No Image

Institutional implementation of clinical tumor profiling on an unselected cancer population.

October 5, 2018 dna 0
Icon for American Society for Clinical Investigation Icon for PubMed Central Related Articles

Institutional implementation of clinical tumor profiling on an unselected cancer population.

JCI Insight. 2016 11 17;1(19):e87062

Authors: Sholl LM, Do K, Shivdasani P, Cerami E, Dubuc AM, Kuo FC, Garcia EP, Jia Y, Davineni P, Abo RP, Pugh TJ, van Hummelen P, Thorner AR, Ducar M, Berger AH, Nishino M, Janeway KA, Church A, Harris M, Ritterhouse LL, Campbell JD, Rojas-Rudilla V, Ligon AH, Ramkissoon S, Cleary JM, Matulonis U, Oxnard GR, Chao R, Tassell V, Christensen J, Hahn WC, Kantoff PW, Kwiatkowski DJ, Johnson BE, Meyerson M, Garraway LA, Shapiro GI, Rollins BJ, Lindeman NI, MacConaill LE

Abstract
BACKGROUND. Comprehensive genomic profiling of a patient’s cancer can be used to diagnose, monitor, and recommend treatment. Clinical implementation of tumor profiling in an enterprise-wide, unselected cancer patient population has yet to be reported. METHODS. We deployed a hybrid-capture and massively parallel sequencing assay (OncoPanel) for all adult and pediatric patients at our combined cancer centers. Results were categorized by pathologists based on actionability. We report the results for the first 3,727 patients tested. RESULTS. Our cohort consists of cancer patients unrestricted by disease site or stage. Across all consented patients, half had sufficient and available (>20% tumor) material for profiling; once specimens were received in the laboratory for pathology review, 73% were scored as adequate for genomic testing. When sufficient DNA was obtained, OncoPanel yielded a result in 96% of cases. 73% of patients harbored an actionable or informative alteration; only 19% of these represented a current standard of care for therapeutic stratification. The findings recapitulate those of previous studies of common cancers but also identify alterations, including in AXL and EGFR, associated with response to targeted therapies. In rare cancers, potentially actionable alterations suggest the utility of a “cancer-agnostic” approach in genomic profiling. Retrospective analyses uncovered contextual genomic features that may inform therapeutic response and examples where diagnoses revised by genomic profiling markedly changed clinical management. CONCLUSIONS. Broad sequencing-based testing deployed across an unselected cancer cohort is feasible. Genomic results may alter management in diverse scenarios; however, additional barriers must be overcome to enable precision cancer medicine on a large scale. FUNDING. This work was supported by DFCI, BWH, and the National Cancer Institute (5R33CA155554 and 5K23CA157631).

PMID: 27882345 [PubMed – indexed for MEDLINE]

No Image

Current and Emerging Reconstituted HDL-apoA-I and HDL-apoE Approaches to Treat Atherosclerosis.

October 5, 2018 dna 0
Related Articles

Current and Emerging Reconstituted HDL-apoA-I and HDL-apoE Approaches to Treat Atherosclerosis.

J Pers Med. 2018 Oct 03;8(4):

Authors: Valanti EK, Dalakoura-Karagkouni K, Sanoudou D

Abstract
Atherosclerosis affects millions of people worldwide. However, the wide variety of limitations in the current therapeutic options leaves much to be desired in future lipid-lowering therapies. For example, although statins, which are the first-line treatment for coronary heart disease (CHD), reduce the risk of cardiovascular events in a large percentage of patients, they lead to optimal levels of low density lipoprotein-cholesterol (LDL-C) in only about one-third of patients. A new promising research direction against atherosclerosis aims to improve lipoprotein metabolism. Novel therapeutic approaches are being developed to increase the levels of functional high density lipoprotein (HDL) particles. This review aims to highlight the atheroprotective potential of the in vitro synthesized reconstituted HDL particles containing apolipoprotein E (apoE) as their sole apolipoprotein component (rHDL-apoE). For this purpose, we provide: (1) a summary of the atheroprotective properties of native plasma HDL and its apolipoprotein components, apolipoprotein A-I (apoA-I) and apoE; (2) an overview of the anti-atherogenic functions of rHDL-apoA-I and apoA-I-containing HDL, i.e., natural HDL isolated from transgenic Apoa1-/- × Apoe-/- mice overexpressing human apoA-I (HDL-apoA-I); and (3) the latest developments and therapeutic potential of HDL-apoE and rHDL-apoE. Novel rHDL formulations containing apoE could possibly present enhanced biological functions, leading to improved therapeutic efficacy against atherosclerosis.

PMID: 30282955 [PubMed]

No Image

The triennial International Pigment Cell Conference (IPCC).

October 5, 2018 dna 0
Icon for BioMed Central Related Articles

The triennial International Pigment Cell Conference (IPCC).

J Transl Med. 2018 Oct 03;16(1):252

Authors: Box NF, Larue L, Manga P, Montoliu L, Spritz RA, Filipp FV

Abstract
The International Federation of Pigment Cell Societies (IFPCS) held its XXIII triennial International Pigment Cell Conference (IPCC) in Denver, Colorado in August 2017. The goal of the summit was to provide a venue promoting a vibrant interchange among leading basic and clinical researchers working on leading-edge aspects of melanocyte biology and disease. The philosophy of the meeting, entitled Breakthroughs in Pigment Cell and Melanoma Research, was to deliver a comprehensive program in an inclusive environment fostering scientific exchange and building new academic bridges. This document provides an outlook on the history, accomplishments, and sustainability of the pigment cell and melanoma research community. Shared progress in the understanding of cellular homeostasis of pigment cells but also clinical successes and hurdles in the treatment of melanoma and dermatological disorders continue to drive future research activities. A sustainable direction of the societies creates an international forum identifying key areas of imminent needs in laboratory research and clinical care and ensures the future of this vibrant, diverse and unique research community at the same time. Important advances showcase wealth and breadth of the field in melanocyte and melanoma research and include emerging frontiers in melanoma immunotherapy, medical and surgical oncology, dermatology, vitiligo, albinism, genomics and systems biology, precision bench-to-bedside approaches, epidemiology, pigment biophysics and chemistry, and evolution. This report recapitulates highlights of the federate meeting agenda designed to advance clinical and basic research frontiers from melanoma and dermatological sciences followed by a historical perspective of the associated societies and conferences.

PMID: 30285864 [PubMed – in process]

No Image

Differential expression of hemoglobin receptor, HmbR, between carriage and invasive isolates of Neisseria meningitidis contributes to virulence: lessons from a clonal outbreak.

October 3, 2018 dna 0
Icon for Taylor & Francis Icon for PubMed Central Related Articles

Differential expression of hemoglobin receptor, HmbR, between carriage and invasive isolates of Neisseria meningitidis contributes to virulence: lessons from a clonal outbreak.

Virulence. 2018 12 31;9(1):923-929

Authors: Sevestre J, Diene SM, Aouiti-Trabelsi M, Deghmane AE, Tournier I, François P, Caron F, Taha MK

Abstract
Carriage and invasion balance in the pathogenesis of Neisseria meningitidis was analyzed during a recent clonal outbreak of meningococcal B in Normandy, France, that offered the opportunity to compare six isolates undistinguable by conventional typing (B:14:P1.7,16:F3-3/ST-32) isolated from invasive disease or pharyngeal asymptomatic carriage. Data from animal model (transgenic mice rendered susceptible to N. meningitidis infection) showed an absence of virulence for two non-capsulated carriage isolates, an intermediate virulence for two capsulated carriage isolates and a marked virulence for two capsulated invasive isolates. This differential pathogenesis well correlated with whole genome sequencing analysis that clustered both isolates of each group together, forming their own arm within the Norman cluster. Gene-by-gene analysis specified that genes involved in iron acquisition were among the elements differentially represented in cluster of invasive isolates compared to cluster of capsulated carriage isolates. The hemoglobin receptor encoding gene hmbR was in an ON-phase in the capsulated invasive isolates while carriage capsulated isolates were in an OFF-phase. An ON-phase variant of a capsulated carriage isolate showed enhanced virulence. These data underline the role of phase variation (ON/OFF) of HmbR in the balance between disease isolates/carriage isolates.

PMID: 29638173 [PubMed – indexed for MEDLINE]

No Image

High participation rate among 25 721 patients with broad age range in a hospital-based research project involving whole-genome sequencing – the Lausanne Institutional Biobank.

October 3, 2018 dna 0
Icon for EMH Swiss Medical Publishers Ltd. Related Articles

High participation rate among 25 721 patients with broad age range in a hospital-based research project involving whole-genome sequencing – the Lausanne Institutional Biobank.

Swiss Med Wkly. 2017;147:w14528

Authors: Bochud M, Currat C, Chapatte L, Roth C, Mooser V

Abstract
AIMS: We aimed to evaluate the interest of adult inpatients and selected outpatients in engaging in a large, real-life, hospital-based, genomic medicine research project and in receiving clinically actionable incidental findings.
METHODS: Within the framework of the cross-sectional Institutional Biobank of Lausanne, Switzerland, a total of 25721 patients of the CHUV University Hospital were systematically invited to grant researchers access to their biomedical data and to donate blood for future analyses, including whole-genome sequencing. Multivariable logistic regression analysis was used to identify personal factors, including age, gender, religion, ethnicity, citizenship, education level and mode of admission, associated with willingness to participate in this genomic research project and with interest in receiving clinically actionable incidental findings.
RESULTS: The overall participation rate was 79% (20343/25721). Participation rate declined progressively with age, averaging 83%, 75%, 67% and 62% in patients aged <64 years (n = 13108), ≥64 years (n = 12613), ≥80 years (n = 4557) and ≥90 years (n = 1050), respectively. Factors associated with participation substantially differed between age strata. Patients less likely to participate included women (odds ratio 0.86, [95% confidence interval 0.79-0.95] and 0.78 [0.71-0.85] before and after age 64, respectively), non-Swiss (0.81 [0.74-0.90] and 0.58 [0.52-0.65]) and those admitted through the emergency ward (0.88 [0.79-0.98] and 0.66 [0.60-0.73]). Religion and marital status were associated with participation among patients aged <64 years. A total of 19 018 (93%) participants were willing to be re-contacted for incidental findings. A high education level was associated with higher participation rate, but not with higher willingness to receive incidental findings within the population who had agreed to participate.
CONCLUSION: A large proportion of adult patients, even among the elderly, are willing to actively participate and receive incidental findings in this systematic hospital-based precision and genomic medicine research program with broad consent.

PMID: 29063527 [PubMed – indexed for MEDLINE]

No Image

PLATO software provides analytic framework for investigating complexity beyond genome-wide association studies.

October 3, 2018 dna 0
Icon for Nature Publishing Group Icon for PubMed Central Related Articles

PLATO software provides analytic framework for investigating complexity beyond genome-wide association studies.

Nat Commun. 2017 10 27;8(1):1167

Authors: Hall MA, Wallace J, Lucas A, Kim D, Basile AO, Verma SS, McCarty CA, Brilliant MH, Peissig PL, Kitchner TE, Verma A, Pendergrass SA, Dudek SM, Moore JH, Ritchie MD

Abstract
Genome-wide, imputed, sequence, and structural data are now available for exceedingly large sample sizes. The needs for data management, handling population structure and related samples, and performing associations have largely been met. However, the infrastructure to support analyses involving complexity beyond genome-wide association studies is not standardized or centralized. We provide the PLatform for the Analysis, Translation, and Organization of large-scale data (PLATO), a software tool equipped to handle multi-omic data for hundreds of thousands of samples to explore complexity using genetic interactions, environment-wide association studies and gene-environment interactions, phenome-wide association studies, as well as copy number and rare variant analyses. Using the data from the Marshfield Personalized Medicine Research Project, a site in the electronic Medical Records and Genomics Network, we apply each feature of PLATO to type 2 diabetes and demonstrate how PLATO can be used to uncover the complex etiology of common traits.

PMID: 29079728 [PubMed – indexed for MEDLINE]

No Image

Polη O-GlcNAcylation governs genome integrity during translesion DNA synthesis.

October 3, 2018 dna 0
Icon for Nature Publishing Group Icon for PubMed Central Related Articles

Polη O-GlcNAcylation governs genome integrity during translesion DNA synthesis.

Nat Commun. 2017 12 05;8(1):1941

Authors: Ma X, Liu H, Li J, Wang Y, Ding YH, Shen H, Yang Y, Sun C, Huang M, Tu Y, Liu Y, Zhao Y, Dong MQ, Xu P, Tang TS, Guo C

Abstract
DNA polymerase η (Polη) facilitates translesion DNA synthesis (TLS) across ultraviolet (UV) irradiation- and cisplatin-induced DNA lesions implicated in skin carcinogenesis and chemoresistant phenotype formation, respectively. However, whether post-translational modifications of Polη are involved in these processes remains largely unknown. Here, we reported that human Polη undergoes O-GlcNAcylation at threonine 457 by O-GlcNAc transferase upon DNA damage. Abrogation of this modification results in a reduced level of CRL4CDT2-dependent Polη polyubiquitination at lysine 462, a delayed p97-dependent removal of Polη from replication forks, and significantly enhanced UV-induced mutagenesis even though Polη focus formation and its efficacy to bypass across cyclobutane pyrimidine dimers after UV irradiation are not affected. Furthermore, the O-GlcNAc-deficient T457A mutation impairs TLS to bypass across cisplatin-induced lesions, causing increased cellular sensitivity to cisplatin. Our findings demonstrate a novel role of Polη O-GlcNAcylation in TLS regulation and genome stability maintenance and establish a new rationale to improve chemotherapeutic treatment.

PMID: 29208956 [PubMed – indexed for MEDLINE]

No Image

Advances in Engineering the Fly Genome with the CRISPR-Cas System.

October 3, 2018 dna 0
Icon for HighWire Icon for PubMed Central Related Articles

Advances in Engineering the Fly Genome with the CRISPR-Cas System.

Genetics. 2018 01;208(1):1-18

Authors: Bier E, Harrison MM, O’Connor-Giles KM, Wildonger J

Abstract
Drosophila has long been a premier model for the development and application of cutting-edge genetic approaches. The CRISPR-Cas system now adds the ability to manipulate the genome with ease and precision, providing a rich toolbox to interrogate relationships between genotype and phenotype, to delineate and visualize how the genome is organized, to illuminate and manipulate RNA, and to pioneer new gene drive technologies. Myriad transformative approaches have already originated from the CRISPR-Cas system, which will likely continue to spark the creation of tools with diverse applications. Here, we provide an overview of how CRISPR-Cas gene editing has revolutionized genetic analysis in Drosophila and highlight key areas for future advances.

PMID: 29301946 [PubMed – indexed for MEDLINE]

No Image

Highlights from the 2018 WIN Symposium, 25-26 June 2018, Paris: designing the future of precision oncology.

October 1, 2018 dna 0
Icon for PubMed Central Related Articles

Highlights from the 2018 WIN Symposium, 25-26 June 2018, Paris: designing the future of precision oncology.

Ecancermedicalscience. 2018;12:871

Authors: Davies W

Abstract
The Worldwide Innovative Networking (WIN) Symposium is the annual gathering of WIN consortium members from across the globe, representing academic institutions, pharmaceutical partners, technology companies and charitable organisations, to discuss ongoing research and the latest developments in precision oncology. The symposium held in Paris, France on 25-26 June was structured into five plenary sessions, two open forums and poster presentations. This year marked the 10th anniversary of the consortium, and the programme anchored itself with retrospectives of recent breakthroughs in personalised medicine, programme sessions reviewing the iterative design of trials in precision oncology at present, and the future of implementing personalised medicine initiatives in US and EU healthcare systems for the maximum patient benefit. This year was also marked by the absence of Dr John Mendelsohn, who has stepped down as chairman, and co-founder Professor Tomas Tursz, who passed away in April this year. The latter was given a brief memorial session at the conclusion of the symposium.

PMID: 30263062 [PubMed]

No Image

Exploring neurologists’ perspectives on the return of next generation sequencing results to their patients: a needed step in the development of guidelines.

October 1, 2018 dna 0
Icon for BioMed Central Related Articles

Exploring neurologists’ perspectives on the return of next generation sequencing results to their patients: a needed step in the development of guidelines.

BMC Med Ethics. 2018 Sep 29;19(1):81

Authors: Hurlimann T, Jaitovich Groisman I, Godard B

Abstract
BACKGROUND: The use of Next Generation Sequencing such as Whole Genome Sequencing (WGS) is a promising step towards a better understanding and treatment of neurological diseases. WGS can result into unexpected information (incidental findings, IFs), and information with uncertain clinical significance. In the context of a Genome Canada project on ‘Personalized Medicine in the Treatment of Epilepsy’, we intended to address these challenges surveying neurologists’ opinions about the type of results that should be returned, and their professional responsibility toward recontacting patients regarding new discovered mutations.
METHODS: Potential participants were contacted through professional organizations or direct invitations.
RESULTS: A total of 204 neurologists were recruited. Fifty nine percent indicated that to be conveyed, WGS results should have a demonstrated clinical utility for diagnosis, prognosis or treatment. Yet, 41% deemed appropriate to return results without clinical utility, when they could impact patients’ reproductive decisions, or on patients’ request. Current use of targeted genetic testing and age of patients influenced respondents’ answers. Respondents stated that analysis of genomics data resulting from WGS should be limited to the genes likely to be relevant for the patient’s specific medical condition (69%), so as to limit IFs. Respondents felt responsible to recontact patients and inform them about newly discovered mutations related to the medical condition that triggered the test (75%) for as long as they are following up on the patient (55%). Finally, 53.5% of the respondents felt responsible to recontact and inform patients of clinically significant, newly discovered IFs.
CONCLUSION: Our results show the importance of formulating professional guidelines sensitive to the various – and sometimes opposite – viewpoints that may prevail within a same community of practice, as well as flexible so as to be attuned to the characteristics of the neurological conditions that triggered a WGS.

PMID: 30268121 [PubMed – in process]