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Key Points The gene map for the extended major histocompatibility complex (xMHC) comprises 421 loci (excluding RNA genes) in a sequence length of 7.6 Mb — extending the previous gene map of the classical MHC, which was 3.6 Mb long and contained 224 loci. All 421 xMHC loci have been assigned definitive and approved gene symbols. About 50% of the xMHC gene loci are present in clusters or superclusters that are not restricted only to immune genes. The two largest clusters, comprising histone and tRNA genes are the largest of their type in the genome. Transcription hotspot analysis indicates that it is just as likely that the classical MHC is hitch-hiking with gene clusters of the xMHC as the reverse. About 22% of the expressed xMHC genes show a higher than average number of non-synonymous coding polymorphisms. About 28% of the xMHC genes can be associated with immune system function. About 10% of the xMHC genes are currently known to be disease-causing or disease-associated. About 20% of the xMHC genes have putative paralogues elsewhere in the genome, indicating considerable potential for functional redundancy. The gene map of the xMHC provides an invaluable resource for the study of the most important genetic region of the human genome in relation to infectious, inflammatory and autoimmune diseases. The major histocompatibility complex (MHC) is the most important region in the vertebrate genome with respect to infection and autoimmunity, and is crucial in adaptive and innate immunity. Decades of biomedical research have revealed many MHC genes that are duplicated, polymorphic and associated with more diseases than any other region of the human genome. The recent completion of several large-scale studies offers the opportunity to assimilate the latest data into an integrated gene map of the extended human MHC. Here, we present this map and review its content in relation to paralogy, polymorphism, immune function and disease. The gene map of the xMHC is also available as a poster, which accompanies this issue and is available at http://www.nature.com/nrg/posters/mhcmap/index.html .

During B cell development, cells that fail to productively rearrange their immunoglobulin VH-DJH gene segments to generate an in-frame junction that codes for a functional pre-B cell receptor are deleted. Markus Müschen and colleagues now report that Bach2 is a key component of this pre-B cell receptor checkpoint that enables the elimination of normal and transformed B cells with nonfunctional V(D)J rearrangements by regulating the expression of p53. The B cell–specific transcription factor BACH2 is required for affinity maturation of B cells. Here we show that Bach2-mediated activation of p53 is required for stringent elimination of pre-B cells that failed to productively rearrange immunoglobulin V H -DJ H gene segments. After productive V H -DJ H gene rearrangement, pre-B cell receptor signaling ends BACH2-mediated negative selection through B cell lymphoma 6 (BCL6)-mediated repression of p53. In patients with pre-B acute lymphoblastic leukemia, the BACH2-mediated checkpoint control is compromised by deletions, rare somatic mutations and loss of its upstream activator, PAX5. Low levels of BACH2 expression in these patients represent a strong independent predictor of poor clinical outcome. In this study, we demonstrate that Bach2 +/+ pre-B cells resist leukemic transformation by Myc through Bach2-dependent upregulation of p53 and do not initiate fatal leukemia in transplant-recipient mice. Chromatin immunoprecipitation sequencing and gene expression analyses carried out by us revealed that BACH2 competes with BCL6 for promoter binding and reverses BCL6-mediated repression of p53 and other cell cycle checkpoint–control genes. These findings identify BACH2 as a crucial mediator of negative selection at the pre-B cell receptor checkpoint and a safeguard against leukemogenesis.

It is now clear that tyrosine kinases represent attractive targets for therapeutic intervention in cancer. Recent advances in DNA sequencing technology now provide the opportunity to survey mutational changes in cancer in a high-throughput and comprehensive manner. Here we report on the sequence analysis of members of the receptor tyrosine kinase (RTK) gene family in the genomes of glioblastoma brain tumors. Previous studies have identified a number of molecular alterations in glioblastoma, including amplification of the RTK epidermal growth factor receptor. We have identified mutations in two other RTKs: (i) fibroblast growth receptor 1, including the first mutations in the kinase domain in this gene observed in any cancer, and (ii) a frameshift mutation in the platelet-derived growth factor receptor-α gene. Fibroblast growth receptor 1, platelet-derived growth factor receptor-α, and epidermal growth factor receptor are all potential entry points to the phosphatidylinositol 3-kinase and mitogen-activated protein kinase intracellular signaling pathways already known to be important for neoplasia. Our results demonstrate the utility of applying DNA sequencing technology to systematically assess the coding sequence of genes within cancer genomes.

Anjan Dhar1,2, Alexander Newman2, Vikki Rand2 Department of Gastroenterology1, Darlington Memorial Hospital and School of Health and Life Sciences2, Teesside University, UKBackgroundGastrointestinal (GI) manifestations of COVID-19 have been increasingly reported from many centres but it is not clear as to whether the presence of GI manifestations influences the outcomes of COVID-19. The data from the UK is still emerging and there is significant variability between the North of England and the rest of the UK.Aim of this studyDarCoVE was a single centre epidemiological study initiated over a 3 week period during the peak of the first wave of the COVID-19 pandemic in the United Kingdom. This prospective cohort analysis evaluated the GI and non-GI manifestations of the disease and produced a multi-variate analysis of prognosticators for COVID-19.MethodsConsecutive patients admitted with fever, cough or shortness of breath to the Acute Medical Admissions Service of Darlington Memorial Hospital between 26 March 2020 – 12 April 2020 were recruited to an electronic database, and divided into two cohorts: RT-PCR positive for SARS-CoV-2 (COVID+) and negative (COVID-). Demographic parameters, underlying co-morbidities, GI and non-GI symptoms, BMI, haematological and biochemical laboratory parameters, chest radiology, need for supplemental oxygen, need for high dependency and intensive care treatment, length of hospital stay and mortality were recorded. Univariate survival analysis was performed by Cox proportional hazard model in R, multi variate analysis was done by forward selection model, cumulative survival by Kaplan-Meier method using log-rank test.Results275 patients formed the dataset for analysis, 130 COVID+. Median age of COVID+ was 70(range 23-95yrs), 63% were over age 65yrs, M:F=1.28. 73% had at least one co-morbidity, diabetes commonest. Median BMI 29.7 (range 13.9-44.9). 60.8% patients had a BMI>30, compared to UK average of 10.9% (p<0.001). GI manifestations included: diarrhoea in 10.1%, vomiting 13%, abdominal discomfort 9.4%, loss of appetite 5.7%, abnormal liver functions 37%, mean ALT 52.4 IU/L, ALT >150 in 5.1%. Of 43 clinical and biochemical factors investigated for prognostic value, 9 factors were associated with outcome at p<0.05 with cough and diarrhoea associated with lower risk of death compared to the other 7 factors. On multivariate analysis, high frailty score > 5, worst oxygenation SpO2 < 93%, platelets < 100 x 109/L and immunocompromised were poor prognosticators. None of the GI manifestations co-related with risk of death in this analysis, with a trend for ALT >150 to be associated with higher mortality. Overall mortality was 30.8% compared to UK national mortality of 26%, with ITU mortality higher at 37%.ConclusionThis study has shown a regional variation in the outcome of COVID-19, with slightly different prognosticators. GI manifestations continue to be significant in COVID-19, with a trend seen with high ALT. The data from this analysis will help management in future pandemics.

IntroductionDuring and following the COVID-19 pandemic, there has been a major expansion of self-administered subcutaneous biologics for the management of inflammatory bowel disease. These agents are more difficult to monitor since patients do not need to attend the Biologics infusion unit and there is no audit trail to confirm administration of the drug at the scheduled time points.Aims and MethodsFollowing a successful NHS X bid for funding, a pilot proof of concept project to assess the feasibility and uptake of a digital technology (Health Beacon Digital Sharps Box®) to record and monitor subcutaneous injectable pen use was implemented in 50 consecutive IBD patients who were being treated with subcutaneous infliximab (Remsima®), Adalimumab (Amgevita®) or Vedolizumab (Entyvio®), on a 2-weekly schedule. The Health Beacon ICMS is comprised of a Smart Sharps Bin, pre-programmed with a patient’s individual treatment schedule. The bin electronically captures each time a used injection is disposed of, to create a time-stamped record as a proxy for medication adherence. This is accompanied by Health Beacon’s Companion App and Care Team support. Patients were also sent electronic dose reminders if they failed to dispose of a scheduled injection within certain time periods. Adherence data from the HealthBeacon ICMS, as well as patient satisfaction, transmission reports of data to the IBD Team and any technical issues were recorded over the 6-month period.ResultsOf 50 patients invited to join the programme, 45 registered patients had complete record of 6 months follow up; 4 patients deactivated recruitment and 1 left the programme. 21 patients were on Vedolizumab, 18 on Adalimumab and 8 on Infliximab, all 2-weekly SC injection. 45% patients were in the 36–50year age group, with the remaining spread between 18–75 years. M: F=21:24. of 418 scheduled drops, 360 were made, with overall adherence being 86%. On time adherence was 76%. The study showed that up to 24% pts on SC Biologics at home delay their scheduled drug administration. Patient satisfaction was high. Reasons for delay in administration included forgetting, being away from home and being busy. Reminders were acknowledged.ConclusionsThis is the first study to our knowledge exploring adherence to subcutaneous biologics at home for IBD. It showed that a digital injection monitoring and support system is useful and acceptable to track adherence. of the patients involved in the study there is an overall adherence of 90%, with up to 24% patients delaying their scheduled administration. Further studies are needed to analyse patient behaviour and impact on disease course.Abstract O50 Figure 1

A rare constitutional translocation between chromosomes 15 and 21 predisposes to catastrophic chromosomal damage followed by amplification of megabase regions, causing a specific subtype of acute lymphoblastic leukaemia. Chromothripsis in acute lymphoblastic leukaemia A subgroup comprising some 2% of patients with the childhood cancer acute lymphoblastic leukaemia (ALL) carries an intrachromosomal amplification of one copy of chromosome 21, iAMP21, with distinct prognostic and therapeutic implications. Peter Campbell and colleagues combined genomic, cytogenetic, transcriptional and bioinformatic analyses to reconstruct the evolution of this form of ALL. They find that the rare constitutional Robertsonian translocation between chromosomes 15 and 21 greatly increases the risk of developing iAMP21 ALL. In these cases, amplification is initiated by chromothripsis (multiple chromosome rearrangements) involving both sister chromatids of the Robertsonian chromosome, a novel mechanism for cancer predisposition. In sporadic iAMP21, breakage-fusion-bridge cycles are typically the initiating event, often followed by chromothripsis. The data indicate that dicentric chromosomes may be an important precipitant of chromothripsis. Changes in gene dosage are a major driver of cancer, known to be caused by a finite, but increasingly well annotated, repertoire of mutational mechanisms 1 . This can potentially generate correlated copy-number alterations across hundreds of linked genes, as exemplified by the 2% of childhood acute lymphoblastic leukaemia (ALL) with recurrent amplification of megabase regions of chromosome 21 (iAMP21) 2 , 3 . We used genomic, cytogenetic and transcriptional analysis, coupled with novel bioinformatic approaches, to reconstruct the evolution of iAMP21 ALL. Here we show that individuals born with the rare constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10)c, have approximately 2,700-fold increased risk of developing iAMP21 ALL compared to the general population. In such cases, amplification is initiated by a chromothripsis event involving both sister chromatids of the Robertsonian chromosome, a novel mechanism for cancer predisposition. In sporadic iAMP21, breakage-fusion-bridge cycles are typically the initiating event, often followed by chromothripsis. In both sporadic and rob(15;21)c-associated iAMP21, the final stages frequently involve duplications of the entire abnormal chromosome. The end-product is a derivative of chromosome 21 or the rob(15;21)c chromosome with gene dosage optimized for leukaemic potential, showing constrained copy-number levels over multiple linked genes. Thus, dicentric chromosomes may be an important precipitant of chromothripsis, as we show rob(15;21)c to be constitutionally dicentric and breakage-fusion-bridge cycles generate dicentric chromosomes somatically. Furthermore, our data illustrate that several cancer-specific mutational processes, applied sequentially, can coordinate to fashion copy-number profiles over large genomic scales, incrementally refining the fitness benefits of aggregated gene dosage changes.

Children with B-cell non-Hodgkin lymphoma (B-NHL) have an excellent chance of survival, however, current clinical risk stratification places as many as half of patients in a high-risk group receiving very intensive chemo-immunotherapy. TP53 alterations are associated with adverse outcome in many malignancies; however, whilst common in paediatric B-NHL, their utility as a risk classifier is unknown. We evaluated the clinical significance of TP53 abnormalities (mutations, deletion and/or copy number neutral loss of heterozygosity) in a large UK paediatric B-NHL cohort and determined their impact on survival. TP53 abnormalities were present in 54.7% of cases and were independently associated with a significantly inferior survival compared to those without a TP53 abnormality (PFS 70.0% vs 100%, p < 0.001, OS 78.0% vs 100%, p = 0.002). Moreover, amongst patients clinically defined as high-risk (stage III with high LDH or stage IV), those without a TP53 abnormality have superior survival compared to those with TP53 abnormalities (PFS 100% vs 55.6%, p = 0.005, OS 100% vs 66.7%, p = 0.019). Biallelic TP53 abnormalities were either maintained from the presentation or acquired at progression in all paired diagnosis/progression Burkitt lymphoma cases. TP53 abnormalities thus define clinical risk groups within paediatric B-NHL and offer a novel molecular risk stratifier, allowing more personalised treatment protocols.

We reconstructed the natural history and temporal evolution of the most common childhood brain malignancy, medulloblastoma, by single-cell whole-genome sequencing (sc-WGS) of tumours representing its major molecular sub-classes and clinical risk groups. Favourable-risk disease sub-types assessed (MBWNT and infant desmoplastic/nodular MBSHH) typically comprised a single clone with no evidence of further evolution. In contrast, highest risk sub-classes (MYC-amplified MBGroup3 and TP53-mutated MBSHH) were most clonally diverse and displayed gradual evolutionary trajectories. Clinically adopted biomarkers (e.g. chromosome 6/17 aberrations; CTNNB1/TP53 mutations) were typically early-clonal/initiating events, exploitable as targets for early-disease detection; in analyses of spatially distinct tumour regions, a single biopsy was sufficient to assess their status. Importantly, sc-WGS revealed novel events which arise later and/or sub-clonally and more commonly display spatial diversity; their clinical significance and role in disease evolution post-diagnosis now require establishment. These findings reveal diverse modes of tumour initiation and evolution in the major medulloblastoma sub-classes, with pathogenic relevance and clinical potential.

Tumour diversity Ependymoma is a type of neural tumour that arises throughout the central nervous system. Using comparative transcriptomics in mouse and human tumours, Johnson et al . home in on mutations that are specific to individual tumour subgroups. In the course of their study, the authors generate the first mouse model of ependymoma and demonstrate the power of interspecific genomic comparisons to interrogate cancer subgroups. Ependymoma is a type of neural tumour that arises throughout the central nervous system. Using comparative transcriptomics in mouse and human tumours, these authors home in on mutations that are specific to individual tumour subgroups. In doing so, they generate the first mouse model of ependymoma and demonstrate the power of interspecific genomic comparisons to interrogate cancer subgroups. Understanding the biology that underlies histologically similar but molecularly distinct subgroups of cancer has proven difficult because their defining genetic alterations are often numerous, and the cellular origins of most cancers remain unknown 1 , 2 , 3 . We sought to decipher this heterogeneity by integrating matched genetic alterations and candidate cells of origin to generate accurate disease models. First, we identified subgroups of human ependymoma, a form of neural tumour that arises throughout the central nervous system (CNS). Subgroup-specific alterations included amplifications and homozygous deletions of genes not yet implicated in ependymoma. To select cellular compartments most likely to give rise to subgroups of ependymoma, we matched the transcriptomes of human tumours to those of mouse neural stem cells (NSCs), isolated from different regions of the CNS at different developmental stages, with an intact or deleted Ink4a/Arf locus (that encodes Cdkn2a and b). The transcriptome of human supratentorial ependymomas with amplified EPHB2 and deleted INK4A/ARF matched only that of embryonic cerebral Ink4a/Arf −/− NSCs. Notably, activation of Ephb2 signalling in these, but not other, NSCs generated the first mouse model of ependymoma, which is highly penetrant and accurately models the histology and transcriptome of one subgroup of human supratentorial tumour. Further, comparative analysis of matched mouse and human tumours revealed selective deregulation in the expression and copy number of genes that control synaptogenesis, pinpointing disruption of this pathway as a critical event in the production of this ependymoma subgroup. Our data demonstrate the power of cross-species genomics to meticulously match subgroup-specific driver mutations with cellular compartments to model and interrogate cancer subgroups.

Although chronic inflammation is implicated in the pathogenesis of diffuse large B‐cell lymphoma (DLBCL), the mechanisms responsible are unknown. We demonstrate that the overexpression of the collagen receptor, DDR1, correlates with reduced expression of spindle checkpoint genes, with three transcriptional signatures of aneuploidy and with a higher frequency of copy number alterations, pointing to a potential role for DDR1 in the acquisition of aneuploidy in DLBCL. In support of this, we found that collagen treatment of primary germinal centre B cells transduced with DDR1, not only partially recapitulated the aberrant transcriptional programme of DLBCL but also downregulated the expression of CENPE, a mitotic spindle that has a crucial role in preventing chromosome mis‐segregation. CENPE expression was also downregulated following DDR1 activation in two B‐cell lymphoma lines and was lost in most DDR1‐expressing primary tumours. Crucially, the inhibition of CENPE and the overexpression of a constitutively activated DDR1 were able to induce aneuploidy in vitro. Our findings identify a novel mechanistic link between DDR1 signalling and chromosome instability in B cells and provide novel insights into factors driving aneuploidy in DLBCL.