Cet article passe en revue les travaux récents sur la mise en évidence d'anomalies génomiques dans les leucémies lymphocytaires chroniques

Chronic lymphocytic leukemia: molecular heterogeneity revealed by high-throughput genomics

Landau, Dan ; Wu, Catherine

Chronic lymphocytic leukemia (CLL) has been consistently at the forefront of genetic research owing to its prevalence and the accessibility of sample material. Recently, genome-wide technologies have been intensively applied to CLL genetics, with remarkable progress. Single nucleotide polymorphism arrays have identified recurring chromosomal aberrations, thereby focusing functional studies on discrete genomic lesions and leading to the first implication of somatic microRNA disruption in cancer. [...]

Menée sur 46 patients pédiatriques atteints d'une leucémie aiguë lymphoblastique à précurseurs B, cette étude analyse, à l'échelle du génome, les modifications de méthylation de l'ADN et, en intégrant des données du transcriptome, identifie 17 gènes susceptibles d'être impliqués dans la genèse de la maladie

Integration of high-resolution methylome and transcriptome analyses to dissect epigenomic changes in childhood acute lymphoblastic leukemia

Busche, Stephan ; Ge, Bing ; Vidal, Ramon ; Spinella, Jean-Francois ; Saillour, Virginie ; Richer, Chantal ; Healy, Jasmine ; Chen, Shu-Huang ; Droit, Arnaud ; Sinnett, Daniel ; Pastinen, Tomi

B-cell precursor acute lymphoblastic leukemia (pre-B ALL) is the most common pediatric cancer. Although the genetic determinants underlying disease onset remain unclear, epigenetic modifications including DNA methylation are suggested to contribute significantly to leukemogenesis. Using the Illumina 450k array we assessed DNA methylation in matched tumor-normal samples of 46 childhood pre-B ALL patients, extending single CpG-site resolution analysis of the pre-B ALL methylome beyond CpG-islands [...]

Menée à l'aide d'une technique de séquençage de prochaine génération sur des lignées cellulaires de cancer du poumon présentant des mutations du gène EGFR, cette étude met en évidence des altérations de l'ADN associées à la résistance à un inhibiteur de tyrosine kinase d'EGFR

Next-generation sequencing of paired tyrosine kinase inhibitor-sensitive and -resistant EGFR mutant lung cancer cell lines identifies spectrum of DNA changes associated with drug resistance

Jia, Peilin ; Jin, Hailing ; Meador, Catherine B, ; Xia, Junfeng ; Ohashi, Kadoaki ; Liu, Lin ; Pirazzoli, Valentina ; Dahlman, Kimberly B. ; Politi, Katerina ; Michor, Franziska ; Zhao, Zhongming ; Pao, William

Somatic mutations in genes encoding kinases are associated with increased sensitivity of some solid tumors to kinase inhibitors, but patients with metastatic cancer eventually develop disease progression. A common method used to model acquired resistance involves culturing parental drug-sensitive cells with increasing concentrations of drug until cells emerge that are resistant. In EGFR mutant lung cancer, this modeling has reliably identified clinically relevant EGFR tyrosine kinase inhibitor [...]

A partir de données de génotypage portant sur 1 683 patients atteints d'un cancer du poumon non à petites cellules (NAPC), puis menée sur des échantillons tumoraux prélevés sur 34 patients atteints d'un cancer du poumon NAPC avec réarrangements du gène ALK et ayant développé une résistance au crizotinib, cette étude montre que, si une tumeur présente des réarrangements du gène ALK, les gènes EGFR et KRAS ne sont pas mutés, et réciproquement

ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1683 patients with non-small cell lung cancer

Gainor, Justin F. ; Varghese, Anna M. ; Ou, Sai-Hong Ignatius ; Kabraji, Sheheryar ; Awad, Mark M. ; Katayama, Ryohei ; Pawlak, Amanda ; Mino-Kenudson, Mari ; Yeap, Beow Y. ; Riely, Gregory J. ; Iafrate, A. John ; Arcila, Maria E. ; Ladanyi, Marc ; Engelman, Jeffrey A. ; Dias-Santagata, Dora ; Shaw, Alice T.

Background: Anaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of non-small cell lung cancer (NSCLC). Recently, several case reports and small series have reported that ALK rearrangements can overlap with other oncogenic drivers in NSCLC in crizotinib-naïve and resistant cancers. Methods: We reviewed clinical genotyping data from 1683 NSCLC patients and investigated the prevalence of concomitant EGFR or KRAS mutations among patients with ALK-positive NSCLC. [...]

Menée sur 31 échantillons de tissu normal, de néoplasie précoce et de carcinome prélevés sur 6 patientes atteintes d'un cancer du sein, cette étude de séquençage du génome entier met en évidence, pour chaque patiente, l'évolution des événements génomiques d'un stade à l'autre

Genome evolution during progression to breast cancer

Newburger, Daniel E. ; Kashef-Haghighi, Dorna ; Weng, Ziming ; Salari, Raheleh ; Sweeney, Robert T. ; Brunner, Alayne L. ; Zhu, Shirley X. ; Guo, Xiangqian ; Varma, Sushama ; Troxell, Megan L. ; West, Robert B. ; Batzoglou, Serafim ; Sidow, Arend

Cancer evolution involves cycles of genomic damage, epigenetic deregulation, and increased cellular proliferation that eventually culminate in the carcinoma phenotype. Early neoplasias, which are often found concurrently with carcinomas and are histologically distinguishable from normal breast tissue, are less advanced in phenotype than carcinomas and are thought to represent precursor stages. To elucidate their role in cancer evolution we performed comparative whole-genome sequencing of early [...]

Menée in vitro et sur une cohorte de patients atteints d'un carcinome hépatocellulaire, cette étude met en évidence un mécanisme par lequel, en régulant l'expression de la sirtuine 1, le micro-ARN 29c joue un rôle de suppresseur de tumeurs

MicroRNA-29c functions as a tumor suppressor by direct targeting oncogenic SIRT1 in hepatocellular carcinoma

Bae, H. J. ; Noh, J. H. ; Kim, J. K. ; Eun, J. W. ; Jung, K. H. ; Kim, M. G. ; Chang, Y. G. ; Shen, Q. ; Kim, S. J. ; Park, W. S. ; Lee, J. Y. ; Nam, S. W.

Mammalian sirtuin 1 (SIRT1) has connected to an ever widening circle of activities that encompass cellular stress resistance, energy metabolism and tumorigenesis. However, underlying mechanisms leading to oncogenic SIRT1 overexpression are less understood. In this study, we identified SIRT1 regulatory microRNA (miRNA) and its function in hepatocellular carcinoma (HCC). Aberrant SIRT1 overexpression was demonstrated in a subset of human HCCs. SIRT1 knockdown suppressed HCC cell growth by [...]

Cet article passe en revue les travaux récents sur les rôles d'oncogène et de suppresseur de tumeurs joués par le gène HGMB1

HMGB1 in Cancer: Good, Bad, or Both?

Kang, Rui ; Zhang, Qiuhong ; Zeh, Herbert J ; Lotze, Michael ; Tang, Daolin

Forty years ago, high mobility group box 1 (HMGB1) was discovered in calf thymus and named according to its electrophoretic mobility in polyacrylamide gels. Now, we know that HMGB1 performs dual functions. Inside the cell, HMGB1 is a highly conserved chromosomal protein acting as a DNA chaperone. Outside of the cell, HMGB1 is a prototypical damage-associated molecular pattern, acting with cytokine, chemokine, and growth factor. During tumor development and in cancer therapy, HMGB1 has been [...]

Menée à l'aide d'un modèle murin transgénique, cette étude met en évidence un mécanisme par lequel la voie de signalisation Notch favorise la formation d'un cholangiocarcinome

A Critical Role for Notch Signaling in the Formation of Cholangiocellular Carcinomas

Zender, Steffen ; Nickeleit, Irina ; Wuestefeld, Torsten ; Sörensen, Inga ; Dauch, Daniel ; Bozko, Przemyslaw ; El-Khatib, Mona ; Geffers, Robert ; Bektas, Hueseyin ; Manns, Michael P ; Gossler, Achim ; Wilkens, Ludwig ; Plentz, Ruben ; Zender, Lars ; Malek, Nisar P

The incidence of cholangiocellular carcinoma (CCC) is increasing worldwide. Using a transgenic mouse model, we found that expression of the intracellular domain of Notch 1 (NICD) in mouse livers results in the formation of intrahepatic CCCs. These tumors display features of bipotential hepatic progenitor cells, indicating that intrahepatic CCC can originate from this cell type. We show that human and mouse CCCs are characterized by high expression of the cyclin E protein and identified the [...]

Menée in vitro, cette étude montre que les cellules de cancer du poumon avec mutation du gène LKB1 présentent un dysfonctionnement du métabolisme des nucléotides leur conférant une hypersensibilité à l'inhibition de la kinase DTYMK

Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a target in LKB1 Mutant Lung Cancer

Liu, Yan ; Marks, Kevin ; Cowley, Glenn S. ; Carretero, Julian ; Liu, Qingsong ; Nieland, Thomas J.F. ; Xu, Chunxiao ; Cohoon, Travis J ; Gao, Peng ; Zhang, Yong ; Chen, Zhao ; Altabef, Abigail B ; Tchaicha, Jeremy H ; Wang, Xiaoxu ; Choe, Sung ; Driggers, Edward M ; Zhang, Jianming ; Bailey, Sean T ; Sharpless, Norman E ; Hayes, D. Neil ; Patel, Nirali M ; Jänne, Pasi A. ; Bardeesy, Nabeel ; Engelman, Jeffrey A. ; Manning, Brendan D ; Shaw, Reuben J ; Asara, John M ; Scully, Ralph ; Kimmelman, Alec C. ; Byers, Lauren Averett ; Gibbons, Don L ; Wistuba, Ignacio I. ; Heymach, John V. ; Kwiatkowski, David J ; Kim, William Y. ; Kung, Andrew L. ; Gray, Nathanael S. ; Root, David E ; Cantley, Lewis C ; Wong, Kwok-Kin

The LKB1/STK11 tumor suppressor encodes a serine/threonine kinase which coordinates cell growth, polarity, motility, and metabolism. In non-small cell lung cancer, LKB1 is somatically inactivated in 25-30% of cases, often concurrently with activating KRAS mutation. Here, we employed an integrative approach to define novel therapeutic targets in KRAS-driven LKB1 mutant lung cancers. High-throughput RNAi screens in lung cancer cell lines from genetically engineered mouse models driven by [...]

Menée à l'aide d'un modèle murin de cancer du poumon, cette étude montre notamment que la perte d'expression de PTEN, à elle seule, ne suffit pas à induire une activation du gène Akt

PTEN-null Tumors Cohabiting the Same Lung Display Differential Akt Activation and Sensitivity to Dietary Restriction

Curry, Natasha L ; Mino-Kenudson, Mari ; Oliver, Trudy G ; Yilmaz, Ömer H ; Yilmaz, Vedat O ; Moon, Jade Y ; Jacks, Tyler ; Sabatini, David M ; Kalaany, Nada Y

PTEN loss is considered a biomarker for activated PI3K/Akt, a pathway frequently mutated in cancer, and recently shown to confer resistance to dietary restriction (DR). Here we demonstrate that PTEN loss is not sufficient to drive Akt activation and resistance to DR in tumors with low growth factor receptor levels. We describe a murine PTEN-null Kras-driven lung cancer model that harbors both DR-resistant, higher-grade, bronchiolar tumors with high-Akt-activity, and DR-sensitive, lower-grade, [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes selon lesquels, en fonction du contexte, le gène ZBTB7A peut jouer un rôle d'oncogène ou de suppresseur de tumeurs dans les cancers de la prostate n'exprimant pas PTEN

Zbtb7a suppresses prostate cancer through repression of a Sox9-dependent pathway for cellular senescence bypass and tumor invasion

Wang, Guocan ; Lunardi, Andrea ; Zhang, Jiangwen ; Chen, Zhenbang ; Ala, Ugo ; Webster, Kaitlyn A. ; Tay, Yvonne ; Gonzalez-Billalabeitia, Enrique ; Egia, Ainara ; Shaffer, David R. ; Carver, Brett ; Liu, Xue-Song ; Taulli, Riccardo ; Kuo, Winston Patrick ; Nardella, Caterina ; Signoretti, Sabina ; Cordon-Cardo, Carlos ; Gerald, William L. ; Pandolfi, Pier Paolo

Zbtb7a has previously been described as a powerful proto-oncogene. Here we unexpectedly demonstrate that Zbtb7a has a critical oncosuppressive role in the prostate. Prostate-specific inactivation of Zbtb7a leads to a marked acceleration of Pten loss–driven prostate tumorigenesis through bypass of Pten loss–induced cellular senescence (PICS). We show that ZBTB7A physically interacts with SOX9 and functionally antagonizes its transcriptional activity on key target genes such as MIA, which is [...]

Menée à l'aide de xénogreffes de cancer colorectal, cette étude met en évidence des mécanismes de nature épigénétique par lesquels, en stabilisant la chromatine, la forme non phosphorylée du gène STAT5A joue un rôle de suppresseur de tumeurs

Unphosphorylated STAT5A stabilizes heterochromatin and suppresses tumor growth

Hu, Xiaoyu ; Dutta, Pranabananda ; Tsurumi, Amy ; Li, Jinghong ; Wang, Jingtong ; Land, Hartmut ; Li, Willis X.

Tumor suppressors known to date impede cancer growth by arresting the cell cycle or promoting apoptosis. Here we show that unphosphorylated human STAT5A functions as a tumor suppressor capable of repressing multiple oncogenes via heterochromatin formation. Unphosphorylated STAT5A binds to heterochromatin protein 1α (HP1α) and stabilizes heterochromatin. Expressing unphosphorylated STAT5A or HP1α inhibits colon cancer growth in mouse xenograft models. Transcriptome profiling shows that [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en régulant la stabilité de la protéine p53, le gène BRIT1, situé sur la région chromosomique 8p23.1, joue un rôle de suppresseur de tumeurs dans les cancers du sein

BRIT1 Regulates p53 Stability and Functions as a Tumor Suppressor in Breast Cancer

Zhang, Bo ; Wang, Edward ; Dai, Hui ; Hu, Ruozhen ; Liang, Yulong ; Li, Kaiyi ; Wang, Guobin ; Peng, Guang ; Lin, Shiaw-Yih

In humans, gene encoding the BRIT1 protein is located on chromosome 8p23.1, a region implicated in the development of several malignancies, including breast cancer. Previous studies by our group and others suggested that BRIT1 might function as a novel tumor suppressor. Thus, identifying the molecular mechanisms that underlie BRIT1’s tumor suppressive function is important to understand cancer etiology and to identify effective therapeutic strategies for BRIT1-deficient tumors. We thus [...]

Cet article passe en revue les travaux récents sur le processus métastatique d'un mélanome

Melanoma metastasis: new concepts and evolving paradigms

Damsky, W. E. ; Theodosakis, N. ; Bosenberg, M.

Melanoma progression is typically depicted as a linear and stepwise process in which metastasis occurs relatively late in disease progression. Significant evidence suggests that in a subset of melanomas, progression is much more complex and less linear in nature. Epidemiologic and experimental observations in melanoma metastasis are reviewed here and are incorporated into a comprehensive model for melanoma metastasis, which takes into account the varied natural history of melanoma formation and [...]

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence le rôle joué par des fragments d'ADN extracellulaire dans le processus métastatique d'un cancer du pancréas

Extracellular DNA in pancreatic cancer promotes cell invasion and metastasis

Wen, Fushi ; Shen, Alex ; Choi, Andrew ; Gerner, Eugene W ; Shi, Jiaqi

Aggressive metastasis is the chief cause of the high morbidity and mortality associated with pancreatic cancer, yet the basis for its aggressive behavior remains elusive. Extracellular DNA (exDNA) is a recently discovered component of inflammatory tissue states. Here we report that exDNA is present on the surface of pancreatic cancer cells where it is critical for driving metastatic behavior. ExDNA was abundant on the surface and vicinity of cultured pancreatic cancer cells, but absent from [...]

A partir d'échantillons tumoraux prélevés sur des patients atteints d'un cancer du poumon, cette étude met en évidence des mécanismes par lesquels une histone déméthylase, RBP2, favorise le processus métastatique

Histone Demethylase RBP2 Promotes Lung Tumorigenesis and Cancer Metastasis

Teng, Yu-Ching ; Lee, Cheng-Feng ; Li, Ying-Shiuan ; Chen, Yi-Ren ; Hsiao, Pei-Wen ; Chan, Meng-Yu ; Lin, Feng-Mao ; Huang, Hsien-Da ; Chen, Yen-Ting ; Jeng, Yung-Ming ; Hsu, Chih-Hung ; Yan, Qin ; Tsai, Ming-Daw ; Juan, Li-Jung

The retinoblastoma binding protein RBP2 (KDM5A) is a histone demethylase that promotes gastric cancer cell growth and is enriched in drug-resistant lung cancer cells. In tumor-prone mice lacking the tumor suppressor gene RB or MEN1, genetic ablation of RBP2 can suppress tumor initiation, but the pathogenic breadth and mechanistic aspects of this effect relative to human tumors have not been defined. Here we approached this question in the context of lung cancer. RBP2 was overexpressed in human [...]

Mené à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par la protéine HMGA2 dans le processus métastatique d'un cancer du sein

HMGA2 is a Driver of Tumor Metastasis

Morishita, Asahiro ; Zaidi, M. Raza ; Mitoro, Akira ; Sankarasharma, Devipriya ; Szabolcs, Matthias ; Okada, Yasunori ; D'Armiento, Jeanine ; Chada, Kiran

The non-histone chromatin binding protein HMGA2 is expressed predominantly in the mesenchyme prior to its differentiation, but it is also expressed in tumors of epithelial origin. Ectopic expression of HMGA2 in epithelial cells induces epithelial-mesenchymal transition (EMT), which has been implicated in the acquisition of metastatic characters in tumor cells. However, little is known regarding in vivo modulation of HMGA2 and its effector functions in tumor metastasis. Here we report that HMGA2 [...]

Menée à l'aide de modèles murins et sur le poisson zèbre, cette étude montre qu'un réseau microvasculaire, situé à proximité de divers organes, est susceptible de constituer une niche abritant des cellules tumorales dormantes disséminées à partir d'un cancer du sein

The perivascular niche regulates breast tumour dormancy

Ghajar, Cyrus M. ; Peinado, Hector ; Mori, Hidetoshi ; Matei, Irina R. ; Evason, Kimberley J. ; Brazier, Hélène ; Almeida, Dena ; Koller, Antonius ; Hajjar, Katherine A. ; Stainier, Didier Y. R. ; Chen, Emily I. ; Lyden, David ; Bissell, Mina J.

In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumour cells (DTCs) are kept dormant, and what wakes them up, are fundamental problems in tumour biology. To address these questions, we used metastasis assays in mice and showed that dormant DTCs reside on microvasculature of lung, bone marrow and brain. We then engineered organotypic microvascular niches to determine whether endothelial cells directly [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en induisant une transition épithélio-mésenchymateuse et l'activation de la signalisation Akt/GSK-3β/Snail, la petite GTPase Rab25 favorise le processus métastatique d'un cancer de la vessie

Overexpression of Rab25 contributes to metastasis of bladder cancer through induction of epithelial-mesenchymal transition and activation of Akt/GSK-3β/Snail signaling

Zhang, Jia-Xing ; Wei, Jinhuan ; Lu, Jian ; Tong, Zhuting ; Liao, Bing ; Yu, Bin ; Zheng, Fang ; Huang, Xiaoxia ; Chen, Zhenhua ; Fang, Yong ; Li, Bin ; Chen, Wei ; Xie, Dan ; Luo, Junhang

Rab25, an epithelial-specific member of the Rab family of small GTPases, is associated with several human cancers. The goal of this study was to determine its function in bladder cancer (BC). We examined the Rab25 expression pattern in two different cohorts of BC patients treated with radical cystectomy by quantitative polymerase chain reaction, western blotting and immunohistochemical staining. A series of in vitro and in vivo assays were performed to elucidate the function of Rab25 in BC and [...]

Cet article passe en revue les perspectives offertes par la modélisation numérique du comportement des tumeurs pour prédire la réponse thérapeutique

Clinically Relevant Modeling of Tumor Growth and Treatment Response

Yankeelov, Thomas E. ; Atuegwu, Nkiruka ; Hormuth, David ; Weis, Jared A. ; Barnes, Stephanie L. ; Miga, Michael I. ; Rericha, Erin C. ; Quaranta, Vito

Current mathematical models of tumor growth are limited in their clinical application because they require input data that are nearly impossible to obtain with sufficient spatial resolution in patients even at a single time point—for example, extent of vascularization, immune infiltrate, ratio of tumor-to-normal cells, or extracellular matrix status. Here we propose the use of emerging, quantitative tumor imaging methods to initialize a new generation of predictive models. In the near future, [...]

Cet article présente des méthodes numériques permettant de découvrir et de mesurer des biais dans les données de séquençage fournies par les plateformes Illumina, Ion Torrent, Pacific Biosciences et Complete Genomics

Characterizing and measuring bias in sequence data

Ross, Michael ; Russ, Carsten ; Costello, Maura ; Hollinger, Andrew ; Lennon, Niall ; Hegarty, Ryan ; Nusbaum, Chad ; Jaffe, David

BACKGROUND:DNA sequencing technologies deviate from the ideal uniform distribution of reads. These biases impair scientific and medical applications. Accordingly, we have developed computational methods for discovering, describing and measuring bias. RESULTS:We applied these methods to the Illumina, Ion Torrent, Pacific Biosciences and Complete Genomics sequencing platforms, using data from human and from a set of microbes with diverse base compositions. As in previous work, library [...]

Cet article présente une nouvelle méthode pour identifier des mutations rares de gènes impliqués dans la cancérogenèse

Integrated analysis of recurrent properties of cancer genes to identify novel drivers

D'Antonio, Matteo ; Ciccarelli, Francesca

The heterogeneity of cancer genomes in terms of acquired mutations complicates the identification of genes whose modification may exert a driver role in tumorigenesis. In this study, we present a novel method that integrates expression profiles, mutation effects, and systemic properties of mutated genes to identify novel cancer drivers. We applied our method to ovarian cancer samples and were able to identify putative drivers in the majority of carcinomas without mutations in known cancer [...]

Cet article présente le projet "Genome of the Netherlands" de séquençage du génome de 250 trios familiaux (parents et enfant)

The Genome of the Netherlands: design, and project goals

Boomsma, Dorret I. ; Wijmenga, Cisca ; Slagboom, Eline P. ; Swertz, Morris A. ; Karssen, Lennart C. ; Abdellaoui, Abdel ; Ye, Kai ; Guryev, Victor ; Vermaat, Martijn ; van Dijk, Freerk ; Francioli, Laurent C. ; Jan Hottenga, Jouke ; Laros, Jeroen F. J. ; Li, Qibin ; Li, Yingrui ; Cao, Hongzhi ; Chen, Ruoyan ; Du, Yuanping ; Li, Ning ; Cao, Sujie ; van Setten, Jessica ; Menelaou, Androniki ; Pulit, Sara L. ; Hehir-Kwa, Jayne Y. ; Beekman, Marian ; Elbers, Clara C. ; Byelas, Heorhiy ; de Craen, Anton J. M. ; Deelen, Patrick ; Dijkstra, Martijn ; T den Dunnen, Johan ; de Knijff, Peter ; Houwing-Duistermaat, Jeanine ; Koval, Vyacheslav ; Estrada, Karol ; Hofman, Albert ; Kanterakis, Alexandros ; Enckevort, David van ; Mai, Hailiang ; Kattenberg, Mathijs ; van Leeuwen, Elisabeth M. ; Neerincx, Pieter B. T. ; Oostra, Ben ; Rivadeneira, Fernanodo ; Suchiman, Eka H. D. ; Uitterlinden, André G. ; Willemsen, Gonneke ; Wolffenbuttel, Bruce H. ; Wang, Jun ; de Bakker, Paul I. W. ; van Ommen, Gert-Jan ; van Duijn, Cornelia M.

Within the Netherlands a national network of biobanks has been established (Biobanking and Biomolecular Research Infrastructure-Netherlands (BBMRI-NL)) as a national node of the European BBMRI. One of the aims of BBMRI-NL is to enrich biobanks with different types of molecular and phenotype data. Here, we describe the Genome of the Netherlands (GoNL), one of the projects within BBMRI-NL. GoNL is a whole-genome-sequencing project in a representative sample consisting of 250 trio-families from [...]