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BACKGROUND: Contralateral breast cancer (CBC) is the most common second primary cancer diagnosed in breast cancer survivors, yet the understanding of the genetic susceptibility of CBC, particularly with respect to common variants, remains incomplete. This study aimed to investigate the genetic basis of CBC to better understand this malignancy. FINDINGS: We performed a genome-wide association analysis in the Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study of women with first breast cancer diagnosed at age < 55 years including 1161 with CBC who served as cases and 1668 with unilateral breast cancer (UBC) who served as controls. We observed two loci (rs59657211, 9q32, SLC31A2/FAM225A and rs3815096, 6p22.1, TRIM31) with suggestive genome-wide significant associations (P < 1 × 10-6). We also found an increased risk of CBC associated with a breast cancer-specific polygenic risk score (PRS) comprised of 239 known breast cancer susceptibility single nucleotide polymorphisms (SNPs) (rate ratio per 1-SD change: 1.25; 95% confidence interval 1.14-1.36, P < 0.0001). The protective effect of chemotherapy on CBC risk was statistically significant only among patients with an elevated PRS (Pheterogeneity = 0.04). The AUC that included the PRS and known breast cancer risk factors was significantly elevated. CONCLUSIONS: The present GWAS identified two previously unreported loci with suggestive genome-wide significance. We also confirm that an elevated risk of CBC is associated with a comprehensive breast cancer susceptibility PRS that is independent of known breast cancer risk factors. These findings advance our understanding of genetic risk factors involved in CBC etiology.
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Neoplasias de la Mama , Supervivientes de Cáncer , Humanos , Femenino , Persona de Mediana Edad , Estudio de Asociación del Genoma Completo , Mama , Predisposición Genética a la Enfermedad , Puntuación de Riesgo Genético , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína LigasasRESUMEN
Vemurafenib, an oral BRAF inhibitor, has demonstrated high response rates in relapsed/refractory (R/R) hairy cell leukemia (HCL). However, little is known about long-term outcomes and response to retreatment. Herein, we report the results of 36 patients with R/R HCL treated with vemurafenib from the United States arm of the phase 2 clinical trial (NCT01711632). The best overall response rate was 86%, including 33% complete response (CR) and 53% partial response (PR). After a median follow-up of 40 months, 21 of 31 responders (68%) experienced relapse with a median relapse-free survival (RFS) of 19 months (range, 12.5-53.9 months). There was no significant difference in the RFS for patients with CR vs PR. Fourteen of 21 (67%) relapsed patients were retreated with vemurafenib, with 86% achieving complete hematologic response. Two patients acquired resistance to vemurafenib with the emergence of new KRAS and CDKN2A mutations, respectively. Six of 12 (50%) responders to vemurafenib retreatment experienced another relapse with a median RFS of 12.7 months. Overall survival (OS) was 82% at 4 years, with a significantly shorter OS in patients who relapsed within 1 year of initial treatment with vemurafenib. Higher cumulative doses or a longer duration of treatment did not lengthen the durability of response. All adverse events in the retreatment cohort were grade 1/2 except for 1 case of a grade 3 rash and 1 grade 3 fever/pneumonia. Our data suggest that vemurafenib retreatment is a safe and effective option for patients with R/R HCL.
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Antineoplásicos , Leucemia de Células Pilosas , Humanos , Vemurafenib/uso terapéutico , Leucemia de Células Pilosas/tratamiento farmacológico , Leucemia de Células Pilosas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Inducción de Remisión , Antineoplásicos/efectos adversosRESUMEN
Leukemic transformation (LT) of myeloproliferative neoplasm (MPN) has a dismal prognosis and is largely fatal. Mutational inactivation of TP53 is the most common somatic event in LT; however, the mechanisms by which TP53 mutations promote LT remain unresolved. Using an allelic series of mouse models of Jak2/Trp53 mutant MPN, we identify that only biallelic inactivation of Trp53 results in LT (to a pure erythroleukemia [PEL]). This PEL arises from the megakaryocyte-erythroid progenitor population. Importantly, the bone morphogenetic protein 2/SMAD pathway is aberrantly activated during LT and results in abnormal self-renewal of megakaryocyte-erythroid progenitors. Finally, we identify that Jak2/Trp53 mutant PEL is characterized by recurrent copy number alterations and DNA damage. Using a synthetic lethality strategy, by targeting active DNA repair pathways, we show that this PEL is highly sensitive to combination WEE1 and poly(ADP-ribose) polymerase inhibition. These observations yield new mechanistic insights into the process of p53 mutant LT and offer new, clinically translatable therapeutic approaches.
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Trastornos Mieloproliferativos , Proteína p53 Supresora de Tumor , Animales , Proteína Morfogenética Ósea 2/genética , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Células Progenitoras de Megacariocitos y Eritrocitos/metabolismo , Megacariocitos/metabolismo , Ratones , Mutación , Trastornos Mieloproliferativos/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
AIMS: B lymphoblastic leukaemia/lymphoma (B-ALL) is thought to originate from Pro/Pre-B cells and the genetic aberrations largely reside in lymphoid-committed cells. A recent study demonstrated that a proportion of paediatric B-ALL patients have BCR::ABL1 fusion in myeloid cells, suggesting a chronic myeloid leukaemia (CML)-like biology in this peculiar subset of B-ALL, although it is not entirely clear if the CD19-negative precursor compartment is a source of the myeloid cells. Moreover, the observation has not yet been extended to other fusion-driven B-ALLs. METHODS AND RESULTS: In this study we investigated a cohort of KMT2A-rearranged B-ALL patients with a comparison to BCR::ABL1-rearranged B-ALL by performing cell sorting via flow cytometry followed by FISH (fluorescence in situ hybridization) analysis on each of the sorted populations. In addition, RNA sequencing was performed on one of the sorted populations. These analyses showed that (1) multilineage involvement was present in 53% of BCR::ABL1 and 36% of KMT2A-rearranged B-ALL regardless of age, (2) multilineage involvement created pitfalls for residual disease monitoring, and (3) HSPC transcriptome signatures were upregulated in KMT2A-rearranged B-ALL with multilineage involvement. CONCLUSIONS: In summary, multilineage involvement is common in both BCR::ABL1-rearranged and KMT2A-rearranged B-ALL, which should be taken into consideration when interpreting the disease burden during the clinical course.
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N-Metiltransferasa de Histona-Lisina , Proteína de la Leucemia Mieloide-Linfoide , Humanos , Proteína de la Leucemia Mieloide-Linfoide/genética , N-Metiltransferasa de Histona-Lisina/genética , Femenino , Niño , Masculino , Preescolar , Adolescente , Proteínas de Fusión bcr-abl/genética , Adulto , Hibridación Fluorescente in Situ , Lactante , Reordenamiento Génico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Adulto Joven , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , AncianoRESUMEN
Our work was motivated by the question whether, and to what extent, well-established risk factors mediate the racial disparity observed for colorectal cancer (CRC) incidence in the United States. Mediation analysis examines the relationships between an exposure, a mediator and an outcome. All available methods require access to a single complete data set with these three variables. However, because population-based studies usually include few non-White participants, these approaches have limited utility in answering our motivating question. Recently, we developed novel methods to integrate several data sets with incomplete information for mediation analysis. These methods have two limitations: (i) they only consider a single mediator and (ii) they require a data set containing individual-level data on the mediator and exposure (and possibly confounders) obtained by independent and identically distributed sampling from the target population. Here, we propose a new method for mediation analysis with several different data sets that accommodates complex survey and registry data, and allows for multiple mediators. The proposed approach yields unbiased causal effects estimates and confidence intervals with nominal coverage in simulations. We apply our method to data from U.S. cancer registries, a U.S.-population-representative survey and summary level odds-ratio estimates, to rigorously evaluate what proportion of the difference in CRC risk between non-Hispanic Whites and Blacks is mediated by three potentially modifiable risk factors (CRC screening history, body mass index, and regular aspirin use).
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Neoplasias Colorrectales , Análisis de Mediación , Humanos , Neoplasias Colorrectales/etnología , Neoplasias Colorrectales/epidemiología , Estados Unidos/epidemiología , Factores de Riesgo , Simulación por Computador , Aspirina/uso terapéutico , Incidencia , Sistema de Registros , Disparidades en el Estado de Salud , Población Blanca/estadística & datos numéricos , Femenino , Negro o Afroamericano/estadística & datos numéricos , Fuentes de InformaciónRESUMEN
Plasmacytoid dendritic cells (pDCs) are the principal natural type I interferon-producing dendritic cells. Neoplastic expansion of pDCs and pDC precursors leads to blastic plasmacytoid dendritic cell neoplasm (BPDCN), and clonal expansion of mature pDCs has been described in chronic myelomonocytic leukemia. The role of pDC expansion in acute myeloid leukemia (AML) is poorly studied. Here, we characterize patients with AML with pDC expansion (pDC-AML), which we observe in â¼5% of AML cases. pDC-AMLs often possess cross-lineage antigen expression and have adverse risk stratification with poor outcome. RUNX1 mutations are the most common somatic alterations in pDC-AML (>70%) and are much more common than in AML without pDC expansion and BPDCN. We demonstrate that pDCs are clonally related to, as well as originate from, leukemic blasts in pDC-AML. We further demonstrate that leukemic blasts from RUNX1-mutated AML upregulate a pDC transcriptional program, poising the cells toward pDC differentiation and expansion. Finally, tagraxofusp, a targeted therapy directed to CD123, reduces leukemic burden and eliminates pDCs in a patient-derived xenograft model. In conclusion, pDC-AML is characterized by a high frequency of RUNX1 mutations and increased expression of a pDC transcriptional program. CD123 targeting represents a potential treatment approach for pDC-AML.
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Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Células Dendríticas/patología , Leucemia Mieloide Aguda/genética , Adulto , Anciano , Crisis Blástica/genética , Crisis Blástica/patología , Células Dendríticas/metabolismo , Femenino , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
We aim to identify predictors of therapy-related myeloid neoplasms (t-MN) in patients with breast cancer (BC) and cytopenias to determine the timing of bone marrow biopsy (BMBx). Patients with BC and cytopenias who were referred for BMBx between 2002-2018 were identified using the Memorial Sloan Kettering Cancer Center institutional database. Characteristics associated with the risk of t-MN were evaluated by multivariable logistic regression and included in a predictive model. The average area under the receiver operating characteristic curve (AUC) was estimated by 5-fold cross-validation. Of the 206 BC patients who underwent BMBx included in our study, 107 had t-MN. By multivariable analysis, white blood cell count 4-11 K/mcL, absolute neutrophil count (ANC) ≥1.5 K/mcL, hemoglobin ≥12.2 g/dL, red cell distribution width 11.5-14.5%, the presence of bone metastasis and a time from BC diagnosis to BMBx <15 months significantly decreased the likelihood of t-MN. The average AUC was 0.88. We stratified our cohort by bone metastasis and by findings on peripheral smear. In both the subset without bone metastasis (n=159) and in the cohort with no blasts or dysplastic cells on peripheral smear (n=96) our variables had similar effects on the risk of t-MN. Among the 47 patients with bone metastasis, an ANC ≥1.5 K/mcL was the only variable associated with a decreased risk of t-MN. Our findings show that in patients with BC and unexplained cytopenias, clinical and laboratory parameters can predict t-MN and assist clinicians in determining the timing of a BMBx.
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Neoplasias Óseas , Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/etiología , Neoplasias de la Mama/patología , Biopsia , Médula Ósea/patología , Curva ROCRESUMEN
Monoclonal immunoglobulin deposition disease (MIDD), often associated with plasma cell dyscrasias, predominantly affects the kidneys. In this disease, hematologic response (HR) to treatment can be reliably assessed by International Myeloma Working Group (IMWG) consensus criteria, while uniform criteria for assessing renal response are lacking. We report a retrospective analysis of renal outcomes among 34 patients with MIDD. With most patients treated with bortezomib and autologous stem cell transplantation, 26 of 28 (94%) achieved very good partial HR or better. We demonstrate that both IMWG (based on estimated glomerular filtration rate, eGFR) and amyloid (based on proteinuria) criteria are needed to capture renal response: among 28 evaluable patients, 6 (21%) had isolated proteinuria, while 13 (46%) had isolated decreased eGFR. Using both criteria, which were concordant in patients with both decreased eGFR and proteinuria, 22 of 28 patients (79%) achieved a renal response, including 2 of 7 discontinuing dialyses. All 6 patients (100%) with isolated proteinuria and 7 of 13 (54%) with isolated decreased eGFR achieved renal response, suggesting that isolated proteinuria is an early manifestation of MIDD associated with reversible renal damage. Baseline eGFR predicted renal response (p = .02 by quartile) and survival (p = .02), while HR (CR vs. non-CR) did not, probably because of high HR rate. With a median follow-up of 110 months, the median overall survival was 136 months (95% CI: 79-NR) and median renal survival had not been reached. Prospective studies using uniform renal response criteria are needed to optimize the management of MIDD.
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Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Humanos , Mieloma Múltiple/complicaciones , Mieloma Múltiple/tratamiento farmacológico , Estudios Retrospectivos , Consenso , Estudios Prospectivos , Trasplante Autólogo , Riñón , Proteinuria/etiología , InmunoglobulinasRESUMEN
Measurable residual disease (MRD) is a powerful prognostic factor in acute myeloid leukemia (AML). However, pre-treatment molecular predictors of immunophenotypic MRD clearance remain unclear. We analyzed a dataset of 211 patients with pre-treatment next-generation sequencing who received induction chemotherapy and had MRD assessed by serial immunophenotypic monitoring after induction, subsequent therapy, and allogeneic stem cell transplant (allo-SCT). Induction chemotherapy led to MRD- remission, MRD+ remission, and persistent disease in 35%, 27%, and 38% of patients, respectively. With subsequent therapy, 34% of patients with MRD+ and 26% of patients with persistent disease converted to MRD-. Mutations in CEBPA, NRAS, KRAS, and NPM1 predicted high rates of MRD- remission, while mutations in TP53, SF3B1, ASXL1, and RUNX1 and karyotypic abnormalities including inv (3), monosomy 5 or 7 predicted low rates of MRD- remission. Patients with fewer individual clones were more likely to achieve MRD- remission. Among 132 patients who underwent allo-SCT, outcomes were favorable whether patients achieved early MRD- after induction or later MRD- after subsequent therapy prior to allo-SCT. As MRD conversion with chemotherapy prior to allo-SCT is rarely achieved in patients with specific baseline mutational patterns and high clone numbers, upfront inclusion of these patients into clinical trials should be considered.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Pronóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Trasplante de Células Madre , Inducción de Remisión , Trasplante Homólogo , Neoplasia Residual/genéticaRESUMEN
Immunity may play a role in preventing cancer progression. We studied associations of immune-related conditions with cancer-specific mortality among older adults in the United States. We evaluated 1 229 443 patients diagnosed with 20 common cancer types (age 67-99, years 1993-2013) using Surveillance Epidemiology and End Results-Medicare data. With Medicare claims, we ascertained immune-related medical conditions diagnosed before cancer diagnosis (4 immunosuppressive conditions [n = 3380 affected cases], 32 autoimmune conditions [n = 155 766], 3 allergic conditions [n = 101 366]). For each cancer site, we estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for cancer-specific mortality associated with each condition, applying a Bonferroni cutoff for significance (P < 5.1 × 10-5 ). Bayesian metaanalysis methods were used to detect patterns across groups of conditions and cancers. We observed 21 associations with cancer-specific mortality at the Bonferroni threshold. Increased cancer-specific mortality was observed with rheumatoid arthritis for patients with melanoma (aHR 1.51, 95% CI 1.31-1.75) and breast cancer (1.24, 1.15-1.33)), and with hemolytic anemia for bladder cancer (2.54, 1.68-3.82). Significant inverse associations with cancer-specific mortality were observed for allergic rhinitis (range of aHRs: 0.84-0.94) and asthma (0.83-0.95) for cancers of the lung, breast, and prostate. Cancer-specific mortality was nominally elevated in patients with immunosuppressive conditions for eight cancer types (aHR range: 1.27-2.36; P-value range: 7.5 × 10-5 to 3.1 × 10-2 ) and was strongly associated with grouped immunosuppressive conditions using Bayesian metaanalyses methods. For older patients with several cancer types, certain immunosuppressive and autoimmune conditions were associated with increased cancer-specific mortality. In contrast, inverse associations with allergic conditions may reflect enhanced immune control of cancer.
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Enfermedades Autoinmunes , Hipersensibilidad , Neoplasias , Anciano , Anciano de 80 o más Años , Enfermedades Autoinmunes/epidemiología , Teorema de Bayes , Estudios de Casos y Controles , Humanos , Hipersensibilidad/complicaciones , Hipersensibilidad/epidemiología , Masculino , Medicare , Programa de VERF , Estados Unidos/epidemiologíaRESUMEN
Incidence of venous thromboembolism (VTE) varies across different regimens in newly diagnosed multiple myeloma (NDMM) patients. Limited data exist on the use of direct oral anticoagulants as thromboprophylaxis in the setting of haematologic malignancies, specifically multiple myeloma. In this retrospective study of 305 NDMM patients, VTE rates in those treated with carfilzomib, lenalidomide, dexamethasone (KRD) + aspirin (ASA), bortezomib, lenalidomide, dexamethasone (RVD) + ASA, and KRD + rivaroxaban were statistically significant, 16·1%, 4·8%, and 4·8%, respectively. The findings confirm a higher incidence of VTE when using KRD induction compared to RVD induction and reveal that the use of low-dose rivaroxaban thromboprophylaxis can mitigate this risk without an observable increase in bleeding rates.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/complicaciones , Mieloma Múltiple/tratamiento farmacológico , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/etiología , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Aspirina/administración & dosificación , Bortezomib/administración & dosificación , Dexametasona/administración & dosificación , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Humanos , Incidencia , Lenalidomida/administración & dosificación , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Clasificación del Tumor , Estadificación de Neoplasias , Oligopéptidos/administración & dosificación , Estudios Retrospectivos , Tromboembolia Venosa/diagnósticoRESUMEN
INTRODUCTION: Pernicious anemia (PA) is a risk factor for gastric cancer. Other autoimmune conditions may also contribute. METHODS: In a case-control study, we evaluated 47 autoimmune conditions among 39,125 gastric cancers and 200,000 cancer-free controls. RESULTS: Six conditions were associated with increased gastric cancer risk (range of adjusted odds ratios: 1.28-1.93, P < 0.05): PA, membranous nephropathy, primary biliary cirrhosis, pure red cell aplasia, primary sclerosing cholangitis, and Graves disease. PA was associated with 8 other autoimmune conditions (adjusted odds ratios: 1.57-4.54, P < 0.05). DISCUSSION: Autoimmune conditions associated with gastric cancer or PA may reflect effects of autoimmune gastritis or other carcinogenic pathways.
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Anemia Perniciosa , Enfermedades Autoinmunes , Neoplasias Gástricas , Adulto , Anciano , Anemia Perniciosa/complicaciones , Anemia Perniciosa/epidemiología , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/epidemiología , Estudios de Casos y Controles , Humanos , Neoplasias Gástricas/complicaciones , Neoplasias Gástricas/etiología , Estados Unidos/epidemiologíaRESUMEN
PURPOSE: Our goal was to identify discrete clinical characteristics associated with safe discharge from an emergency department/urgent care for patients with a history of cancer and concurrent COVID-19 infection during the SARS-CoV-2 pandemic and prior to widespread vaccination. PATIENTS AND METHODS: We retrospectively analyzed 255 adult patients with a history of cancer who presented to Memorial Sloan Kettering Cancer Center (MSKCC) urgent care center (UCC) from March 1, 2020 to May 31, 2020 with concurrent COVID-19 infection. We evaluated associations between patient characteristics and 30-day mortality from initial emergency department (ED) or urgent care center (UCC) visit and the absence of a severe event within 30 days. External validation was performed on a retrospective data from 29 patients followed at Fred Hutchinson Cancer Research Center that presented to the local emergency department. A late cohort of 108 additional patients at MSKCC from June 1, 2020 to January 31, 2021 was utilized for further validation. RESULTS: In the MSKCC cohort, 30-day mortality and severe event rate was 15% and 32% respectively. Using stepwise regression analysis, elevated BUN and glucose, anemia, and tachypnea were selected as the main predictors of 30-day mortality. Conversely, normal albumin, BUN, calcium, and glucose, neutrophil-lymphocyte ratio <3, lack of (severe) hypoxia, lack of bradycardia or tachypnea, and negative imaging were selected as the main predictors of an uneventful course as defined as a Lack Of a Severe Event within Thirty Days (LOSETD). Utilizing this information, we devised a tool to predict 30-day mortality and LOSETD which achieved an area under the operating curve (AUC) of 79% and 74% respectively. Similar estimates of AUC were obtained in an external validation cohort. A late cohort at MSKCC was consistent with the prior, albeit with a lower AUC. CONCLUSION: We identified easily obtainable variables that predict 30-day mortality and the absence of a severe event for patients with a history of cancer and concurrent COVID-19. This has been translated into a bedside tool that the clinician may utilize to assist disposition of this group of patients from the emergency department or urgent care setting.
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COVID-19/terapia , Neoplasias/complicaciones , Anciano , Servicio de Urgencia en Hospital , Femenino , Humanos , Masculino , Estudios Retrospectivos , SARS-CoV-2 , Resultado del TratamientoRESUMEN
OBJECTIVE: To assess whether prediagnostic metabolites were associated with incident pancreatic ductal adenocarcinoma (PDAC) in a prospective cohort study. DESIGN: We conducted an untargeted analysis of 554 known metabolites measured in prediagnostic serum (up to 24 years) to determine their association with incident PDAC in a nested case-control study of male smokers (372 matched case-control sets) and an independent nested case-control study that included women and non-smokers (107 matched sets). Metabolites were measured using Orbitrap Elite or Q-Exactive high-resolution/accurate mass spectrometers. Controls were matched to cases by age, sex, race, date of blood draw, and follow-up time. We used conditional logistic regression adjusted for age to calculate ORs and 95% CIs for a 1 SD increase in log-metabolite level separately in each cohort and combined the two ORs using a fixed-effects meta-analysis. RESULTS: Thirty-one metabolites were significantly associated with PDAC at a false discovery rate <0.05 with 12 metabolites below the Bonferroni-corrected threshold (p<9.04×10-5). Similar associations were observed in both cohorts. The dipeptides glycylvaline, aspartylphenylalanine, pyroglutamylglycine, phenylalanylphenylalanine, phenylalanylleucine and tryptophylglutamate and amino acids aspartate and glutamate were positively while the dipeptides tyrosylglutamine and α-glutamyltyrosine, fibrinogen cleavage peptide DSGEGDFXAEGGGVR and glutathione-related amino acid cysteine-glutathione disulfide were inversely associated with PDAC after Bonferroni correction. Five top metabolites demonstrated significant time-varying associations (p<0.023) with the strongest associations observed 10-15 years after participants' blood collection and attenuated thereafter. CONCLUSION: Our results suggest that prediagnostic metabolites related to subclinical disease, γ-glutamyl cycle metabolism and adiposity/insulin resistance are associated with PDAC.
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Carcinoma Ductal Pancreático/epidemiología , Carcinoma Ductal Pancreático/metabolismo , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/metabolismo , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Carcinoma Ductal Pancreático/diagnóstico , Estudios de Casos y Controles , Femenino , Humanos , Incidencia , Modelos Logísticos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/diagnóstico , FumarRESUMEN
Meta-analysis of multiple genome-wide association studies (GWAS) is effective for detecting single- or multimarker associations with complex traits. We develop a flexible procedure (subset testing and analysis of multiple phenotypes [STAMP]) based on mixture models to perform a region-based meta-analysis of different phenotypes using data from different GWAS and identify subsets of associated phenotypes. Our model framework helps distinguish true associations from between-study heterogeneity. As a measure of association, we compute for each phenotype the posterior probability that the genetic region under investigation is truly associated. Extensive simulations show that STAMP is more powerful than standard approaches for meta-analyses when the proportion of truly associated outcomes is between 25% and 50%. For other settings, the power of STAMP is similar to that of existing methods. We illustrate our method on two examples, the association of a region on chromosome 9p21 with the risk of 14 cancers, and the associations of expression of quantitative trait loci from two genetic regions with their cis-single-nucleotide polymorphisms measured in 17 tissue types using data from The Cancer Genome Atlas.
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Estudio de Asociación del Genoma Completo/métodos , Estudios de Casos y Controles , Simulación por Computador , Humanos , Modelos Genéticos , Neoplasias/patología , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo/genéticaRESUMEN
We consider the scenario where there is an exposure, multiple biologically defined sets of biomarkers, and an outcome. We propose a new two-step procedure that tests if any of the sets of biomarkers mediate the exposure/outcome relationship, while maintaining a prespecified familywise error rate. The first step of the proposed procedure is a screening step that removes all groups that are unlikely to be strongly associated with both the exposure and the outcome. The second step adapts recent advances in postselection inference to test if there are true mediators in each of the remaining candidate sets. We use simulation to show that this simple two-step procedure has higher statistical power to detect true mediating sets when compared with existing procedures. We then use our two-step procedure to identify a set of Lysine-related metabolites that potentially mediate the known relationship between increased body mass index and the increased risk of estrogen-receptor positive breast cancer in postmenopausal women.
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Neoplasias de la Mama , Análisis de Mediación , Neoplasias de la Mama/diagnóstico , Simulación por Computador , Femenino , HumanosRESUMEN
Impaired metabolism may play an important role in the pathogenesis of lethal prostate cancer, yet there is a paucity of evidence regarding the association. We conducted a large prospective serum metabolomic analysis of lethal prostate cancer in 523 cases and 523 matched controls nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Median time from baseline fasting serum collection to prostate cancer death was 18 years (maximum 30 years). We identified 860 known biochemicals through an ultrahigh-performance LC-MS/MS platform. Conditional logistic regression models estimated odds ratios (OR) and 95% confidence intervals of risk associated with 1-standard deviation (s.d.) increases in log-metabolite signals. We identified 34 metabolites associated with lethal prostate cancer with a false discovery rate (FDR) < 0.15. Notably, higher serum thioproline, and thioproline combined with two other cysteine-related amino acids and redox metabolites, cystine and cysteine, were associated with reduced risk (1-s.d. OR = 0.75 and 0.71, respectively; p ≤ 8.2 × 10-5 ). By contrast, the dipeptide leucylglycine (OR = 1.36, p = 8.2 × 10-5 ), and three gamma-glutamyl amino acids (OR = 1.28-1.30, p ≤ 4.6 × 10-4 ) were associated with increased risk of lethal prostate cancer. Cases with metastatic disease at diagnosis (n = 179) showed elevated risk for several lipids, including especially the ketone body 3-hydroxybutyrate (BHBA), acyl carnitines, and dicarboxylic fatty acids (1.37 ≤ OR ≤ 1.49, FDR < 0.15). These findings provide a prospective metabolomic profile of lethal prostate cancer characterized by altered biochemicals in the redox, dipeptide, pyrimidine, and gamma-glutamyl amino acid pathways, whereas ketone bodies and fatty acids were associated specifically with metastatic disease.
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Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/metabolismo , Aminoácidos/sangre , Aminoácidos/metabolismo , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/metabolismo , Estudios de Casos y Controles , Cromatografía Liquida/métodos , Método Doble Ciego , Ácidos Grasos/sangre , Ácidos Grasos/metabolismo , Humanos , Modelos Logísticos , Masculino , Metabolómica/métodos , Persona de Mediana Edad , Oportunidad Relativa , Estudios Prospectivos , Factores de Riesgo , Espectrometría de Masas en Tándem/métodos , alfa-Tocoferol/sangre , alfa-Tocoferol/metabolismo , beta Caroteno/sangre , beta Caroteno/metabolismoRESUMEN
The Consortium of Metabolomics Studies (COMETS) was established in 2014 to facilitate large-scale collaborative research on the human metabolome and its relationship with disease etiology, diagnosis, and prognosis. COMETS comprises 47 cohorts from Asia, Europe, North America, and South America that together include more than 136,000 participants with blood metabolomics data on samples collected from 1985 to 2017. Metabolomics data were provided by 17 different platforms, with the most frequently used labs being Metabolon, Inc. (14 cohorts), the Broad Institute (15 cohorts), and Nightingale Health (11 cohorts). Participants have been followed for a median of 23 years for health outcomes including death, cancer, cardiovascular disease, diabetes, and others; many of the studies are ongoing. Available exposure-related data include common clinical measurements and behavioral factors, as well as genome-wide genotype data. Two feasibility studies were conducted to evaluate the comparability of metabolomics platforms used by COMETS cohorts. The first study showed that the overlap between any 2 different laboratories ranged from 6 to 121 metabolites at 5 leading laboratories. The second study showed that the median Spearman correlation comparing 111 overlapping metabolites captured by Metabolon and the Broad Institute was 0.79 (interquartile range, 0.56-0.89).
Asunto(s)
Epidemiología/organización & administración , Salud Global , Metabolómica/organización & administración , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Índice de Masa Corporal , Niño , Métodos Epidemiológicos , Femenino , Conductas Relacionadas con la Salud , Pruebas Hematológicas , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores Socioeconómicos , Adulto JovenRESUMEN
Motivation: Genome-wide association studies are now shifting focus from analysis of common to rare variants. As power for association testing for individual rare variants may often be low, various aggregate level association tests have been proposed to detect genetic loci. Typically, power calculations for such tests require specification of large number of parameters, including effect sizes and allele frequencies of individual variants, making them difficult to use in practice. We propose to approximate power to a varying degree of accuracy using a smaller number of key parameters, including the total genetic variance explained by multiple variants within a locus. Results: We perform extensive simulation studies to assess the accuracy of the proposed approximations in realistic settings. Using these simplified power calculations, we develop an analytic framework to obtain bounds on genetic architecture of an underlying trait given results from genome-wide association studies with rare variants. Finally, we provide insights into the required quality of annotation/functional information for identification of likely causal variants to make meaningful improvement in power. Availability and implementation: A shiny application that allows a variety of Power Analysis of GEnetic AssociatioN Tests (PAGEANT), in R is made publicly available at https://andrewhaoyu.shinyapps.io/PAGEANT/. Contact: nilanjan@jhu.edu. Supplementary information: Supplementary data are available at Bioinformatics online.
Asunto(s)
Sitios Genéticos , Variación Genética , Estudio de Asociación del Genoma Completo/métodos , Modelos Genéticos , Programas Informáticos , Frecuencia de los Genes , Genética de Población/métodos , HumanosRESUMEN
INTRODUCTION: Sleep is increasingly being viewed as an issue of public health concern, yet few epidemiologic studies have explored associations between sleep habits and metabolomic profile. OBJECTIVES: To assess the association between sleep and blood metabolites. METHODS: We examined the association between sleep and 891 fasting plasma metabolites in a subgroup of 106 participants from the Dietary Approaches to Stop Hypertension (DASH)-Sodium feeding trial (1997-1999). We produced two sleep variables to analyze, sleep midpoint (median time between bedtime and waketime) and sleep duration, as well as bedtime and wake time. Metabolites were measured using liquid and gas chromatography, coupled with mass spectrometry. We assessed associations between sleep variables and log transformed metabolites using linear mixed-effects models. We combined the resulting p-values using Fisher's method to calculate associations between sleep and 38 metabolic pathways. RESULTS: Sixteen pathways were associated (p < 0.05) with midpoint. Only the γ-glutamyl amino acid metabolism pathway reached Bonferroni-corrected threshold (0.0013). Eighty-three metabolites were associated with midpoint (FDR < 0.20). Similar associations were found for wake time. Neither bed time nor duration were strongly associated. The top metabolites (pathways given in brackets) associated with sleep were erythrulose (advanced glycation end-product) (positive association) and several γ-glutamyl pathway metabolites, including CMPF (fatty acid, dicarboxylate), isovalerate (valine, leucine and isoleucine and fatty acid metabolism) and HWESASXX (polypeptide) (inverse association). CONCLUSION: Within our study, several metabolites that have previously been linked to inflammation and oxidative stress (processes involved in diseases such as cardiovascular disease and cancer) were found to be associated with sleep.