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Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

PURPOSE The classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) plays a pivotal role in the management of metastatic germ cell tumors but relies on data of patients treated between 1975 and 1990. MATERIALS AND METHODS Data on 9,728 men with metastatic nonseminomatous germ cell tumors treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Europe, North America, and Australia. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS). The survival estimates were updated for the current era. Additionally, a novel prognostic model for PFS was developed in 3,542 patients with complete information on potentially relevant variables. The results were validated in an independent data set. RESULTS Compared with the original IGCCCG publication, 5-year PFS remained similar in patients with good prognosis with 89% (87%-91%) versus 90% (95% CI, 89 to 91), but the 5-year OS increased from 92% (90%-94%) to 96% (95%-96%). In patients with intermediate prognosis, PFS remained similar with 75% (71%-79%) versus 78% (76%-80%) and the OS increased from 80% (76%-84%) to 89% (88%-91%). In patients with poor prognosis, the PFS increased from 41% (95% CI, 35 to 47) to 54% (95% CI, 52 to 56) and the OS from 48% (95% CI, 42 to 54) to 67% (95% CI, 65 to 69). A more granular prognostic model was developed and independently validated. This model identified a new cutoff of lactate dehydrogenase at a 2.5 upper limit of normal and increasing age and presence of lung metastases as additional adverse prognostic factors. An online calculator is provided ( https://www.eortc.org/IGCCCG-Update ). CONCLUSION The IGCCCG Update model improves individual prognostication in metastatic nonseminomatous germ cell tumors. Increasing age and lung metastases add granularity to the original IGCCCG classification as adverse prognostic factors.

The mammalian germline is characterized by extensive epigenetic reprogramming during its development into functional eggs and sperm. Specifically, the epigenome requires resetting before parental marks can be established and transmitted to the next generation. In the female germline, X-chromosome inactivation and reactivation are among the most prominent epigenetic reprogramming events, yet very little is known about their kinetics and biological function. Here, we investigate X-inactivation and reactivation dynamics using a tailor-made in vitro system of primordial germ cell-like cell (PGCLC) differentiation from mouse embryonic stem cells. We find that X-inactivation in PGCLCs in vitro and in germ cell-competent epiblast cells in vivo is moderate compared to somatic cells, and frequently characterized by escaping genes. X-inactivation is followed by step-wise X-reactivation, which is mostly completed during meiotic prophase I. Furthermore, we find that PGCLCs which fail to undergo X-inactivation or reactivate too rapidly display impaired meiotic potential. Thus, our data reveal fine-tuned X-chromosome remodelling as a critical feature of female germ cell development towards meiosis and oogenesis. This work was supported by the Spanish Ministry of Science, Innovation and Universities (BFU2014-55275-P, BFU2017-88407-P to B.P.), the Agencia Estatal de Investigación (AEI) (EUR2019-103817 to B.P.), the AXA Research Fund (to B.P.) and the Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR, 2017 SGR 346 to B.P.). We would like to thank the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership and to the “Centro de Excelencia Severo Ochoa.” We also acknowledge support of the CERCA Programme of the Generalitat de Catalunya. N.A. is supported by an EMBO postdoctoral fellowship (LTF 695-2019). J.S. and M.B. were supported by La Caixa International PhD Fellowships and J.S. by a travel grant from the Company of Biologists (Development Journal). P.A. has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 751651

Although germline copy-number variants (CNVs) are the genetic cause of multiple hereditary diseases, detecting them from targeted next-generation sequencing data (NGS) remains a challenge. Existing tools perform well for large CNVs but struggle with single and multi-exon alterations. The aim of this work is to evaluate CNV calling tools working on gene panel NGS data and their suitability as a screening step before orthogonal confirmation in genetic diagnostics strategies. Five tools (DECoN, CoNVaDING, panelcn.MOPS, ExomeDepth, and CODEX2) were tested against four genetic diagnostics datasets (two in-house and two external) for a total of 495 samples with 231 single and multi-exon validated CNVs. The evaluation was performed using the default and sensitivity-optimized parameters. Results showed that most tools were highly sensitive and specific, but the performance was dataset dependant. When evaluating them in our diagnostics scenario, DECoN and panelcn.MOPS detected all CNVs with the exception of one mosaic CNV missed by DECoN. However, DECoN outperformed panelcn.MOPS specificity achieving values greater than 0.90 when using the optimized parameters. In our in-house datasets, DECoN and panelcn.MOPS showed the highest performance for CNV screening before orthogonal confirmation. Benchmarking and optimization code is freely available at https://github.com/TranslationalBioinformaticsIGTP/CNVbenchmarkeR.

The ultrastructural characteristics of the mature spermatozoon of the aspidogastrean Rohdella amazonica (Aspidogastridae, Rohdellinae) were studied by means of transmission electron microscopy. The sperm cell shows two axonemes of the 9 + '1' trepaxonematan pattern of Platyhelminthes, parallel cortical microtubules, a well-developed lateral expansion, external ornamentation of the plasma membrane, one mitochondrion, an electron-dense ring, a nucleus and granules of glycogen. The present results were compared with those observed in the aspidogastreans studied to date and in other Platyhelminthes. The lateral expansion and the electron-dense ring are typical characters for aspidogastreans. Although a lateral expansion has been described in other Platyhelminthes such as monogeneans and digeneans, the Aspidogastrea shows a much larger lateral expansion with both peripheral and internal microtubules. The dense ring is observed as a cylinder in a longitudinal view and shows a more granular appearance in sperm cells from the seminal vesicle in comparison to a more electron-dense appearance in sperm cells from the seminal uterine receptacle.

Resumen La tecnología de la edición génica por CRISPR ha revolucionado tanto la investigación en biotecnología como en biomedicina. Esta técnica tan poderosa y versátil permite editar los genes de cualquier especie a la carta. A pesar de su potencia y efectividad, quedan muchas cuestiones para resolver y controlar su resultado final, particularmente en las aplicaciones sobre el genoma de los seres humanos. En este artículo se plantean tanto los puntos fuertes y puntos débiles de la técnica, como otras cuestiones abiertas sobre la edición génica, sobre si debe dirigirse a la terapia o a la mejora, si la modificación debe constreñirse a células somáticas o también a editar a embriones, modificando el genoma de los seres humanos del futuro. Abstract Gene editing using CRISPR has completely revolutionized the research in biotechnology and biomedicine. This powerful and versatile technique enables the precise edition of genes from any organism. Even though the technique is so effective and amenable, many questions remain to be solved before the final genetic outcome can be fully controlled, particularly in its uses on the human genome. In this article, I discuss the current strengths and weaknesses of the technique. I also pose other open questions on gene editing, such as whether it should be used for either therapy or genetic enhancement, and whether it should be used only on somatic cells or also for embryo gene editing, the latter resulting in the modification of future human beings. Resum La tecnologia de l'edició gènica mitjançant CRISPR ha revolucionat tant la recerca en biotecnologia com en biomedicina. Aquesta tècnica tan poderosa i versàtil permet editar els gens de qualsevol espècie a la carta. Malgrat la seva potència i efectivitat, queden moltes qüestions per resoldre i controlar el seu resultat final, particularment en les aplicacions sobre el genoma dels éssers humans. En aquest article es plantegen els punts forts i els punts febles de la tècnica, així com altres qüestions obertes sobre l'edició gènica, si ha de dirigir-se a la teràpia o a la millora, si la modificació ha de constrènyer-se a cèl·lules somàtiques o també es poden editar en embrions, modificant el genoma dels éssers humans del futur.

© 2019 The Authors., Somatic epigenetic inactivation of the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) is frequent in colorectal cancer (CRC); however, its involvement in CRC predisposition remains unexplored. We assessed the role and relevance of MGMT germline mutations and epimutations in familial and early-onset CRC. Mutation and promoter methylation screenings were performed in 473 familial and/or early-onset mismatch repair-proficient nonpolyposis CRC cases. No constitutional MGMT inactivation by promoter methylation was observed. Of six rare heterozygous germline variants identified, c.346C > T (p.H116Y) and c.476G > A (p.R159Q), detected in three and one families respectively, affected highly conserved residues and showed segregation with cancer in available family members. In vitro, neither p.H116Y nor p.R159Q caused statistically significant reduction of MGMT repair activity. No evidence of somatic second hits was found in the studied tumors. Case-control data showed over-representation of c.346C > T (p.H116Y) in familial CRC compared to controls, but no overall association of MGMT mutations with CRC predisposition. In conclusion, germline mutations and constitutional epimutations in MGMT are not major players in hereditary CRC. Nevertheless, the over-representation of c.346C > T (p.H116Y) in our familial CRC cohort warrants further research., This work was funded by the Spanish Ministry of Science, Innovation and Universities, co-funded by FEDER funds -a way to build Europe- [SAF2016-80888-R (LV), SAF2014-55000-R (ME), SAF2015-68016-R (GC/MP), Juan de la Cierva and Sara Borrell postdoctoral contracts (PM)]; Instituto de Salud Carlos III [DTS16/00153 (ME) and CIBERONC CB16/12/00234]; the Government of Catalonia [Pla Estratègic de Recerca i Innovació en Salut SLT002/16/0037, 2017SGR1282, 2017SGR1080, 2014SGR633 and 2009SGR1315]; and Fundación Olga Torres. We thank the CERCA/Generalitat de Catalunya Program for institutional support. This study has been enabled by COST Action CA17118.

Gene editing using CRISPR has completely revolutionized the research in biotechnology and biomedicine. This powerful and versatile technique enables the precise edition of genes from any organism. Even though the technique is so effective and amenable, many questions remain to be solved before the final genetic outcome can be fully controlled, particularly in its uses on the human genome. In this article, I discuss the current strengths and weaknesses of the technique. I also pose other open questions on gene editing, such as whether it should be used for either therapy or genetic enhancement, and whether it should be used only on somatic cells or also for embryo gene editing, the latter resulting in the modification of future human beings.

Genomic imprinting is a form of epigenetic regulation that results in the expression of either the maternally or paternally inherited allele of a subset of genes (Ramowitz and Bartolomei 2011). This imprinted expression of transcripts is crucial for normal mammalian development. In humans, loss-of-imprinting of specific loci results in a number of diseases exemplified by the reciprocal growth phenotypes of the Beckwith-Wiedemann and Silver-Russell syndromes, and the behavioral disorders Angelman and Prader-Willi syndromes (Kagami et al. 2008; Buiting 2010; Choufani et al. 2010; Eggermann 2010; Kelsey 2010; Mackay and Temple 2010). In addition, aberrant imprinting also contributes to multigenic disorders associated with various complex traits and cancer (Kong et al. 2009; Monk 2010). Imprinted loci contain differentially methylated regions (DMRs) where cytosine methylation marks one of the parental alleles, providing cis-acting regulatory elements that influence the allelic expression of surrounding genes. Some DMRs acquire their allelic methylation during gametogenesis, when the two parental genomes are separated, resulting from the cooperation of the de novo methyltransferase DNMT3A and its cofactor DNMT3L (Bourc'his et al. 2001; Hata et al. 2002). These primary, or germline imprinted DMRs are stably maintained throughout somatic development, surviving the epigenetic reprogramming at the oocyte-to-embryo transition (Smallwood et al. 2011; Smith et al. 2012). To confirm that an imprinted DMR functions as an imprinting control region (ICR), disruption of the imprinted expression upon genetic deletion of that DMR, either through experimental targeting in mouse or that which occurs spontaneously in humans, is required. A subset of DMRs, known as secondary DMRs, acquire methylation during development and are regulated by nearby germline DMRs in a hierarchical fashion (Coombes et al. 2003; Lopes et al. 2003; Kagami et al. 2010). With the advent of large-scale, base-resolution methylation technologies, it is now possible to discriminate allelic methylation dictated by sequence variants from imprinted methylation. Yet our knowledge of the total number of imprinted DMRs in humans, and their developmental dynamics, remains incomplete, hampered by genetic heterogeneity of human samples. Here we present high-resolution mapping of human imprinted methylation. We performed whole-genome-wide bisulfite sequencing (WGBS) on leukocyte-, brain-, liver-, and placenta-derived DNA samples to identify partially methylated regions common to all tissues consistent with imprinted DMRs. We subsequently confirmed the partial methylated states in tissues using high-density methylation microarrays. The parental origin of methylation was determined by comparing microarray data for DNA samples from reciprocal genome-wide uniparental disomy (UPD) samples, in which all chromosomes are inherited from one parent (Lapunzina and Monk 2011), and androgenetic hydatidiform moles, which are created by the fertilization of an oocyte lacking a nucleus by a sperm that endoreduplicates. The use of uniparental disomies and hydatidiform moles meant that our analyses were not subjected to genotype influences, enabling us to characterize all known imprinted DMRs at base-pair resolution and to identify 21 imprinted domains, which we show are absent in mice. Lastly, we extended our analyses to determine the methylation profiles of all imprinted DMRs in sperm, stem cells derived from parthenogenetically activated metaphase-2 oocyte blastocytes (phES) (Mai et al. 2007; Harness et al. 2011), and stem cells (hES) generated from both six-cell blastomeres and the inner cell mass of blastocysts, delineating the extent of embryonic reprogramming that occurs at these loci during human development.

The optimal cell lineage for cardiac regeneration remains elusive; and current treatments, with the exception of heart transplantation, are not enough to restore myocardial function. Thus, new strategies, such as cardiac tissue engineering, are now emerging as a new therapeutic modality. On the other hand, cardiac cells are normally subjected to electrical and mechanical forces that regulate gene expression and cellular function. Therefore, our hypothesis claims that in vitro individual or combined synchronous electro-mechanical stimuli mimicking the cardiac environment, could mature or induce cardiac differentiation on therapeutic cells to benefit further retention and integration into the myocardium. This thesis proposal had several goals: 1. Design an ad-hoc device to supply electrical and mechanical stimuli, individually or synchronously, to a monolayer cell culture. 2. Design a protocol for electrical, mechanical and electromechanical conditioning. 3. Analyze the cardiomyogenic effect of electrical, mechanical and electromechanical conditioning on adipose tissue-derived progenitor cells (ATDPCs) and cardiomyocyte progenitor cells (CMPCs). 4. Study the feasibility of a tissue engineered construct with trained cardiac adipose tissue-derived progenitor cells (cardiac ATDPCs). 5. Examine the regenerative capacity of electromechanically conditioned cardiac ATDPCs within a myocardial infarction murine model. Summing up, the conclusions derived from this thesis project are: 1. A new device for ad-hoc electrical and mechanical stimulation, individually or synchronously, has been developed in collaboration with the Electronic and Biomedical Instrumentation Group from the Universitat Politècnica de Barcelona. This device has been patented (WO 2013185818 A1) including some results obtained in this thesis. 2. Protocols for electrical, mechanical and electromechanical conditioning on cardiac ATDPCs culture were designed and optimized with the aim to mimic the cardiac environment. 3. Electrical stimulation on cardiac ATDPCs and CMPCs enhances the expression of cardiac transcription factors (MEF2A and GATA-4) crucial for cardiac differentiation. In addition, electrical conditioning promotes cardiac ATDPCs elongation and cell alignment. 4. Mechanical stimulation on cardiac ATDPCs upregulates cardiac transcription factors (GATA-4 and Tbx5) and structural genes (α-actinin and cTnI) expression, strongly dependent on the patterned surface. 5. In vitro electro-mechanical stimulation pre-commits the cell population against the hostile cardiac milieu through increased expression of cardiac transcription factors (Tbx5 and GATA-4), structural genes (b-MyHC) and, most importantly, calcium handling genes (Cx43 and SERCA2). 6. Conditioned cardiac ATDPCs fibrin constructs scarcely migrate to the murine myocardium, de novo express cTnI in vivo, increase vessel density and promote the sprouting of functional blood vessels, and improve cardiac function with only 105 implanted cells., El llinatge cel·lular òptim per a la regeneració cardíaca continua sent un gran desconegut. Els tractaments actuals són insuficients per a restablir la funció cardíaca, exceptuant el trasplantament de cor. Per això, noves estratègies, com l’enginyeria tissular cardíaca, estan emergent com a noves modalitats terapèutiques. D’altra banda, les cèl·lules cardíaques estan normalment subjectes a estímuls elèctrics i mecànics, que regulen la seva expressió gènica i la funció cel·lular. Per tant, la hipòtesi d’aquest treball és que el pre-condicionament in vitro, mitjançant estímuls biofísics similars a l’entorn cardíac, podria madurar i induir cert grau de diferenciaicó cardíaca a les cèl·lules terapèutiques. Així es milloraria la seva retenció i integració al miocardi hoste, i beneficiaria el tractament de l’infart de miocardi. Els objectius d’aquest treball són: 1. Disseny i producció d’un aparell apte per a portar a terme el condicionament elèctric i mecànica, individualment o de manera combinada, a un cultiu cel·lular en monocapa de cèl·lules progenitores derivades de teixit adipós cardíac (ATDPCs cardíaques). 2. Disseny d’un protocol per al condicionament elèctric, mecànic i electromecànic. 3. Caracterització de les cèl·lules obtingudes de cadascun dels condicionaments. 4. Estudi de la viabilitat d’un constructe d’enginyeria amb ATDPCs cardíaques condicionades. 5. Examinar l’efecte del condicionament electromecànic de les ATDPCs cardíaques implantades, mitjançant un constructe tridimensional, en el model murí d’infart de miocardi. Les conclusions obtingudes són: 1. S’ha desenvolupat un aparell apte per a l’estimulació elèctrica i mecànica, individual o sincrònicament, en col·laboració amb el Grup d’Instrumentació Electrònica i Biomèdica de la Universitat Politècnica de Catalunya. Aquest aparell s’ha patentat (WO 2013185818 A1) amb alguns dels resultats derivats d’aquesta tesi. 2. S’ha dissenyat i optimitzat un protocol per al condicionament elèctric, mecànic i electromecànic de les ATDPCs cardíaques amb la intenció de mimetitzar l’ambient cardíac. 3. L’estimulació elèctrica de les ATDPCs cardíaques i les CMPCs millora l’expressió de factors de transcripció (MEF2A i GATA-4) crucials per a la diferenciació cardíaca. A més, el condicionament elèctric de les ATDPCs cardíaques promou la seva elongació i alineament acord al patró de la superfície. 4. L’estimulació mecànica de les ATDPCs cardíaques incrementa l’expressió genètica de factors de transcripció (GATA-4 i Tbx5) i gens estructurals (α-actinin i cTnI), i és fortament dependent del patró de la superfície. 5. L’estimulació electromecànica in vitro prepara les ATDPCs cardíaques per a l’hostil entorn cardíac augmentant l’expressió de factors de transcripció cardíacs (Tbx5 i GATA-4), gens estructurals (β-MyHC) i gens relacionats amb el maneig del calci (Cx43 i SERCA2). 6. El pegat de fibrina amb ATDPCs cardíaques electromecànicament entrenades promou una escassa migració al miocardi murí, una lleu expressió proteica de cTnI, l’increment de la densitat vascular a la vora de la cicatriu de l’infart, la formació de vasos sanguinis funcionals al miocardi i al constructe, i una millora de la funció cardíaca del 8% amb només 105 cèl·lules.

Epigenetic reprogramming is a central process during mammalian germline development. Genome-wide DNA demethylation in primordial germ cells (PGCs) is a prerequisite for the erasure of epigenetic memory, preventing the transmission of epimutations to the next generation. Apart from DNA demethylation, germline reprogramming has been shown to entail reprogramming of histone marks and chromatin remodelling. Contrary to other animal models, there is limited information about the epigenetic dynamics during early germ cell development in humans. Here, we provide further characterization of the epigenetic configuration of the early human gonadal PGCs. We show that early gonadal human PGCs are DNA hypomethylated and their chromatin is characterized by low H3K9me2 and high H3K27me3 marks. Similarly to previous observations in mice, human gonadal PGCs undergo dynamic chromatin changes concomitant with the erasure of genomic imprints. Interestingly, and contrary to mouse early germ cells, expression of BLIMP1/PRDM1 persists in through all gestational stages in human gonadal PGCs and is associated with nuclear lysine-specific demethylase-1. Our work provides important additional information regarding the chromatin changes associated with human PGCs development between 6 and 13 weeks of gestation in male and female gonads.

This study was undertaken to investigate the expression and predictive value for outcome of multidrug resistance-associated (MDR) proteins P-glycoprotein (Pgp), MRP1, BCRP, and LRP, in advanced testicular germ-cell tumours (TGCT). Paraffin-embedded sections from 56 previously untreated patients with metastatic TGCT were immunostained for Pgp, MRP1, BCRP, and LRP. All patients received platinum-based chemotherapy after orchidectomy. Immunostaining was related to clinicopathological parameters, response to chemotherapy, and outcome. Strong and intermediate expressions of the different MDR-related proteins were: 27 and 41% (Pgp), 54 and 37% (MRP1), 86 and 7% (BCRP), and 14 and 29% (LRP). P-glycoprotein and MRP1 associated, respectively, to low AFP (P=0.026) and high LDH levels (P=0.014), whereas LRP expression associated with high beta-hCG levels (P=0.003) and stage IV tumours (P=0.029). No correlation was found between Pgp, MRP1, and BCRP expression and response to chemotherapy and survival. In contrast, patients with LRP-positive tumours (strong or intermediate expression) had shorter progression-free (P=0.0006) and overall survival (P=0.0116) than LRP-negative patients, even after individual log-rank adjustments by statistically associated variables. Our data suggest that a positive LRP immunostaining at the time of diagnosis in metastatic TGCT is associated with an adverse clinical outcome.

Germinal centre B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is a common malignancy, yet the signalling pathways that are deregulated and the factors leading to its systemic dissemination are poorly defined1,2. Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a Gα12 and Gα13 coupled receptor, promotes growth regulation and local confinement of germinal centre B cells3,4. Recent deep sequencing studies of GCB-DLBCL have revealed mutations in many genes in this cancer, including in GNA13 (encoding Gα13) and S1PR2 (refs 5,6, 7). Here we show, using in vitro and in vivo assays, that GCB-DLBCL-associated mutations occurring in S1PR2 frequently disrupt the receptor's Akt and migration inhibitory functions. Gα13-deficient mouse germinal centre B cells and human GCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and Gα13-deficient mice developed germinal centre B-cell-derived lymphoma. Germinal centre B cells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency in Gα13, but not S1PR2, led to germinal centre B-cell dissemination into lymph and blood. GCB-DLBCL cell lines frequently carried mutations in the Gα13 effector ARHGEF1, and Arhgef1 deficiency also led to germinal centre B-cell dissemination. The incomplete phenocopy of Gα13- and S1PR2 deficiency led us to discover that P2RY8, an orphan receptor that is mutated in GCB-DLBCL and another germinal centre B-cell-derived malignancy, Burkitt's lymphoma, also represses germinal centre B-cell growth and promotes confinement via Gα13. These findings identify a Gα13-dependent pathway that exerts dual actions in suppressing growth and blocking dissemination of germinal centre B cells that is frequently disrupted in germinal centre B-cell-derived lymphoma.