Practical considerations for optimising homologous recombination repair mutation testing in patients with metastatic prostate cancer

Reparació per recombinació homòloga; Càncer de pròstata metastàtic; Inhibidors de la poli(ADP-ribosa) polimerasaReparación por recombinación homóloga; Cáncer de próstata metastásico; Inhibidores de la poli(ADP-ribosa) polimerasaHomologous recombination repair; Metastatic prostate cancer; Poly(ADP-ribose) polymerase inhibitorsAnalysis of the genomic landscape of prostate cancer has identified different molecular subgroups with relevance for novel or existing targeted therapies. The recent approvals of the poly(ADP-ribose) polymerase (PARP) inhibitors olaparib and rucaparib in the metastatic castration-resistant prostate cancer (mCRPC) setting signal the need to embed molecular diagnostics in the clinical pathway of patients with mCRPC to identify those who can benefit from targeted therapies. Best practice guidelines in overall biospecimen collection and processing for molecular analysis are widely available for several tumour types. However, there is no standard protocol for molecular diagnostic testing in prostate cancer. Here, we provide a series of recommendations on specimen handling, sample pre-analytics, laboratory workflow, and testing pathways to maximise the success rates for clinical genomic analysis in prostate cancer. Early involvement of a multidisciplinary team of pathologists, urologists, oncologists, radiologists, nurses, molecular scientists, and laboratory staff is key to enable optimal workflow for specimen selection and preservation at the time of diagnosis so that samples are available for molecular analysis when required. Given the improved outcome of patients with mCRPC and homologous recombination repair gene alterations who have been treated with PARP inhibitors, there is an urgent need to incorporate high-quality genomic testing in the routine clinical pathway of these patients.JM has served on advisory boards for Amgen, AstraZeneca, Clovis Oncology, Janssen, Merck/MSD, and Roche; has participated in speaker bureaus for AstraZeneca, Pfizer, Janssen, Sanofi, and Astellas Pharma; and has received research funding from AstraZeneca and Pfizer Oncology through grants to his institution

Identification of DEK as a potential therapeutic target for neuroendocrine prostate cancer

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer which does not respond to hormone therapy. Research of NEPC has been hampered by a lack of clinically relevant in vivo models. Recently, we developed a first-in-field patient tissue-derived xenograft model of complete neuroendocrine transdifferentiation of prostate adenocarcinoma. By comparing gene expression profiles of a transplantable adenocarcinoma line (LTL331) and its NEPC subline (LTL331R), we identified DEK as a potential biomarker and therapeutic target for NEPC. In the present study, elevated DEK protein expression was observed in all NEPC xenograft models and clinical NEPC cases, as opposed to their benign counterparts (0%), hormonal naïve prostate cancer (2.45%) and castration-resistant prostate cancer (29.55%). Elevated DEK expression was found to be an independent clinical risk factor, associated with shorter disease-free survival of hormonal naïve prostate cancer patients. DEK silencing in PC-3 cells led to a marked reduction in cell proliferation, cell migration and invasion. The results suggest that DEK plays an important role in the progression of prostate cancer, especially to NEPC, and provides a potential biomarker to aid risk stratification of prostate cancer and a novel target for therapy of NEPC

Circumstellar discs: What will be next?

This prospective chapter gives our view on the evolution of the study of circumstellar discs within the next 20 years from both observational and theoretical sides. We first present the expected improvements in our knowledge of protoplanetary discs as for their masses, sizes, chemistry, the presence of planets as well as the evolutionary processes shaping these discs. We then explore the older debris disc stage and explain what will be learnt concerning their birth, the intrinsic links between these discs and planets, the hot dust and the gas detected around main sequence stars as well as discs around white dwarfs.Comment: invited review; comments welcome (32 pages

Allele-informed copy number evaluation of plasma DNA samples from metastatic prostate cancer patients: the PCF_SELECT consortium assay.

Sequencing of cell-free DNA (cfDNA) in cancer patients' plasma offers a minimally-invasive solution to detect tumor cell genomic alterations to aid real-time clinical decision-making. The reliability of copy number detection decreases at lower cfDNA tumor fractions, limiting utility at earlier stages of the disease. To test a novel strategy for detection of allelic imbalance, we developed a prostate cancer bespoke assay, PCF_SELECT, that includes an innovative sequencing panel covering ∼25 000 high minor allele frequency SNPs and tailored analytical solutions to enable allele-informed evaluation. First, we assessed it on plasma samples from 50 advanced prostate cancer patients. We then confirmed improved detection of genomic alterations in samples with <10% tumor fractions when compared against an independent assay. Finally, we applied PCF_SELECT to serial plasma samples intensively collected from three patients previously characterized as harboring alterations involving DNA repair genes and consequently offered PARP inhibition. We identified more extensive pan-genome allelic imbalance than previously recognized in prostate cancer. We confirmed high sensitivity detection of BRCA2 allelic imbalance with decreasing tumor fractions resultant from treatment and identified complex ATM genomic states that may be incongruent with protein losses. Overall, we present a framework for sensitive detection of allele-specific copy number changes in cfDNA

Extrasolar planet population synthesis IV. Correlations with disk metallicity, mass and lifetime

Context. This is the fourth paper in a series showing the results of planet population synthesis calculations. Aims. Our goal in this paper is to systematically study the effects of important disk properties, namely disk metallicity, mass and lifetime on fundamental planetary properties. Methods. For a large number of protoplanetary disks we calculate a population of planets with our core accretion formation model including planet migration and disk evolution. Results. We find a large number of correlations: Regarding the planetary initial mass function, metallicity, disk mass and disk lifetime have different roles: For high [Fe/H], giant planets are more frequent. For high disk masses, giant planets are more massive. For long disk lifetimes, giant planets are both more frequent and massive. At low metallicities, very massive giant planets cannot form, but otherwise giant planet mass and metallicity are uncorrelated. In contrast, planet masses and disk gas masses are correlated. The sweet spot for giant planet formation is at 5 AU. In- and outside this distance, higher planetesimals surface densities are necessary. Low metallicities can be compensated by high disk masses, and vice versa, but not ad infinitum. At low metallicities, giant planets only form outside the ice line, while at high metallicities, giant planet formation occurs throughout the disk. The extent of migration increases with disk mass and lifetime and usually decreases with metallicity. No clear correlation of metallicity and the semimajor axis of giant planets exists because in low [Fe/H] disks, planets start further out, but migrate more, whereas for high [Fe/H] they start further in, but migrate less. Close-in low mass planets have a lower mean metallicity than Hot Jupiters. Conclusions. The properties of protoplanetary disks are decisive for the properties of planets, and leave many imprints.Comment: 23 pages, 16 figures. Accepted for A&

Allele-informed copy number evaluation of plasma DNA samples from metastatic prostate cancer patients: the PCF_SELECT consortium assay

Sequencing of cell-free DNA (cfDNA) in cancer patients' plasma offers a minimally-invasive solution to detect tumor cell genomic alterations to aid real-time clinical decision-making. The reliability of copy number detection decreases at lower cfDNA tumor fractions, limiting utility at earlier stages of the disease. To test a novel strategy for detection of allelic imbalance, we developed a prostate cancer bespoke assay, PCF_SELECT, that includes an innovative sequencing panel covering ∼25 000 high minor allele frequency SNPs and tailored analytical solutions to enable allele-informed evaluation. First, we assessed it on plasma samples from 50 advanced prostate cancer patients. We then confirmed improved detection of genomic alterations in samples with <10% tumor fractions when compared against an independent assay. Finally, we applied PCF_SELECT to serial plasma samples intensively collected from three patients previously characterized as harboring alterations involving DNA repair genes and consequently offered PARP inhibition. We identified more extensive pan-genome allelic imbalance than previously recognized in prostate cancer. We confirmed high sensitivity detection of BRCA2 allelic imbalance with decreasing tumor fractions resultant from treatment and identified complex ATM genomic states that may be incongruent with protein losses. Overall, we present a framework for sensitive detection of allele-specific copy number changes in cfDNA

Kondo effect in coupled quantum dots: a Non-crossing approximation study

The out-of-equilibrium transport properties of a double quantum dot system in the Kondo regime are studied theoretically by means of a two-impurity Anderson Hamiltonian with inter-impurity hopping. The Hamiltonian, formulated in slave-boson language, is solved by means of a generalization of the non-crossing approximation (NCA) to the present problem. We provide benchmark calculations of the predictions of the NCA for the linear and nonlinear transport properties of coupled quantum dots in the Kondo regime. We give a series of predictions that can be observed experimentally in linear and nonlinear transport measurements through coupled quantum dots. Importantly, it is demonstrated that measurements of the differential conductance ${\cal G}=dI/dV$, for the appropriate values of voltages and inter-dot tunneling couplings, can give a direct observation of the coherent superposition between the many-body Kondo states of each dot. This coherence can be also detected in the linear transport through the system: the curve linear conductance vs temperature is non-monotonic, with a maximum at a temperature $T^*$ characterizing quantum coherence between both Kondo states.Comment: 20 pages, 17 figure