Efficiency considerations in the construction of interpolated potential energy surfaces for the calculation of quantum observables by diffusion Monte Carlo

A modified Shepard interpolation scheme is used to construct global potential energy surfaces (PES) in order to calculate quantum observables--vibrationally averaged internal coordinates, fully anharmonic zero-point energies and nuclear radial distribution functions--for a prototypical loosely bound molecular system, the water dimer. The efficiency of PES construction is examined with respect to (a) the method used to sample configurational space, (b) the method used to choose which points to add to the PES data set, and (c) the use of either a one- or two-part weight function. The most efficient method for constructing the PES is found to require a quantum sampling regime, a combination of both h-weight and rms methods for choosing data points and use of the two-part weight function in the interpolation. Using this regime, the quantum diffusion Monte Carlo zero-point energy converges to the exact result within addition of 50 data points. The vibrationally averaged O-O distance and O-O radial distribution function, however, converge more slowly and require addition of over 500 data points. The methods presented here are expected to be applicable to both other loosely bound complexes as well as tightly bound molecular species. When combined with high quality ab initio calculations, these methods should be able to accurately characterize the PES of such species.D.L.C. would like to acknowledge the financial support of an Australian Postgraduate Research Award. This work has also been supported by Large Grant No. A00104447 from the Australian Research Council and by grants of computer time from the Australian Partnership in Advanced Computing (APAC) National Merit Allocation Scheme

A classical trajectory study of the photodissociation of T₁ acetaldehyde: the transition from impulsive to statistical dynamics

Previous experimental and theoretical studies of the radical dissociation channel of T(1) acetaldehyde show conflicting behavior in the HCO and CH(3) product distributions. To resolve these conflicts, a full-dimensional potential-energy surface for the dissociation of CH(3)CHO into HCO and CH(3) fragments over the barrier on the T(1) surface is developed based on RO-CCSD(T)/cc-pVTZ(DZ) ab initio calculations. 20,000 classical trajectories are calculated on this surface at each of five initial excess energies, spanning the excitation energies used in previous experimental studies, and translational, vibrational, and rotational distributions of the radical products are determined. For excess energies near the dissociation threshold, both the HCO and CH(3) products are vibrationally cold; there is a small amount of HCO rotational excitation and little CH(3) rotational excitation, and the reaction energy is partitioned dominantly (>90% at threshold) into relative translational motion. Close to threshold the HCO and CH(3) rotational distributions are symmetrically shaped, resembling a Gaussian function, in agreement with observed experimental HCO rotational distributions. As the excess energy increases the calculated HCO and CH(3) rotational distributions are observed to change from a Gaussian shape at threshold to one more resembling a Boltzmann distribution, a behavior also seen by various experimental groups. Thus the distribution of energy in these rotational degrees of freedom is observed to change from nonstatistical to apparently statistical, as excess energy increases. As the energy above threshold increases all the internal and external degrees of freedom are observed to gain population at a similar rate, broadly consistent with equipartitioning of the available energy at the transition state. These observations generally support the practice of separating the reaction dynamics into two reservoirs: an impulsive reservoir, fed by the exit channel dynamics, and a statistical reservoir, supported by the random distribution of excess energy above the barrier. The HCO rotation, however, is favored by approximately a factor of 3 over the statistical prediction. Thus, at sufficiently high excess energies, although the HCO rotational distribution may be considered statistical, the partitioning of energy into HCO rotation is not.One of the authors D.L.C. acknowledges the financial support of an Australian Postgraduate Research Award. This work has also been supported in large by Grant No. A00104447 from the Australian Research Council and by grants of computer time from the Australian Partnership in Advanced Computing APAC National Merit Allocation Scheme

A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.DG is supported by the EU-FP7-SUPPRESSTEM project. SN-Z is funded by a Wellcome Trust Intermediate Fellowship (WT100183MA) and is a Wellcome Beit Fellow. For more information, please visit the publisher's website

Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials

Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.

Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases

Signatures of mutational processes in human cancer.

All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy

Landscape of somatic mutations in 560 breast cancer whole-genome sequences.

We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer

Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data.

A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses.We acknowledge support from Cancer Research UK (C5047/A22530, C309/A11566, C368/A6743, A368/A7990, C14303/A17197) and the Dallaglio Foundation. We also acknowledge support from the National Institute of Health Research (NIHR) (The Biomedical Research Centre at The Institute of Cancer Research & The Royal Marsden NHS Foundation Trust and the project "Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT)" [G0500966/75466]). We thank the Wellcome Trust, Bob Champion Cancer Trust, The Orchid Cancer appeal, The RoseTrees Trust, The North West Cancer Research Fund, Big C, The King family, and The Masonic Charitable Foundation for funding. This research is supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202), and the Wellcome Trust (FC001202). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Mutational signatures of ionizing radiation in second malignancies

Ionizing radiation is a potent carcinogen, inducing cancer through DNA damage. The signatures of mutations arising in human tissues following in vivo exposure to ionizing radiation have not been documented. Here, we searched for signatures of ionizing radiation in 12 radiation-associated second malignancies of different tumour types. Two signatures of somatic mutation characterize ionizing radiation exposure irrespective of tumour type. Compared with 319 radiation-naive tumours, radiation-associated tumours carry a median extra 201 deletions genome-wide, sized 1-100 base pairs often with microhomology at the junction. Unlike deletions of radiation-naive tumours, these show no variation in density across the genome or correlation with sequence context, replication timing or chromatin structure. Furthermore, we observe a significant increase in balanced inversions in radiation-associated tumours. Both small deletions and inversions generate driver mutations. Thus, ionizing radiation generates distinctive mutational signatures that explain its carcinogenic potential.This work was supported by funding from the Wellcome Trust (grant reference 077012/Z/05/Z), Skeletal Cancer Action Trust, Rosetrees Trust UK, Bone Cancer Research Trust, the RNOH NHS Trust, the National Institute for Health Research Health Protection Research Unit in Chemical and Radiation Hazards and Threats at Newcastle University in partnership with Public Health England. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health or Public Health England. Tissue was obtained from the RNOH Musculoskeletal Research Programme and Biobank, co-ordinated by Mrs Deidre Brooking and Mrs Ru Grinnell, Biobank staff, RNOH. Support was provided to AMF by the National Institute for Health Research, UCLH Biomedical Research Centre, and the CRUK UCL Experimental Cancer Centre. S.N.Z. and S.B. are personally funded through Wellcome Trust Intermediate Clinical Research Fellowships, P.J.C. through a Wellcome Trust Senior Clinical Research Fellowship

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)