Giorgio E.M. Melloni

Brigham and Women's Hospital | BWH · TIMI Study Group

Importance Polygenic risk scores (PRSs) have proven to be as strong as or stronger than established clinical risk factors for many cardiovascular phenotypes. Whether this is true for aortic stenosis remains unknown. Objective To develop a novel aortic stenosis PRS and compare its aortic stenosis risk estimation to established clinical risk factors...

Whole chromosome and arm-level copy number alterations occur at high frequencies in tumors, but their selective advantages, if any, are poorly understood. Here, utilizing unbiased whole chromosome genetic screens combined with in vitro evolution to generate arm- and subarm-level events, we iteratively selected the fittest karyotypes from aneuploidi...

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% n...

Importance Elevated lipoprotein(a) (Lp[a]) is a putative causal risk factor for atherosclerotic cardiovascular disease (ASCVD). There are conflicting data as to whether Lp(a) may increase cardiovascular risk only in the presence of concomitant inflammation. Objective To investigate whether Lp(a) is associated with cardiovascular risk independent o...

Background: Statin initiation is not recommended for individuals at low clinical risk of ASCVD as defined by the Pooled Cohort Equations (PCE). We sought to evaluate whether CAD PRS can be used to reclassify low ASCVD risk to a range in which a statin should be considered. Methods: We performed a longitudinal cohort study of low-risk participants f...

Background: Coronary artery disease (CAD) polygenic risk scores (PRS) may improve risk stratification, but whether performance differs by ASCVD status remains unclear. Purpose: To compare the predictive ability of a CAD PRS for coronary events in pts with ASCVD and prior event, ASCVD without event, and without overt ASCVD. Methods: We studied genot...

Introduction: A CAD polygenic risk score (CAD PRS) was previously shown to predict major vascular events among patients with established ASCVD. Whether genetic risk can predict the need for complex coronary revascularization procedures, including complex PCI or CABG, has not been established. Methods: The FOURIER trial randomized 27,564 patients wi...

Introduction: Patients receiving bariatric surgery are at risk for sleep apnea (OSA) and need extensive surveillance in the postoperative period. There is evidence of respiratory events (RE) several hours after leaving PACU. We analyzed the late onset of RE in patients recovering from bariatric surgery and their opiate requirements through the firs...

Mosaic variants (MVs) reflect mutagenic processes during embryonic development and environmental exposure, accumulate with aging and underlie diseases such as cancer and autism. The detection of noncancer MVs has been computationally challenging due to the sparse representation of nonclonally expanded MVs. Here we present DeepMosaic, combining an i...

Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic...

Introduction with Aim: Postoperative respiratory depression can complicate a patient’s recovery after surgery. A predictive score (PRODIGY) was recently proposed to evaluate the risk of opioid-induced postoperative respiratory depression. For the first time, we applied this score to a cohort of patients receiving bariatric surgery, stratified by Ob...

Importance The clinical utility of polygenic risk scores (PRS) for coronary artery disease (CAD) has not yet been established. Objective To investigate the ability of a CAD PRS to potentially guide statin initiation in primary prevention after accounting for age and clinical risk. Design, Setting, and Participants This was a longitudinal cohort s...

Introduction: Aortic stenosis (AS) is the most common valvular heart disease. Polygenic risk scores (PRS) use common genetic variants to enhance risk prediction for disease but have not yet been applied in AS. Methods: We generated an AS genetic risk score using summary data from a recently performed GWAS in the Million Veteran Program and score se...

Background An accumulating body of evidence suggests that the number of apolipoprotein B-containing particles (ApoB-P) is more predictive of cardiovascular risk than their lipid content. However, it is unclear if this association is consistent across different lipoprotein types and sizes. Purpose We aimed to evaluate if particle type and size are...

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, e...

Aims Interest in targeted screening programmes for atrial fibrillation (AF) has increased, yet the role of genetics in identifying patients at highest risk of developing AF is unclear. Methods and results A total of 36,662 subjects without prior AF were analyzed from four TIMI trials. Subjects were divided into quintiles using a validated polygeni...

The structure of the human neocortex underlies species-specific traits and reflects intricate developmental programs. Here we sought to reconstruct processes that occur during early development by sampling adult human tissues. We analysed neocortical clones in a post-mortem human brain through a comprehensive assessment of brain somatic mosaicism,...

Background: Pulmonary gas exchange during diving or in a dry hyperbaric environment is affected by increased breathing gas density and possibly water immersion. During free diving there is also the effect of apnea. Few studies have published blood gas data in underwater or hyperbaric environments: this review summarizes the available literature an...

Distilling biologically meaningful information from cancer genome sequencing data requires comprehensive identification of somatic alterations using rigorous computational methods. As the amount and complexity of sequencing data have increased, so has the number of tools for analysing them. Here, we describe the main steps involved in the bioinform...

Background: The clinical utility of polygenic risk scores (PRS) for CAD has not yet been established. We investigated the ability of a CAD PRS to potentially guide statin initiation after accounting for age and clinical risk. Methods: We performed a prospective cohort study in the UK Biobank that included all individuals without a history of CAD an...

Background: Lipid management typically focuses on levels of LDL cholesterol (LDL-C) and, to a lesser extent, triglycerides (TG). Basic investigation and genetic studies, however, suggest that the atherogenic particle subpopulations (LDL & VLDL) are similarly important and that the number of particles is more important than their lipid content. Meth...

Introduction: GWAS have identified SNPs associated with an increased risk of peripheral artery disease (PAD). We sought to compare the performance of a genetic risk score (GRS) comprised of these SNPs with established clinical risk factors to predict PAD and acute limb ischemia (ALI) across five RCTs in cardiometabolic disease. Given high prevalenc...

Importance Lipid management typically focuses on levels of low-density lipoprotein cholesterol (LDL-C) and, to a lesser extent, triglycerides (TG). However, animal models and genetic studies suggest that the atherogenic particle subpopulations (LDL and very-low-density lipoprotein [VLDL]) are both important and that the number of particles is more...

Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis....

AIMS: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. METHODS AND RESULTS: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis....

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, e...

Mutational activation of KRAS promotes the initiation and progression of cancers, especially in the colorectum, pancreas, lung, and blood plasma, with varying prevalence of specific activating missense mutations. Although epidemiological studies connect specific alleles to clinical outcomes, the mechanisms underlying the distinct clinical character...

Background The initial wave of the Covid‐19 pandemic has hit Italy, and Lombardy in particular, with violence, forcing to reshape all hospitals’ activities; this happened even in pediatric hospitals although the young population seemed initially spared from the disease. “Vittore Buzzi” Children’s Hospital, which is a pediatric/maternal hospital loc...

Background - Venous thromboembolism (VTE) is a major cause of cardiovascular morbidity and mortality with a known genetic contribution. We tested the performance of a genetic risk score (GRS) for its ability to predict VTE in three cohorts of patients with cardiometabolic disease. Methods - We included patients from the FOURIER, PEGASUS-TIMI 54, an...

Introduction: Patients with loss of function (LoF) mutations of the LDL receptor gene (LDLR) have lifelong elevations in LDL-C. We investigated their risk of cardiovascular (CV) events compared with patients with intact LDLR function. Methods: We performed a prospective genetic cohort analysis from the FOURIER trial including all 14,297 patients wh...

Background: Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors in five trials across the...

Background: The relationship between cholesterol levels and risk of venous thromboembolism (VTE) is uncertain. We set out to determine the effect of PCSK9 inhibition on the risk of VTE, explore potential mechanisms, and examine the efficacy in clinically and genetically defined risk subgroups. Methods: We performed a post-hoc analysis of the FOURIE...

Abstract Background Interstitial Cystitis (IC) is a debilitating disorder of the bladder, with a multifactorial and poorly understood origin dealing with microcirculation repeated damages. Also Fibromyalgia (FM) is a persistent disorder whose etiology is not completely explained, and its theorized alteration of pain processing can compromise the qu...

Objective: Few reports have evaluated postoperative continuous thoracic epidural analgesia on patients who received a lung transplant. This analgesic modality may facilitate extubation, early ambulation, and achieve adequate pain control with minimization of opioid use. An opioid sparing technique could minimize the side effects of opioids such as...

Objective: Current literature debates whether administration of sugammadex translates into a higher operating room (OR) efficiency when compared to neostigmine. This study is a blinded assessment of the effects of sugammadex versus neostigmine on OR efficiency as determined by time of reversal to time of the next case.Methods: 50 patients undergoin...

It is not clear how spontaneous DNA double-strand breaks (DSBs) form and are processed in normal cells, and whether they predispose to cancer-associated translocations. We show that DSBs in normal mammary cells form upon release of paused RNA polymerase II (Pol II) at promoters, 5′ splice sites and active enhancers, and are processed by end-joining...

Mutations in BRCA1 and/or BRCA2 (BRCA1/2) are the most common indication of deficiency in the homologous recombination (HR) DNA repair pathway. However, recent genome-wide analyses have shown that the same pattern of mutations found in BRCA1/2-mutant tumors is also present in several other tumors. Here, we present a new computational tool called Si...

Loss of p53 function is invariably associated with cancer. Its role in tumor growth was recently linked to its effects on cancer stem cells (CSCs), although the underlying molecular mechanisms remain unknown. Here, we show that c-myc is a transcriptional target of p53 in mammary stem cells (MaSCs) and is activated in breast tumors as a consequence...

Video S1. Contractile Movements in Secondary Basal Organoids, Related to Figure 4

Video S2. Contractile Movements in Tertiary LUM MycER Organoids, Related to Figure 4

Table S1. List of Differentially Expressed Genes (DEGs), Related to Figures 4 and 6

Table S2. List of MaSC and MaProg Genes Regulated in Reprogrammed Mammospheres, Related to Figure 4

Table S3. List of Common p53-Myc DEGs in ErbB2 tumor mammospheres, Related to Figure 6

The original version of this Article contained an error in Fig. 2. In panel a, the two legend items “rare” and “common” were inadvertently swapped. This has been corrected in both the PDF and HTML versions of the Article.

The role of rare variants in complex traits remains uncharted. Here, we conduct deep whole genome sequencing of 1457 individuals from an isolated population, and test for rare variant burdens across six cardiometabolic traits. We identify a role for rare regulatory variation, which has hitherto been missed. We find evidence of rare variant burdens...

Purpose Trials that accrue participants on the basis of genetic biomarkers are a powerful means of testing targeted drugs, but they are often complicated by the rarity of the biomarker-positive population. Umbrella trials circumvent this by testing multiple hypotheses to maximize accrual. However, bigger trials have higher chances of conflicting tr...

Motivation Very low depth sequencing has been proposed as a cost-effective approach to capture low-frequency and rare variation in complex trait association studies. However, a full characterisation of the genotype quality and association power for very low depth sequencing designs is still lacking. Results We perform cohort-wide whole genome sequ...

The availability of genomic datasets in association with clinical, phenotypic, and drug sensitivity information represents an invaluable source for potential therapeutic applications, supporting the identification of new drug sensitivity biomarkers and pharmacological targets. Drug discovery and precision oncology can largely benefit from the integ...

The Supplementary File to “PATRI, a Genomics Data Integration Tool for Biomarker Discovery”, by Ukmar, G. et al., contains the following 3 sections: (1) Supplementary Figures 1-7 (Supplementary Figure 1: PATRI database scheme; Supplementary Figure 2: PATRI graphical user interface: Analysis windows; Supplementary Figure 3: PATRI graphical user inte...

Introduction A common source of tumorigenesis in several cancer types such as breast and ovarian is a defect in the homologous recombination (HR) machinery. HR defect can be detected by identifying single nucleotide variants (SNVs), deletions, duplications, and other errors generated by the alternative double-strand break repair machineries. Howeve...

Introduction AML is hierarchically organised with at the apex Leukaemia Stem Cells (LSCs), a rare cell population able to initiate and sustain the tumour growth. LSCs share many functional properties with normal Hematopoietic Stem Cells (HSCs) including self-renewal capacity and quiescence. Quiescent LSCs can survive to radiation and chemotherapy a...

The E3 ubiquitin ligase (E3) WWP1 is an oncogenic factor implicated in the maintenance of different types of epithelial cancers. The role of WWP1 in haematological neoplasms remains unknown. Acute myeloid leukaemia (AML) is characterized by the expansion of malignant myeloid cells blocked at different stages of differentiation. Here, we report that...

The role of rare variants in complex traits remains uncharted. Here, we conduct deep whole genome sequencing of 1,457 individuals from an isolated population, and test for rare variant burdens across six cardiometabolic traits. We identify a role for rare regulatory variation, which has hitherto been missed. We find evidence of rare variant burdens...

Brain metastases (BMs) are the most common malignancy of the central nervous system. Recently it has been demonstrated that plasminogen activator inhibitor serpins promote brain metastatic colonization, suggesting that mutations in serpins or other members of the coagulation cascade can provide critical advantages during BM formation. We performed...

Background The landscape of cancer-predisposing genes has been extensively investigated in the last 30 years with various methodologies ranging from candidate gene to genome-wide association studies. However, sequencing data are still poorly exploited in cancer predisposition studies due to the lack of statistical power when comparing millions of v...

It has been shown that individual Acute Myeloid Leukemia (AML) patients are characterized by one of few initiating DNA mutations and 5–10 cooperating mutations not yet defined among hundreds identified by massive sequencing of AML genomes. We report an in vivo insertional mutagenesis screen for genes cooperating with one AML initiating mutations (P...

Unlabelled: The identification of genes maintaining cancer growth is critical to our understanding of tumorigenesis. We report the first in vivo genetic screen of patient-derived tumors, using metastatic melanomas and targeting 236 chromatin genes by expression of specific shRNA libraries. Our screens revealed unprecedented numerosity of genes ind...

The increasing availability of resequencing data has led to a better understanding of the most important genes in cancer development. Nevertheless, the mutational landscape of many tumor types is heterogeneous and encompasses a long tail of potential driver genes that are systematically excluded by currently available methods due to the low frequen...

Next Generation Sequencing (NGS) studies identified 9 functional categories of mutations in acute myeloid leukemia (AML), with >99% of cases having at least one of those mutations (Ley et al. NEJM 2013). However, multiple genetic hits participate to AML pathogenesis, and metabolic dysregulations, as the one induced by IDH1/2 mutations, play oncogen...

Cellular mRNA levels originate from the combined action of multiple regulatory processes, which can be recapitulated by the rates of pre-mRNA synthesis, pre-mRNA processing, and mRNA degradation. Recent experimental and computational advances set the basis to study these intertwined levels of regulation. Nevertheless, software for the comprehensive...

The analyses carried out using two different bioinformatics pipelines (SomaticSniper and MuTect) on the same set of genomic data from 133 Acute Myeloid Leukemia (AML) patients, sequenced inside the Cancer Genome Atlas project, gave discrepant results. We subsequently tested these two variant-calling pipelines on 20 leukemia samples from our series...

A key challenge in the analysis of cancer genomes is the identification of driver genes from the vast number of mutations present in a cohort of patients. DOTS-Finder is a new tool that allows the detection of driver genes through the sequential application of functional and frequentist approaches, and is specifically tailored to the analysis of fe...

Blood Cancer Journal is a peer-reviewed, open access online journal publishing pre-clinical and clinical work in the field of hematology with ramifications into translational biology research down to new therapies