Integrative molecular and functional profiling of ERBB2-amplified breast cancers identifies new genetic dependencies.

Overexpression of the receptor tyrosine kinase ERBB2 (also known as HER2) occurs in around 15% of breast cancers and is driven by amplification of the ERBB2 gene. ERBB2 amplification is a marker of poor prognosis, and although anti-ERBB2-targeted therapies have shown significant clinical benefit, de novo and acquired resistance remains an important problem. Genomic profiling has demonstrated that ERBB2+ve breast cancers are distinguished from ER+ve and 'triple-negative' breast cancers by harbouring not only the ERBB2 amplification on 17q12, but also a number of co-amplified genes on 17q12 and amplification events on other chromosomes. Some of these genes may have important roles in influencing clinical outcome, and could represent genetic dependencies in ERBB2+ve cancers and therefore potential therapeutic targets. Here, we describe an integrated genomic, gene expression and functional analysis to determine whether the genes present within amplicons are critical for the survival of ERBB2+ve breast tumour cells. We show that only a fraction of the ERBB2-amplified breast tumour lines are truly addicted to the ERBB2 oncogene at the mRNA level and display a heterogeneous set of additional genetic dependencies. These include an addiction to the transcription factor gene TFAP2C when it is amplified and overexpressed, suggesting that TFAP2C represents a genetic dependency in some ERBB2+ve breast cancer cell

Tumour microenvironment characterisation to stratify patients for hyperthermic intraperitoneal chemotherapy in high-grade serous ovarian cancer (OVHIPEC-1).

BACKGROUND Hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival in patients with Stage III ovarian cancer following interval cytoreductive surgery (CRS). Optimising patient selection is essential to maximise treatment efficacy and avoid overtreatment. This study aimed to identify biomarkers that predict HIPEC benefit by analysing gene signatures and cellular composition of tumours from participants in the OVHIPEC-1 trial. METHODS Whole-transcriptome RNA sequencing data were retrieved from high-grade serous ovarian cancer (HGSOC) samples from 147 patients obtained during interval CRS. We performed differential gene expression analysis and applied deconvolution methods to estimate cell-type proportions in bulk mRNA data, validated by histological assessment. We tested the interaction between treatment and potential predictors on progression-free survival using Cox proportional hazards models. RESULTS While differential gene expression analysis did not yield any predictive biomarkers, the cellular composition, as characterised by deconvolution, indicated that the absence of macrophages and the presence of B cells in the tumour microenvironment are potential predictors of HIPEC benefit. The histological assessment confirmed the predictive value of macrophage absence. CONCLUSION Immune cell composition, in particular macrophages absence, may predict response to HIPEC in HGSOC and these hypothesis-generating findings warrant further investigation. CLINICAL TRIAL REGISTRATION NCT00426257

Carcinogenic Effects in a Phenylketonuria Mouse Model

Phenylketonuria (PKU) is a metabolic disorder caused by impaired phenylalanine hydroxylase (PAH). This condition results in hyperphenylalaninemia and elevated levels of abnormal phenylalanine metabolites, among which is phenylacetic acid/phenylacetate (PA). In recent years, PA and its analogs were found to have anticancer activity against a variety of malignancies suggesting the possibility that PKU may offer protection against cancer through chronically elevated levels of PA. We tested this hypothesis in a genetic mouse model of PKU (PAHenu2) which has a biochemical profile that closely resembles that of human PKU. Plasma levels of phenylalanine in homozygous (HMZ) PAHenu2 mice were >12-fold those of heterozygous (HTZ) littermates while tyrosine levels were reduced. Phenylketones, including PA, were also markedly elevated to the range seen in the human disease. Mice were subjected to 7,12 dimethylbenz[a]anthracene (DMBA) carcinogenesis, a model which is sensitive to the anticancer effects of the PA derivative 4-chlorophenylacetate (4-CPA). Tumor induction by DMBA was not significantly different between the HTZ and HMZ mice, either in total tumor development or in the type of cancers that arose. HMZ mice were then treated with 4-CPA as positive controls for the anticancer effects of PA and to evaluate its possible effects on phenylalanine metabolism in PKU mice. 4-CPA had no effect on the plasma concentrations of phenylalanine, phenylketones, or tyrosine. Surprisingly, the HMZ mice treated with 4-CPA developed an unexplained neuromuscular syndrome which precluded its use in these animals as an anticancer agent. Together, these studies support the use of PAHenu2 mice as a model for studying human PKU. Chronically elevated levels of PA in the PAHenu2 mice were not protective against cancer

Author disambiguation using multi-aspect similarity indicators

Key to accurate bibliometric analyses is the ability to correctly link individuals to their corpus of work, with an optimal balance between precision and recall. We have developed an algorithm that does this disambiguation task with a very high recall and precision. The method addresses the issues of discarded records due to null data fields and their resultant effect on recall, precision and F-measure results. We have implemented a dynamic approach to similarity calculations based on all available data fields. We have also included differences in author contribution and age difference between publications, both of which have meaningful effects on overall similarity measurements, resulting in significantly higher recall and precision of returned records. The results are presented from a test dataset of heterogeneous catalysis publications. Results demonstrate significantly high average F-measure scores and substantial improvements on previous and stand-alone techniques

Immunohistochemical Profile for Unknown Primary Adenocarcinoma

BACKGROUND: Development of tailored treatment based on immunohistochemical profiles (IPs) of tumors for cancers of unknown primary is needed. METHODOLOGY/PRINCIPAL FINDINGS: We developed an algorithm based on primary known adenocarcinoma for testing sensitivity and specificity. Formalin-fixed paraffin-embedded tissue samples from 71 patients of unfavorable subsets of unknown primary adenocarcinoma were obtained. We examined 15 molecular markers using the algorithm incorporating these IPs and classified the tumours into 9 subsets based on the primary tumour site. The sensitivity and specificity of this algorithm were 80.3% and 97.6%, respectively. Apparent primary sites were lung in 17 patients, digestive organs in 13, gynecological organs in 9, prostate in 7, liver or kidney in 6, breast in 4, urothelial organ in 2, biliary tract and pancreatic profile in none, and unclassified in 13. The response rate to chemotherapy was highest for the gynecological IPs. Patients with gynecological or lung cancer IPs had longer median progression-free survival than those with others: 11.2 months for gynecological IPs (p<0.001) and 6.8 months for lung IPs (p = 0.05). Lung, digestive, prostate, and gynecological profiles were associated with significantly longer median survival time than the other profiles. Multivariate analysis confirmed that the IPs were independent prognostic factors for survival. CONCLUSIONS/SIGNIFICANCE: The IPs identified in this study can be used to further stratify patient prognosis for unfavorable subsets of unknown primary adenocarcinoma

BRCA1-mutated and basal-like breast cancers have similar aCGH profiles and a high incidence of protein truncating TP53 mutations

<p>Abstract</p> <p>Background</p> <p>Basal-like breast cancers (BLBC) are aggressive breast cancers for which, so far, no targeted therapy is available because they typically lack expression of hormone receptors and HER2. Phenotypic features of BLBCs, such as clinical presentation and early age of onset, resemble those of breast tumors from <it>BRCA1</it>-mutation carriers. The genomic instability of <it>BRCA1</it>-mutated tumors can be effectively targeted with DNA-damaging agents and poly-(ADP-ribose) polymerase 1 (PARP1) inhibitors. Molecular similarities between BLBCs and <it>BRCA1</it>-mutated tumors may therefore provide predictive markers for therapeutic response of BLBCs.</p> <p>Methods</p> <p>There are several known molecular features characteristic for <it>BRCA1</it>-mutated breast tumors: 1) increased numbers of genomic aberrations, 2) a distinct pattern of genomic aberrations, 3) a high frequency of <it>TP53 </it>mutations and 4) a high incidence of complex, protein-truncating <it>TP53 </it>mutations. We compared the frequency of <it>TP53 </it>mutations and the pattern and amount of genomic aberrations between <it>BRCA1</it>-mutated breast tumors, BLBCs and luminal breast tumors by <it>TP53 </it>gene sequencing and array-based comparative genomics hybridization (aCGH) analysis.</p> <p>Results</p> <p>We found that the high incidence of protein truncating <it>TP53 </it>mutations and the pattern and amount of genomic aberrations specific for BRCA1-mutated breast tumors are also characteristic for BLBCs and different from luminal breast tumors.</p> <p>Conclusions</p> <p>Complex, protein truncating TP53 mutations in BRCA1-mutated tumors may be a direct consequence of genomic instability caused by BRCA1 loss, therefore, the presence of these types of TP53 mutations in sporadic BLBCs might be a hallmark of BRCAness and a potential biomarker for sensitivity to PARP inhibition. Also, our data suggest that a small subset of genomic regions may be used to identify BRCA1-like BLBCs. BLBCs share molecular features that were previously found to be specific for BRCA1-mutated breast tumors. These features might be useful for the identification of tumors with increased sensitivity to (high-dose or dose-dense) alkylating agents and PARP inhibitors.</p

Culturally valuable minority crops provide a succession of floral resources for flower visitors in traditional orchard gardens

Agricultural intensification typically has detrimental effects on pollinator communities, but diverse cropping systems that contain sequentially-flowering crops have the potential to benefit pollinators through the provision of additional floral resources. In this study we investigate the importance of cultivated flora for flower visitors in ten agricultural gardens in South Sinai, Egypt. Insect-flower interactions in gardens and unmanaged plots were surveyed across a four-month period in two environmentally distinct years (pre-flood and post-flood). Despite containing an equal abundance and diversity of wild plants as unmanaged habitat, gardens supported a higher abundance and diversity of flower visitors due to the additional presence of cultivated flora. Visitation networks exhibited dramatic intra-annual changes in composition, with cultivated plants becoming increasingly important in later months. Trends were highly conserved across 2 years despite highly contrasting rainfall. Several key crop species were strongly involved in shaping the structure of the networks, the majority of which were herbs with strong cultural significance (fennel, rosemary, mint) and grown incidentally alongside the primary orchard crops. Minority crops are frequently overlooked in agricultural systems due to their low economic value, but we show that they can have a dramatic influence upon the structure of visitation networks, increasing both pollinator abundance and diversity, and emphasising the link between cultural practices and biodiversity conservation