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New technologies and analysis methods are enabling genomic structural variants (SVs) to be detected with ever-increasing accuracy, resolution and comprehensiveness. To help translate these methods to routine research and clinical practice, we developed a sequence-resolved benchmark set for identification of both false-negative and false-positive germline large insertions and deletions. To create this benchmark for a broadly consented son in a Personal Genome Project trio with broadly available cells and DNA, the Genome in a Bottle Consortium integrated 19 sequence-resolved variant calling methods from diverse technologies. The final benchmark set contains 12,745 isolated, sequence-resolved insertion (7,281) and deletion (5,464) calls ≥50 base pairs (bp). The Tier 1 benchmark regions, for which any extra calls are putative false positives, cover 2.51 Gbp and 5,262 insertions and 4,095 deletions supported by ≥1 diploid assembly. We demonstrate that the benchmark set reliably identifies false negatives and false positives in high-quality SV callsets from short-, linked- and long-read sequencing and optical mapping.

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Oncogenesis is driven by germline, environmental and stochastic factors. It is unknown how these interact to produce the molecular phenotypes of tumors. We therefore quantified the influence of germline polymorphisms on the somatic epigenome of 589 localized prostate tumors. Predisposition risk loci influence a tumor's epigenome, uncovering a mechanism for cancer susceptibility. We identified and validated 1,178 loci associated with altered methylation in tumoral but not nonmalignant tissue. These tumor methylation quantitative trait loci influence chromatin structure, as well as RNA and protein abundance. One prominent tumor methylation quantitative trait locus is associated with AKT1 expression and is predictive of relapse after definitive local therapy in both discovery and validation cohorts. These data reveal intricate crosstalk between the germ line and the epigenome of primary tumors, which may help identify germline biomarkers of aggressive disease to aid patient triage and optimize the use of more invasive or expensive diagnostic assays.

Background Recent studies have reported that dihydropyridine calcium channel blockers (dCCBs) may increase the risk of pancreatic cancer, but these studies had methodological limitations. We thus aimed to determine whether dCCBs are associated with an increased risk of pancreatic cancer compared with thiazide diuretics, a clinically relevant comparator. Methods and Results We conducted a new user, active comparator, population‐based cohort study using the UK Clinical Practice Research Datalink. We identified new users of dCCBs and new users of thiazide diuretics between 1990 and 2018, with follow‐up until 2019. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% CIs for pancreatic cancer, comparing dCCBs with thiazide diuretics. Models were weighted using standardized morbidity ratio weights based on calendar time‐specific propensity scores. We also conducted secondary analyses by cumulative duration of use, time since initiation, and individual drugs and assessed for the presence of effect modification by age, sex, smoking status, body mass index, history of chronic pancreatitis, and diabetes. The cohort included 344 480 initiators of dCCBs and 357 968 initiators of thiazide diuretics, generating 3 360 745 person‐years of follow‐up. After a median follow‐up of 4.5 years, the weighted incidence rate per 100 000 person‐years was 37.2 (95% CI, 34.1–40.4) for dCCBs and 39.4 (95% CI, 36.1–42.9) for thiazide diuretics. Overall, dCCBs were not associated with an increased risk of pancreatic cancer (weighted HR, 0.93; 95% CI, 0.80–1.09). Similar results were observed in secondary analyses. Conclusions In this large, population‐based cohort study, dCCBs were not associated with an increased risk of pancreatic cancer compared with thiazide diuretics. These findings provide reassurance regarding the long‐term pancreatic cancer safety of these drugs.

Abstract: Acute megakaryoblastic leukemia (AMKL) represents ∼10% of pediatric acute myeloid leukemia cases and typically affects young children (

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder that may be treated with non-ablative light-based devices; however, no systematic reviews on the topic exist to date. We conducted a systematic review and meta-analysis to determine efficacy of non-ablative light-based devices in treating HS. Specifically, a systematic review was conducted using MEDLINE, EMBASE, Web of Science and CINAHL. We analyzed the use of non-ablative light-based devices in the treatment of HS. At least two investigators performed title/abstract review and data extraction. Meta-analysis was conducted using comprehensive meta-analysis software. 5 RCTs and 11 case reports/series were included (n = 211 unique patients). No observational studies were found. For Nd:YAG laser, meta-analysis of 3 RCTs reported improvement in modified HS Lesion Area and Severity Index (HS-LASI) when compared to control subjects. In addition, three case reports/series reported HS-LASI, Physician Global Assessment (PGA) scores and number-of-lesion improvements in treated patients. For intense pulsed light (IPL), two RCTs reported HS-LASI and Dermatology Life Quality Index (DLQI) score improvements. For Alexandrite laser, one case report showed lesion improvement. In conclusion, meta-analysis of Nd:YAG laser in HS patients suggests significant improvement in HS-LASI scores. For IPL, evidence is limited, but suggests improvement in HS-LASI and DLQI scores. For Alexandrite laser, evidence precludes conclusions. Given small sample sizes and inconsistent reporting scales, larger RCTs are required to better determine the efficacy of these modalities in treating HS.

Background Propensity score (PS) methods are frequently used in cardiovascular clinical research. Previous evaluations revealed poor reporting of PS methods, however a comprehensive and current evaluation of PS use and reporting is lacking. The objectives of the present survey were to (1) evaluate the quality of PS methods in cardiovascular publications, (2) summarise PS methods and (3) propose key reporting elements for PS publications.Methods A PubMed search for cardiovascular PS articles published between 2010 and 2017 in high-impact general medical (top five by impact factor) and cardiovascular (top three by impact factor) journals was performed. Articles were evaluated for the reporting of PS techniques and methods. Data extraction elements were identified from the PS literature and extraction forms were pilot tested.Results Of the 306 PS articles identified, most were published in Journal of the American College of Cardiology (29%; n=88), and Circulation (27%, n=81), followed by European Heart Journal (15%; n=47). PS matching was performed most often, followed by direct adjustment, inverse probability of treatment weighting and stratification. Most studies (77%; n=193) selected variables to include in the PS model a priori. A total of 38% (n=116) of studies did not report standardised mean differences, but instead relied on hypothesis testing. For matching, 92% (n=193) of articles presented the balance of covariates. Overall, interpretations of the effect estimates corresponded to the PS method conducted or described in 49% (n=150) of the reviewed articles.Discussion Although PS methods are frequently used in high-impact medical journals, reporting of methodological details has been inconsistent. Improved reporting of PS results is warranted and these proposals should aid both researchers and consumers in the presentation and interpretation of PS methods.

Evidence from clinical trials and observational studies on the association between thiazide diuretics and colorectal cancer risk is conflicting. We aimed to determine whether thiazide diuretics are associated with an increased colorectal cancer risk compared with dihydropyridine calcium channel blockers (dCCBs). A population-based, new-user cohort was assembled using the UK Clinical Practice Research Datalink. Between 1990–2018, we compared thiazide diuretic initiators with dCCB initiators and estimated hazard ratios (HR) with 95% confidence intervals (CIs) of colorectal cancer using Cox proportional hazard models. Models were weighted using standardized morbidity ratio weights generated from calendar time-specific propensity scores. The cohort included 377,760 thiazide diuretic initiators and 364,300 dCCB initiators, generating 3,619,883 person-years of follow-up. Compared with dCCBs, thiazide diuretics were not associated with colorectal cancer (weighted HR = 0.97, 95% CI: 0.90, 1.04). Secondary analyses yielded similar results, although an increased risk was observed among patients with inflammatory bowel disease (weighted HR = 2.45, 95% CI: 1.13, 5.35) and potentially polyps (weighted HR = 1.46, 95% CI: 0.93, 2.30). Compared with dCCBs, thiazide diuretics were not associated with an overall increased colorectal cancer risk. While these findings provide some reassurance, research is needed to corroborate the elevated risks observed among patients with inflammatory bowel disease and history of polyps. [ABSTRACT FROM AUTHOR]

The sole nonredundant role of the thymic medulla is to induce central tolerance, a vital process that depends on promiscuous gene expression (pGE), a unique feature of medullary thymic epithelial cells (mTECs). Although pGE enhances transcription of >3,000 genes in mTECs, its impact on the regulation of protein homeostasis remains unexplored. Here, we report that, because of pGE, mature mTECs synthesize substantially more proteins than other cell types and are exquisitely sensitive to loss of immunoproteasomes (IPs). Indeed, IP deficiency causes proteotoxic stress in mTECs and leads to exhaustion of postnatal mTEC progenitors. Moreover, IP-deficient mice show accelerated thymic involution, which is characterized by a selective loss of mTECs and multiorgan autoimmune manifestations. We conclude that pGE, the quintessential feature of mTECs, is a major burden for the maintenance of proteostasis, which is alleviated by the constitutive expression of IPs in mTECs.

Shwachman-Diamond syndrome (SDS) is a rare and systemic disease mostly caused by mutations in the SBDS gene and characterized by pancreatic insufficiency, skeletal abnormalities, and a bone marrow dysfunction. In addition, SDS patients are predisposed to develop myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), typically during adulthood and associated with TP53 mutations. Although most SDS diagnoses are established in childhood, the nature and frequency of serial bone marrow cell investigations during the patients' lifetime remain a debatable topic. The precise molecular mechanisms leading to AML progression in SDS patients have not been fully elucidated because the patient cohorts are small and most disease monitoring is conducted using standard histological and cytogenetic approaches. Here we report a rare case of a patient with SDS who was diagnosed with AML at 5 years of age and survived. Intermittent neutropenia preceded the AML diagnostic but serial bone marrow monitoring according to the standard of care revealed no cytogenetic anomalies nor signs of clonal hematopoiesis. Using next generation sequencing approaches to find cytogenetically cryptic pathogenic mutations, we identified the cancer hotspot mutation c.394C>T/p.Arg132Cys in IDH1 with high variant allelic frequency in bone marrow cells, suggesting clonal expansion of a major leukemic clone karyotypically normal, in the SDS-associated AML. The mutation was somatic and likely occurred at the leukemic transformation stage, as it was not detected in a matched normal tissue nor in bone marrow smear prior to AML diagnosis. Gain-of-function mutations in IDH1, such as c.394C>T/p.Arg132Cys, create a neo-activity of isocitrate dehydrogenase 1 converting α-ketoglutarate into the oncometabolite D-2-hydroxyglutarate, inhibiting α-ketoglutarate-dependent enzymes, such as histone and DNA demethylases. Overall, our results suggest that along with previously described abnormalities such as TP53 mutations or monosomy7, 7q-, which are all absent in this patient, additional mechanisms including IDH1 mutations drive SDS-related AML and are likely associated with variable outcomes. Sensitive techniques complementary to standard cytogenetics, such as unbiased or targeted panel-based next generation sequencing approaches, warrant testing for monitoring of myelodysplasia, clonal hematopoiesis, and leukemia in the context SDS. Such analyses would also assist treatment decisions and allow to gain insight into the disease biology.