IODNE: An integrated optimization method for identifying the deregulated subnetwork for precision medicine in cancer.

Subnetwork analysis can explore complex patterns of entire molecular pathways for the purpose of drug target identification. In this article, the gene expression profiles of a cohort of patients with breast cancer are integrated with protein-protein interaction (PPI) networks using, simultaneously, both edge scoring and node scoring. A novel optimization algorithm, integrated optimization method to identify deregulated subnetwork (IODNE), is developed to search for the optimal dysregulated subnetwork of the merged gene and protein network. IODNE is applied to select subnetworks for Luminal-A breast cancer from The Cancer Genome Atlas (TCGA) data. A large fraction of cancer-related genes and the well-known clinical targets, ER1/PR and HER2, are found by IODNE. This validates the utility of IODNE. When applying IODNE to the triple-negative breast cancer (TNBC) subtype data, we identified subnetworks that contain genes such as ERBB2, HRAS, PGR, CAD, POLE, and SLC2A1.

Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100.

BACKGROUND: Bevacizumab has broad anti-tumour activity, but substantial risk of hypertension. No reliable markers are available for predicting bevacizumab-induced hypertension. METHODS: A genome-wide association study (GWAS) was performed in the phase III bevacizumab-based adjuvant breast cancer trial, ECOG-5103, to evaluate for an association between genotypes and hypertension. GWAS was conducted in those who had experienced systolic blood pressure (SBP) >160 mm Hg during therapy using binary analysis and a cumulative dose model for the total exposure of bevacizumab. Common toxicity criteria (CTC) grade 3-5 hypertension was also assessed. Candidate SNP validation was performed in the randomised phase III trial, ECOG-2100. RESULTS: When using the phenotype of SBP>160 mm Hg, the most significant association in SV2C (rs6453204) approached and met genome-wide significance in the binary model (P=6.0 × 10(-8); OR=3.3) and in the cumulative dose model (P=4.7 × 10(-8); HR=2.2), respectively. Similar associations with rs6453204 were seen for CTC grade 3-5 hypertension but did not meet genome-wide significance. Validation study from ECOG-2100 demonstrated a statistically significant association between this SNP and grade 3/4 hypertension using the binary model (P-value=0.037; OR=2.4). CONCLUSIONS: A genetic variant in SV2C predicted clinically relevant bevacizumab-induced hypertension in two independent, randomised phase III trials.

Cancer-associated alteration of pericentromeric heterochromatin may contribute to chromosome instability.

Many tumors exhibit elevated chromosome mis-segregation termed chromosome instability (CIN), which is likely to be a potent driver of tumor progression and drug resistance. Causes of CIN are poorly understood but probably include prior genome tetraploidization, centrosome amplification and mitotic checkpoint defects. This study identifies epigenetic alteration of the centromere as a potential contributor to the CIN phenotype. The centromere controls chromosome segregation and consists of higher-order repeat (HOR) alpha-satellite DNA packaged into two chromatin domains: the kinetochore, harboring the centromere-specific H3 variant centromere protein A (CENP-A), and the pericentromeric heterochromatin, considered important for cohesion. Perturbation of centromeric chromatin in model systems causes CIN. As cancer cells exhibit widespread chromatin changes, we hypothesized that pericentromeric chromatin structure could also be affected, contributing to CIN. Cytological and chromatin immunoprecipitation and PCR (ChIP-PCR)-based analyses of HT1080 cancer cells showed that only one of the two HORs on chromosomes 5 and 7 incorporate CENP-A, an organization conserved in all normal and cancer-derived cells examined. Contrastingly, the heterochromatin marker H3K9me3 (trimethylation of H3 lysine 9) mapped to all four HORs and ChIP-PCR showed an altered pattern of H3K9me3 in cancer cell lines and breast tumors, consistent with a reduction on the kinetochore-forming HORs. The JMJD2B demethylase is overexpressed in breast tumors with a CIN phenotype, and overexpression of exogenous JMJD2B in cultured breast epithelial cells caused loss of centromere-associated H3K9me3 and increased CIN. These findings suggest that impaired maintenance of pericentromeric heterochromatin may contribute to CIN in cancer and be a novel therapeutic target.

Association of genotypes of the CYP3A cluster with midazolam disposition in vivo.

The genes that encode for CYP3A4 and CYP3A5 are located in the same region (CYP3A cluster) on chromosome 7. Midazolam (MDZ) is a substrate for both CYP3A4 and CYP3A5. We hypothesize that MDZ disposition in vivo is associated with genotypes of the CYP3A cluster. A meta-analysis of the pharmacokinetic (PK) parameters from seven clinical trials was carried out, in which MDZ was administered both intravenously and orally. DNA samples were available from 116 patients. There were significant ethnic differences in the allelic frequencies of these four common single-nucleotide polymorphisms (SNPs) in the CYP3A cluster. Significant linkage disequilibrium was found between CYP3A5(*)3 and CYP3A4(*)1A in Caucasians, and between CYP3A5(*)1 and CYP3A4(*)1B in African Americans. There were no differences in MDZ disposition in vivo between different genotypes, haplotypes and diplotypes in the CYP3A cluster (P>0.05). No significant differences in MDZ PK parameters were observed between Caucasians and African Americans. Women had higher weight-corrected systemic and oral clearance than men, but dose-adjusted AUC and bioavailability differences were not observed between sexes. The clinical importance of elevated CYP3A activity in women remains to be determined. The r(GC)'s of MDZ PK parameters were between 0.3 and 13.6%. In conclusion, the meta-analysis of seven studies suggests that environmental factors explain the majority of CYP3A activity variation. Further studies are necessary to define the functional significance of SNPs in the CYP3A cluster and the effects of CYP3A genotypes on MDZ disposition in vivo.

A test of the nature of cosmic acceleration using galaxy redshift distortions.

Observations of distant supernovae indicate that the Universe is now in a phase of accelerated expansion the physical cause of which is a mystery. Formally, this requires the inclusion of a term acting as a negative pressure in the equations of cosmic expansion, accounting for about 75 per cent of the total energy density in the Universe. The simplest option for this 'dark energy' corresponds to a 'cosmological constant', perhaps related to the quantum vacuum energy. Physically viable alternatives invoke either the presence of a scalar field with an evolving equation of state, or extensions of general relativity involving higher-order curvature terms or extra dimensions. Although they produce similar expansion rates, different models predict measurable differences in the growth rate of large-scale structure with cosmic time. A fingerprint of this growth is provided by coherent galaxy motions, which introduce a radial anisotropy in the clustering pattern reconstructed by galaxy redshift surveys. Here we report a measurement of this effect at a redshift of 0.8. Using a new survey of more than 10,000 faint galaxies, we measure the anisotropy parameter beta = 0.70 +/- 0.26, which corresponds to a growth rate of structure at that time of f = 0.91 +/- 0.36. This is consistent with the standard cosmological-constant model with low matter density and flat geometry, although the error bars are still too large to distinguish among alternative origins for the accelerated expansion. The correct origin could be determined with a further factor-of-ten increase in the sampled volume at similar redshift.

A large population of galaxies 9 to 12 billion years back in the history of the Universe.

To understand the evolution of galaxies, we need to know as accurately as possible how many galaxies were present in the Universe at different epochs. Galaxies in the young Universe have hitherto mainly been identified using their expected optical colours, but this leaves open the possibility that a significant population remains undetected because their colours are the result of a complex mix of stars, gas, dust or active galactic nuclei. Here we report the results of a flux-limited I-band survey of galaxies at look-back times of 9 to 12 billion years. We find 970 galaxies with spectroscopic redshifts between 1.4 and 5. This population is 1.6 to 6.2 times larger than previous estimates, with the difference increasing towards brighter magnitudes. Strong ultraviolet continua (in the rest frame of the galaxies) indicate vigorous star formation rates of more than 10-100 solar masses per year. As a consequence, the cosmic star formation rate representing the volume-averaged production of stars is higher than previously measured at redshifts of 3 to 4.