlated with hypoxia response genes, unlike the observation in cell lines. Moreover, the ability to predict bad prognosis by a combined signature of one sub-cluster of growth genes and one sub-cluster of hypoxia-induced genes appears to be comparable and perhaps greater than that of known hypoxia signatures.

Conclusions

We present a clustering approach suitable to integrate data from diverse experimental set-ups. Its application to breast cancer cell line datasets reveals new hypoxia-regulated signatures of genes which behave differently when in vitro (cell-line) data is compared with in vivo (clinical) data, and are of a prognostic value comparable or exceeding the state-of-the-art hypoxia signatures.

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Kidney and Brain, an Unbroken Chain

American Journal of Respiratory and Critical Care Medicine, Volume 195, Issue 12, Page 1546-1548, June 15, 2017.


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Update in Sleep-disordered Breathing 2016

American Journal of Respiratory and Critical Care Medicine, Volume 195, Issue 12, Page 1561-1566, June 15, 2017.


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Reply: Is the Muscle the Only Potential Target of Desipramine in Obstructive Sleep Apnea Syndrome?

American Journal of Respiratory and Critical Care Medicine, Volume 195, Issue 12, Page 1678-1679, June 15, 2017.


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Pulmonary Hypertension and Precision Medicine through the “Omics” Looking Glass

American Journal of Respiratory and Critical Care Medicine, Volume 195, Issue 12, Page 1558-1560, June 15, 2017.


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