Integrative DNA methylome analysis of pan-cancer biomarkers in cancer discordant monozygotic twin-pairs

BACKGROUND: A key focus in cancer research is the discovery of biomarkers that accurately diagnose early lesions in non-invasive tissues. Several studies have identified malignancy-associated DNA methylation changes in blood, yet no general cancer biomarker has been identified to date. Here, we explore the potential of blood DNA methylation as a biomarker of pan-cancer (cancer of multiple different origins) in 41 female cancer discordant monozygotic (MZ) twin-pairs sampled before or after diagnosis using the Illumina HumanMethylation450 BeadChip. RESULTS: We analysed epigenome-wide DNA methylation profiles in 41 cancer discordant MZ twin-pairs with affected individuals diagnosed with tumours at different single primary sites: the breast, cervix, colon, endometrium, thyroid gland, skin (melanoma), ovary, and pancreas. No significant global differences in whole blood DNA methylation profiles were observed. Epigenome-wide analyses identified one novel pan-cancer differentially methylated position at false discovery rate (FDR) threshold of 10 % (cg02444695, P = 1.8 × 10(-7)) in an intergenic region 70 kb upstream of the SASH1 tumour suppressor gene, and three suggestive signals in COL11A2, AXL, and LINC00340. Replication of the four top-ranked signals in an independent sample of nine cancer-discordant MZ twin-pairs showed a similar direction of association at COL11A2, AXL, and LINC00340, and significantly greater methylation discordance at AXL compared to 480 healthy concordant MZ twin-pairs. The effects at cg02444695 (near SASH1), COL11A2, and LINC00340 were the most promising in biomarker potential because the DNA methylation differences were found to pre-exist in samples obtained prior to diagnosis and were limited to a 5-year period before diagnosis. Gene expression follow-up at the top-ranked signals in 283 healthy individuals showed correlation between blood methylation and gene expression in lymphoblastoid cell lines at PRL, and in the skin tissue at AXL. A significant enrichment of differential DNA methylation was observed in enhancer regions (P = 0.03). CONCLUSIONS: We identified DNA methylation signatures in blood associated with pan-cancer, at or near SASH1, COL11A2, AXL, and LINC00340. Three of these signals were present up to 5 years prior to cancer diagnosis, highlighting the potential clinical utility of whole blood DNA methylation analysis in cancer surveillance

Renormalisation-theoretic analysis of non-equilibrium phase transitions II: The effect of perturbations on rate coefficients in the Becker-Doring equations

We study in detail the application of renormalisation theory to models of cluster aggregation and fragmentation of relevance to nucleation and growth processes. In particular, we investigate the Becker-Doring (BD) equations, originally formulated to describe and analyse non-equilibrium phase transitions, but more recently generalised to describe a wide range of physicochemical problems. We consider here rate coefficients which depend on the cluster size in a power-law fashion, but now perturbed by small amplitude random noise. Power-law rate coefficients arise naturally in the theory of surface-controlled nucleation and growth processes. The noisy perturbations on these rates reflect the effect of microscopic variations in such mean-field coefficients, thermal fluctuations and/or experimental uncertainties. In the present paper we generalise our earlier work that identified the nine classes into which all dynamical behaviour must fall by investigating how random perturbations of the rate coefficients influence the steady-state and kinetic behaviour of the coarse-grained, renormalised system. We are hence able to confirm the existence of a set of up to nine universality classes for such BD systems.Comment: 30 pages, to appear in J Phys A Math Ge

Kinetic Anomalies in Addition-Aggregation Processes

We investigate irreversible aggregation in which monomer-monomer, monomer-cluster, and cluster-cluster reactions occur with constant but distinct rates K_{MM}, K_{MC}, and K_{CC}, respectively. The dynamics crucially depends on the ratio gamma=K_{CC}/K_{MC} and secondarily on epsilon=K_{MM}/K_{MC}. For epsilon=0 and gamma<2, there is conventional scaling in the long-time limit, with a single mass scale that grows linearly in time. For gamma >= 2, there is unusual behavior in which the concentration of clusters of mass k, c_k decays as a stretched exponential in time within a boundary layer k<k* propto t^{1-2/gamma} (k* propto ln t for gamma=2), while c_k propto t^{-2} in the bulk region k>k*. When epsilon>0, analogous behaviors emerge for gamma<2 and gamma >= 2.Comment: 6 pages, 2 column revtex4 format, for submission to J. Phys.

Fluctuation-driven insulator-to-metal transition in an external magnetic field

We consider a model for a metal-insulator transition of correlated electrons in an external magnetic field. We find a broad region in interaction and magnetic field where metallic and insulating (fully magnetized) solutions coexist and the system undergoes a first-order metal-insulator transition. A global instability of the magnetically saturated solution precedes the local ones and is caused by collective fluctuations due to poles in electron-hole vertex functions.Comment: REVTeX 4 pages, 3 PS figure

Orbital-selective Mott transitions in the anisotropic two-band Hubbard model at finite temperatures

The anisotropic degenerate two-orbital Hubbard model is studied within dynamical mean-field theory at low temperatures. High-precision calculations on the basis of a refined quantum Monte Carlo (QMC) method reveal that two distinct orbital-selective Mott transitions occur for a bandwidth ratio of 2 even in the absence of spin-flip contributions to the Hund exchange. The second transition -- not seen in earlier studies using QMC, iterative perturbation theory, and exact diagonalization -- is clearly exposed in a low-frequency analysis of the self-energy and in local spectra.Comment: 4 pages, 5 figure

Integrating computer log files for process mining: a genetic algorithm inspired technique

Process mining techniques are applied to single computer log files. But many processes are supported by different software tools and are by consequence recorded into multiple log files. Therefore it would be interesting to find a way to automatically combine such a set of log files for one process. In this paper we describe a technique for merging log files based on a genetic algorithm. We show with a generated test case that this technique works and we give an extended overview of which research is needed to optimise and validate this technique

Raman scattering through a metal-insulator transition

The exact solution for nonresonant A1g and B1g Raman scattering is presented for the simplest model that has a correlated metal-insulator transition--the Falicov-Kimball model, by employing dynamical mean field theory. In the general case, the A1g response includes nonresonant, resonant, and mixed contributions, the B1g response includes nonresonant and resonant contributions (we prove the Shastry-Shraiman relation for the nonresonant B1g response) while the B2g response is purely resonant. Three main features are seen in the nonresonant B1g channel: (i) the rapid appearance of low-energy spectral weight at the expense of higher-energy weight; (b) the frequency range for this low-energy spectral weight is much larger than the onset temperature, where the response first appears; and (iii) the occurrence of an isosbestic point, which is a characteristic frequency where the Raman response is independent of temperature for low temperatures. Vertex corrections renormalize away all of these anomalous features in the nonresonant A1g channel. The calculated results compare favorably to the Raman response of a number of correlated systems on the insulating side of the quantum-critical point (ranging from Kondo insulators, to mixed-valence materials, to underdoped high-temperature superconductors). We also show why the nonresonant B1g Raman response is ``universal'' on the insulating side of the metal-insulator transition.Comment: 12 pages, 11 figures, ReVTe

Phase separation and the segregation principle in the infinite-U spinless Falicov-Kimball model

The simplest statistical-mechanical model of crystalline formation (or alloy formation) that includes electronic degrees of freedom is solved exactly in the limit of large spatial dimensions and infinite interaction strength. The solutions contain both second-order phase transitions and first-order phase transitions (that involve phase-separation or segregation) which are likely to illustrate the basic physics behind the static charge-stripe ordering in cuprate systems. In addition, we find the spinodal-decomposition temperature satisfies an approximate scaling law.Comment: 19 pages and 10 figure