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NCBI: db=pubmed; Term=Delft[Affiliation] AND (Reinders M[Author] OR Abeel T[Author] OR Wessels L[Author] OR de Ridder J[Author] OR Lelieveldt B[Author] OR van Ham R[Author])
Updated: 7 hours 58 min ago

TANDEM: a two-stage approach to maximize interpretability of drug response models based on multiple molecular data types.

Thu, 08/03/2017 - 13:16
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TANDEM: a two-stage approach to maximize interpretability of drug response models based on multiple molecular data types.

Bioinformatics. 2016 Sep 01;32(17):i413-i420

Authors: Aben N, Vis DJ, Michaut M, Wessels LF

Abstract
MOTIVATION: Clinical response to anti-cancer drugs varies between patients. A large portion of this variation can be explained by differences in molecular features, such as mutation status, copy number alterations, methylation and gene expression profiles. We show that the classic approach for combining these molecular features (Elastic Net regression on all molecular features simultaneously) results in models that are almost exclusively based on gene expression. The gene expression features selected by the classic approach are difficult to interpret as they often represent poorly studied combinations of genes, activated by aberrations in upstream signaling pathways.
RESULTS: To utilize all data types in a more balanced way, we developed TANDEM, a two-stage approach in which the first stage explains response using upstream features (mutations, copy number, methylation and cancer type) and the second stage explains the remainder using downstream features (gene expression). Applying TANDEM to 934 cell lines profiled across 265 drugs (GDSC1000), we show that the resulting models are more interpretable, while retaining the same predictive performance as the classic approach. Using the more balanced contributions per data type as determined with TANDEM, we find that response to MAPK pathway inhibitors is largely predicted by mutation data, while predicting response to DNA damaging agents requires gene expression data, in particular SLFN11 expression.
AVAILABILITY AND IMPLEMENTATION: TANDEM is available as an R package on CRAN (for more information, see http://ccb.nki.nl/software/tandem).
CONTACT: m.michaut@nki.nl or l.wessels@nki.nl
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID: 27587657 [PubMed - indexed for MEDLINE]

Comparative Cistromics Reveals Genomic Cross-talk between FOXA1 and ERα in Tamoxifen-Associated Endometrial Carcinomas.

Sat, 07/29/2017 - 08:24
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Comparative Cistromics Reveals Genomic Cross-talk between FOXA1 and ERα in Tamoxifen-Associated Endometrial Carcinomas.

Cancer Res. 2016 Jul 01;76(13):3773-84

Authors: Droog M, Nevedomskaya E, Kim Y, Severson T, Flach KD, Opdam M, Schuurman K, Gradowska P, Hauptmann M, Dackus G, Hollema H, Mourits M, Nederlof P, van Boven H, Linn SC, Wessels L, van Leeuwen FE, Zwart W

Abstract
Tamoxifen, a small-molecule antagonist of the transcription factor estrogen receptor alpha (ERα) used to treat breast cancer, increases risks of endometrial cancer. However, no parallels of ERα transcriptional action in breast and endometrial tumors have been found that might explain this effect. In this study, we addressed this issue with a genome-wide assessment of ERα-chromatin interactions in surgical specimens obtained from patients with tamoxifen-associated endometrial cancer. ERα was found at active enhancers in endometrial cancer cells as marked by the presence of RNA polymerase II and the histone marker H3K27Ac. These ERα binding sites were highly conserved between breast and endometrial cancer and enriched in binding motifs for the transcription factor FOXA1, which displayed substantial overlap with ERα binding sites proximal to genes involved in classical ERα target genes. Multifactorial ChIP-seq data integration from the endometrial cancer cell line Ishikawa illustrated a functional genomic network involving ERα and FOXA1 together with the enhancer-enriched transcriptional regulators p300, FOXM1, TEAD4, FNFIC, CEBP8, and TCF12. Immunohistochemical analysis of 230 primary endometrial tumor specimens showed that lack of FOXA1 and ERα expression was associated with a longer interval between breast cancer and the emergence of endometrial cancer, exclusively in tamoxifen-treated patients. Our results define conserved sites for a genomic interplay between FOXA1 and ERα in breast cancer and tamoxifen-associated endometrial cancer. In addition, FOXA1 and ERα are associated with the interval time between breast cancer and endometrial cancer only in tamoxifen-treated breast cancer patients. Cancer Res; 76(13); 3773-84. ©2016 AACR.

PMID: 27197147 [PubMed - indexed for MEDLINE]

Cortical Spreading Depression Causes Unique Dysregulation of Inflammatory Pathways in a Transgenic Mouse Model of Migraine.

Sun, 07/09/2017 - 09:46
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Cortical Spreading Depression Causes Unique Dysregulation of Inflammatory Pathways in a Transgenic Mouse Model of Migraine.

Mol Neurobiol. 2017 May;54(4):2986-2996

Authors: Eising E, Shyti R, 't Hoen PAC, Vijfhuizen LS, Huisman SMH, Broos LAM, Mahfouz A, Reinders MJT, Ferrari MD, Tolner EA, de Vries B, van den Maagdenberg AMJM

Abstract
Familial hemiplegic migraine type 1 (FHM1) is a rare monogenic subtype of migraine with aura caused by mutations in CACNA1A that encodes the α1A subunit of voltage-gated CaV2.1 calcium channels. Transgenic knock-in mice that carry the human FHM1 R192Q missense mutation ('FHM1 R192Q mice') exhibit an increased susceptibility to cortical spreading depression (CSD), the mechanism underlying migraine aura. Here, we analysed gene expression profiles from isolated cortical tissue of FHM1 R192Q mice 24 h after experimentally induced CSD in order to identify molecular pathways affected by CSD. Gene expression profiles were generated using deep serial analysis of gene expression sequencing. Our data reveal a signature of inflammatory signalling upon CSD in the cortex of both mutant and wild-type mice. However, only in the brains of FHM1 R192Q mice specific genes are up-regulated in response to CSD that are implicated in interferon-related inflammatory signalling. Our findings show that CSD modulates inflammatory processes in both wild-type and mutant brains, but that an additional unique inflammatory signature becomes expressed after CSD in a relevant mouse model of migraine.

PMID: 27032388 [PubMed - indexed for MEDLINE]

Insertional mutagenesis identifies drivers of a novel oncogenic pathway in invasive lobular breast carcinoma.

Tue, 06/27/2017 - 18:30

Insertional mutagenesis identifies drivers of a novel oncogenic pathway in invasive lobular breast carcinoma.

Nat Genet. 2017 Jun 26;:

Authors: Kas SM, de Ruiter JR, Schipper K, Annunziato S, Schut E, Klarenbeek S, Drenth AP, van der Burg E, Klijn C, Ten Hoeve JJ, Adams DJ, Koudijs MJ, Wesseling J, Nethe M, Wessels LFA, Jonkers J

Abstract
Invasive lobular carcinoma (ILC) is the second most common breast cancer subtype and accounts for 8-14% of all cases. Although the majority of human ILCs are characterized by the functional loss of E-cadherin (encoded by CDH1), inactivation of Cdh1 does not predispose mice to develop mammary tumors, implying that mutations in additional genes are required for ILC formation in mice. To identify these genes, we performed an insertional mutagenesis screen using the Sleeping Beauty transposon system in mice with mammary-specific inactivation of Cdh1. These mice developed multiple independent mammary tumors of which the majority resembled human ILC in terms of morphology and gene expression. Recurrent and mutually exclusive transposon insertions were identified in Myh9, Ppp1r12a, Ppp1r12b and Trp53bp2, whose products have been implicated in the regulation of the actin cytoskeleton. Notably, MYH9, PPP1R12B and TP53BP2 were also frequently aberrated in human ILC, highlighting these genes as drivers of a novel oncogenic pathway underlying ILC development.

PMID: 28650484 [PubMed - as supplied by publisher]

A novel independence test for somatic alterations in cancer shows that biology drives mutual exclusivity but chance explains most co-occurrence.

Fri, 06/16/2017 - 06:00
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A novel independence test for somatic alterations in cancer shows that biology drives mutual exclusivity but chance explains most co-occurrence.

Genome Biol. 2016 Dec 16;17(1):261

Authors: Canisius S, Martens JW, Wessels LF

Abstract
In cancer, mutually exclusive or co-occurring somatic alterations across genes can suggest functional interactions. Existing tests for such patterns make the unrealistic assumption of identical gene alteration probabilities across tumors. We present Discrete Independence Statistic Controlling for Observations with Varying Event Rates (DISCOVER), a novel test that is more sensitive than other methods and controls its false positive rate. A pan-cancer analysis using DISCOVER finds no evidence for widespread co-occurrence, and most co-occurrences previously detected do not exceed expectation by chance. Many mutual exclusivities are identified involving well-known genes related to cell cycle and growth factor signaling, as well as lesser known regulators of Hedgehog signaling.

PMID: 27986087 [PubMed - indexed for MEDLINE]

Deletion of Polycomb Repressive Complex 2 From Mouse Intestine Causes Loss of Stem Cells.

Tue, 06/06/2017 - 19:58
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Deletion of Polycomb Repressive Complex 2 From Mouse Intestine Causes Loss of Stem Cells.

Gastroenterology. 2016 Oct;151(4):684-697.e12

Authors: Koppens MA, Bounova G, Gargiulo G, Tanger E, Janssen H, Cornelissen-Steijger P, Blom M, Song JY, Wessels LF, van Lohuizen M

Abstract
BACKGROUND & AIMS: The polycomb repressive complex 2 (PRC2) regulates differentiation by contributing to repression of gene expression and thereby stabilizing the fate of stem cells and their progeny. PRC2 helps to maintain adult stem cell populations, but little is known about its functions in intestinal stem cells. We studied phenotypes of mice with intestine-specific deletion of the PRC2 proteins embryonic ectoderm development (EED) (a subunit required for PRC2 function) and enhancer of zeste homolog 2 (EZH2) (a histone methyltransferase).
METHODS: We performed studies of AhCre;EedLoxP/LoxP (EED knockout) mice and AhCre;Ezh2LoxP/LoxP (EZH2 knockout) mice, which have intestine-specific disruption in EED and EZH2, respectively. Small intestinal crypts were isolated and subsequently cultured to grow organoids. Intestines and organoids were analyzed by immunohistochemical, in situ hybridization, RNA sequence, and chromatin immunoprecipitation methods.
RESULTS: Intestines of EED knockout mice had massive crypt degeneration and lower numbers of proliferating cells compared with wild-type control mice. Cdkn2a became derepressed and we detected increased levels of P21. We did not observe any differences between EZH2 knockout and control mice. Intestinal crypts from EED knockout mice had signs of aberrant differentiation of uncommitted crypt cells-these differentiated toward the secretory cell lineage. Furthermore, crypts from EED-knockout mice had impaired Wnt signaling and concomitant loss of intestinal stem cells, this phenotype was not reversed upon ectopic stimulation of Wnt and Notch signaling in organoids. Analysis of gene expression patterns from intestinal tissues of EED knockout mice showed dysregulation of several genes involved in Wnt signaling. Wnt signaling was regulated directly by PRC2.
CONCLUSIONS: In intestinal tissues of mice, PRC2 maintains small intestinal stem cells by promoting proliferation and preventing differentiation in the intestinal stem cell compartment. PRC2 controls gene expression in multiple signaling pathways that regulate intestinal homeostasis. Sequencing data are available in the genomics data repository GEO under reference series GSE81578; RNA sequencing data are available under subseries GSE81576; and ChIP sequencing data are available under subseries GSE81577.

PMID: 27342214 [PubMed - indexed for MEDLINE]

Identifying transposon insertions and their effects from RNA-sequencing data.

Sat, 06/03/2017 - 16:39
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Identifying transposon insertions and their effects from RNA-sequencing data.

Nucleic Acids Res. 2017 Jun 01;:

Authors: de Ruiter JR, Kas SM, Schut E, Adams DJ, Koudijs MJ, Wessels LFA, Jonkers J

Abstract
Insertional mutagenesis using engineered transposons is a potent forward genetic screening technique used to identify cancer genes in mouse model systems. In the analysis of these screens, transposon insertion sites are typically identified by targeted DNA-sequencing and subsequently assigned to predicted target genes using heuristics. As such, these approaches provide no direct evidence that insertions actually affect their predicted targets or how transcripts of these genes are affected. To address this, we developed IM-Fusion, an approach that identifies insertion sites from gene-transposon fusions in standard single- and paired-end RNA-sequencing data. We demonstrate IM-Fusion on two separate transposon screens of 123 mammary tumors and 20 B-cell acute lymphoblastic leukemias, respectively. We show that IM-Fusion accurately identifies transposon insertions and their true target genes. Furthermore, by combining the identified insertion sites with expression quantification, we show that we can determine the effect of a transposon insertion on its target gene(s) and prioritize insertions that have a significant effect on expression. We expect that IM-Fusion will significantly enhance the accuracy of cancer gene discovery in forward genetic screens and provide initial insight into the biological effects of insertions on candidate cancer genes.

PMID: 28575524 [PubMed - as supplied by publisher]

Comparing methods for fetal fraction determination and quality control of NIPT samples.

Thu, 06/01/2017 - 15:03

Comparing methods for fetal fraction determination and quality control of NIPT samples.

Prenat Diagn. 2017 May 31;:

Authors: van Beek DM, Straver R, Weiss MM, Boon EMJ, Amsterdam KH, Oudejans CBM, Reinders MJT, Sistermans EA

Abstract
OBJECTIVE: To compare available analysis methods for determining fetal fraction on single read Next Generation Sequencing data. This is important as the performance of Non-invasive Prenatal Testing procedures depends on the fraction of fetal DNA.
METHODS: We tested six different methods for the detection of fetal fraction in NIPT samples. The same clinically obtained data were used for all methods, allowing us to assess the effect of fetal fraction on the test result, and to investigate the use of fetal fraction for quality control.
RESULTS: We show that non-NIPT methods based on Body Mass Index (BMI) and gestational age are unreliable predictors of fetal fraction, male pregnancy specific methods based on read counts on the Y chromosome perform consistently, the fetal sex-independent new methods SeqFF and SANEFALCON are less reliable but can be used to obtain a basic indication of fetal fraction in case of a female fetus.
CONCLUSION: We recommend the use of a combination of methods to prevent the issue of reports on samples with insufficient fetal DNA; SANEFALCON to check for presence of fetal DNA, SeqFF for estimating the fetal fraction for a female pregnancy, any Y-based method for estimating the fetal fraction for a male pregnancy.

PMID: 28561435 [PubMed - as supplied by publisher]

Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance.

Wed, 05/31/2017 - 14:20
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Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance.

Nat Genet. 2016 May;48(5):544-51

Authors: Desjardins CA, Cohen KA, Munsamy V, Abeel T, Maharaj K, Walker BJ, Shea TP, Almeida DV, Manson AL, Salazar A, Padayatchi N, O'Donnell MR, Mlisana KP, Wortman J, Birren BW, Grosset J, Earl AM, Pym AS

Abstract
A more complete understanding of the genetic basis of drug resistance in Mycobacterium tuberculosis is critical for prompt diagnosis and optimal treatment, particularly for toxic second-line drugs such as D-cycloserine. Here we used the whole-genome sequences from 498 strains of M. tuberculosis to identify new resistance-conferring genotypes. By combining association and correlated evolution tests with strategies for amplifying signal from rare variants, we found that loss-of-function mutations in ald (Rv2780), encoding L-alanine dehydrogenase, were associated with unexplained drug resistance. Convergent evolution of this loss of function was observed exclusively among multidrug-resistant strains. Drug susceptibility testing established that ald loss of function conferred resistance to D-cycloserine, and susceptibility to the drug was partially restored by complementation of ald. Clinical strains with mutations in ald and alr exhibited increased resistance to D-cycloserine when cultured in vitro. Incorporation of D-cycloserine resistance in novel molecular diagnostics could allow for targeted use of this toxic drug among patients with susceptible infections.

PMID: 27064254 [PubMed - indexed for MEDLINE]

Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy.

Sat, 05/27/2017 - 09:55
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Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy.

Eur J Hum Genet. 2017 May 24;:

Authors: Holstege H, van der Lee SJ, Hulsman M, Wong TH, van Rooij JG, Weiss M, Louwersheimer E, Wolters FJ, Amin N, Uitterlinden AG, Hofman A, Ikram MA, van Swieten JC, Meijers-Heijboer H, van der Flier WM, Reinders MJ, van Duijn CM, Scheltens P

Abstract
Accumulating evidence suggests that genetic variants in the SORL1 gene are associated with Alzheimer disease (AD), but a strategy to identify which variants are pathogenic is lacking. In a discovery sample of 115 SORL1 variants detected in 1908 Dutch AD cases and controls, we identified the variant characteristics associated with SORL1 variant pathogenicity. Findings were replicated in an independent sample of 103 SORL1 variants detected in 3193 AD cases and controls. In a combined sample of the discovery and replication samples, comprising 181 unique SORL1 variants, we developed a strategy to classify SORL1 variants into five subtypes ranging from pathogenic to benign. We tested this pathogenicity screen in SORL1 variants reported in two independent published studies. SORL1 variant pathogenicity is defined by the Combined Annotation Dependent Depletion (CADD) score and the minor allele frequency (MAF) reported by the Exome Aggregation Consortium (ExAC) database. Variants predicted strongly damaging (CADD score >30), which are extremely rare (ExAC-MAF <1 × 10(-5)) increased AD risk by 12-fold (95% CI 4.2-34.3; P=5 × 10(-9)). Protein-truncating SORL1 mutations were all unknown to ExAC and occurred exclusively in AD cases. More common SORL1 variants (ExAC-MAF≥1 × 10(-5)) were not associated with increased AD risk, even when predicted strongly damaging. Findings were independent of gender and the APOE-ɛ4 allele. High-risk SORL1 variants were observed in a substantial proportion of the AD cases analyzed (2%). Based on their effect size, we propose to consider high-risk SORL1 variants next to variants in APOE, PSEN1, PSEN2 and APP for personalized risk assessments in clinical practice.European Journal of Human Genetics advance online publication, 24 May 2017; doi:10.1038/ejhg.2017.87.

PMID: 28537274 [PubMed - as supplied by publisher]

Mining for osteogenic surface topographies: In silico design to in vivo osseo-integration.

Thu, 05/25/2017 - 08:04
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Mining for osteogenic surface topographies: In silico design to in vivo osseo-integration.

Biomaterials. 2017 May 12;137:49-60

Authors: Hulshof FFB, Papenburg B, Vasilevich A, Hulsman M, Zhao Y, Levers M, Fekete N, de Boer M, Yuan H, Singh S, Beijer N, Bray MA, Logan DJ, Reinders M, Carpenter AE, van Blitterswijk C, Stamatialis D, de Boer J

Abstract
Stem cells respond to the physicochemical parameters of the substrate on which they grow. Quantitative material activity relationships - the relationships between substrate parameters and the phenotypes they induce - have so far poorly predicted the success of bioactive implant surfaces. In this report, we screened a library of randomly selected designed surface topographies for those inducing osteogenic differentiation of bone marrow-derived mesenchymal stem cells. Cell shape features, surface design parameters, and osteogenic marker expression were strongly correlated in vitro. Furthermore, the surfaces with the highest osteogenic potential in vitro also demonstrated their osteogenic effect in vivo: these indeed strongly enhanced bone bonding in a rabbit femur model. Our work shows that by giving stem cells specific physicochemical parameters through designed surface topographies, differentiation of these cells can be dictated.

PMID: 28535442 [PubMed - as supplied by publisher]

Mycobacterium tuberculosis Whole Genome Sequences From Southern India Suggest Novel Resistance Mechanisms and the Need for Region-Specific Diagnostics.

Sat, 05/13/2017 - 21:46
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Mycobacterium tuberculosis Whole Genome Sequences From Southern India Suggest Novel Resistance Mechanisms and the Need for Region-Specific Diagnostics.

Clin Infect Dis. 2017 May 12;:

Authors: Manson AL, Abeel T, Galagan JE, Sundaramurthi JC, Salazar A, Gehrmann T, Shanmugam SK, Palaniyandi K, Narayanan S, Swaminathan S, Earl AM

Abstract
Background.: India is home to 25% of all tuberculosis cases and the second highest number of multidrug resistant cases worldwide. However, little is known about the genetic diversity and resistance determinants of Indian Mycobacterium tuberculosis, particularly for the primary lineages found in India, lineages 1 and 3.
Methods.: We whole genome sequenced 223 randomly selected M. tuberculosis strains from 196 patients within the Tiruvallur and Madurai districts of Tamil Nadu in Southern India. Using comparative genomics, we examined genetic diversity, transmission patterns, and evolution of resistance.
Results.: Genomic analyses revealed (11) prevalence of strains from lineages 1 and 3, (11) recent transmission of strains among patients from the same treatment centers, (11) emergence of drug resistance within patients over time, (11) resistance gained in an order typical of strains from different lineages and geographies, (11) underperformance of known resistance-conferring mutations to explain phenotypic resistance in Indian strains relative to studies focused on other geographies, and (11) the possibility that resistance arose through mutations not previously implicated in resistance, or through infections with multiple strains that confound genotype-based prediction of resistance.
Conclusions.: In addition to substantially expanding the genomic perspectives of lineages 1 and 3, sequencing and analysis of M. tuberculosis whole genomes from Southern India highlight challenges of infection control and rapid diagnosis of resistant tuberculosis using current technologies. Further studies are needed to fully explore the complement of diversity and resistance determinants within endemic M. tuberculosis populations.

PMID: 28498943 [PubMed - as supplied by publisher]

Automatic quantification of bone marrow edema on MRI of the wrist in patients with early arthritis: A feasibility study.

Wed, 05/10/2017 - 19:01
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Automatic quantification of bone marrow edema on MRI of the wrist in patients with early arthritis: A feasibility study.

Magn Reson Med. 2017 May 07;:

Authors: Aizenberg E, Roex EAH, Nieuwenhuis WP, Mangnus L, van der Helm-van Mil AHM, Reijnierse M, Bloem JL, Lelieveldt BPF, Stoel BC

Abstract
PURPOSE: To investigate the feasibility of automatic quantification of bone marrow edema (BME) on MRI of the wrist in patients with early arthritis.
METHODS: For 485 early arthritis patients (clinically confirmed arthritis of one or more joints, symptoms for less than 2 years), MR scans of the wrist were processed in three automatic stages. First, super-resolution reconstruction was applied to fuse coronal and axial scans into a single high-resolution 3D image. Next, the carpal bones were located and delineated using atlas-based segmentation. Finally, the extent of BME within each bone was quantified by identifying image intensity values characteristic of BME by fuzzy clustering and measuring the fraction of voxels with these characteristic intensities within each bone. Correlation with visual BME scores was assessed through Pearson correlation coefficient.
RESULTS: Pearson correlation between quantitative and visual BME scores across 485 patients was r=0.83, P<0.001.
CONCLUSIONS: Quantitative measurement of BME on MRI of the wrist has the potential to provide a feasible alternative to visual scoring. Complete automation requires automatic detection and compensation of acquisition artifacts. Magn Reson Med, 2017. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

PMID: 28480581 [PubMed - as supplied by publisher]

Towards a global cancer knowledge network: dissecting the current international cancer genomic sequencing landscape.

Mon, 05/01/2017 - 12:47
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Towards a global cancer knowledge network: dissecting the current international cancer genomic sequencing landscape.

Ann Oncol. 2017 May 01;28(5):1145-1151

Authors: Vis DJ, Lewin J, Liao RG, Mao M, Andre F, Ward RL, Calvo F, Teh BT, Camargo AA, Knoppers BM, Sawyers CL, Wessels LFA, Lawler M, Siu LL, Voest E, Clinical Working Group of the Global Alliance for Genomics and Health

Abstract
Background: While next generation sequencing has enhanced our understanding of the biological basis of malignancy, current knowledge on global practices for sequencing cancer samples is limited. To address this deficiency, we developed a survey to provide a snapshot of current sequencing activities globally, identify barriers to data sharing and use this information to develop sustainable solutions for the cancer research community.
Methods: A multi-item survey was conducted assessing demographics, clinical data collection, genomic platforms, privacy/ethics concerns, funding sources and data sharing barriers for sequencing initiatives globally. Additionally, respondents were asked as to provide the primary intent of their initiative (clinical diagnostic, research or combination).
Results: Of 107 initiatives invited to participate, 59 responded (response rate = 55%). Whole exome sequencing (P = 0.03) and whole genome sequencing (P = 0.01) were utilized less frequently in clinical diagnostic than in research initiatives. Procedures to identify cancer-specific variants were heterogeneous, with bioinformatics pipelines employing different mutation calling/variant annotation algorithms. Measurement of treatment efficacy varied amongst initiatives, with time on treatment (57%) and RECIST (53%) being the most common; however, other parameters were also employed. Whilst 72% of initiatives indicated data sharing, its scope varied, with a number of restrictions in place (e.g. transfer of raw data). The largest perceived barriers to data harmonization were the lack of financial support (P < 0.01) and bioinformatics concerns (e.g. lack of interoperability) (P = 0.02). Capturing clinical data was more likely to be perceived as a barrier to data sharing by larger initiatives than by smaller initiatives (P = 0.01).
Conclusions: These results identify the main barriers, as perceived by the cancer sequencing community, to effective sharing of cancer genomic and clinical data. They highlight the need for greater harmonization of technical, ethical and data capture processes in cancer sample sequencing worldwide, in order to support effective and responsible data sharing for the benefit of patients.

PMID: 28453708 [PubMed - in process]