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1.
Nature ; 602(7895): 162-168, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35058638

RESUMEN

Mutations in cancer-associated genes drive tumour outgrowth, but our knowledge of the timing of driver mutations and subsequent clonal dynamics is limited1-3. Here, using whole-genome sequencing of 1,013 clonal haematopoietic colonies from 12 patients with myeloproliferative neoplasms, we identified 580,133 somatic mutations to reconstruct haematopoietic phylogenies and determine clonal histories. Driver mutations were estimated to occur early in life, including the in utero period. JAK2V617F was estimated to have been acquired by 33 weeks of gestation to 10.8 years of age in 5 patients in whom JAK2V617F was the first event. DNMT3A mutations were acquired by 8 weeks of gestation to 7.6 years of age in 4 patients, and a PPM1D mutation was acquired by 5.8 years of age. Additional genomic events occurred before or following JAK2V617F acquisition and as independent clonal expansions. Sequential driver mutation acquisition was separated by decades across life, often outcompeting ancestral clones. The mean latency between JAK2V617F acquisition and diagnosis was 30 years (range 11-54 years). Estimated historical rates of clonal expansion varied substantially (3% to 190% per year), increased with additional driver mutations, and predicted latency to diagnosis. Our study suggests that early driver mutation acquisition and life-long growth and evolution underlie adult myeloproliferative neoplasms, raising opportunities for earlier intervention and a new model for cancer development.


Asunto(s)
Mutación , Trastornos Mieloproliferativos , Neoplasias , Adulto , Preescolar , Células Clonales/patología , Humanos , Janus Quinasa 2/genética , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Filogenia , Proteína Fosfatasa 2C , Secuenciación Completa del Genoma
2.
Nature ; 595(7865): 85-90, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33981037

RESUMEN

The ontogeny of the human haematopoietic system during fetal development has previously been characterized mainly through careful microscopic observations1. Here we reconstruct a phylogenetic tree of blood development using whole-genome sequencing of 511 single-cell-derived haematopoietic colonies from healthy human fetuses at 8 and 18 weeks after conception, coupled with deep targeted sequencing of tissues of known embryonic origin. We found that, in healthy fetuses, individual haematopoietic progenitors acquire tens of somatic mutations by 18 weeks after conception. We used these mutations as barcodes and timed the divergence of embryonic and extra-embryonic tissues during development, and estimated the number of blood antecedents at different stages of embryonic development. Our data support a hypoblast origin of the extra-embryonic mesoderm and primitive blood in humans.


Asunto(s)
Linaje de la Célula/genética , Desarrollo Embrionario/genética , Sistema Hematopoyético/embriología , Sistema Hematopoyético/metabolismo , Mutación , Células Sanguíneas/citología , Células Sanguíneas/metabolismo , Células Clonales/citología , Células Clonales/metabolismo , Análisis Mutacional de ADN , Feto/citología , Feto/embriología , Feto/metabolismo , Estratos Germinativos/citología , Estratos Germinativos/metabolismo , Salud , Sistema Hematopoyético/citología , Humanos , Cariotipificación , Masculino , Mesodermo/citología , Mesodermo/embriología , Mesodermo/metabolismo , Tasa de Mutación , Especificidad de Órganos/genética , Factores de Tiempo , Secuenciación Completa del Genoma , Flujo de Trabajo
3.
Nature ; 597(7876): 387-392, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34433963

RESUMEN

Starting from the zygote, all cells in the human body continuously acquire mutations. Mutations shared between different cells imply a common progenitor and are thus naturally occurring markers for lineage tracing1,2. Here we reconstruct extensive phylogenies of normal tissues from three adult individuals using whole-genome sequencing of 511 laser capture microdissections. Reconstructed embryonic progenitors in the same generation of a phylogeny often contribute to different extents to the adult body. The degree of this asymmetry varies between individuals, with ratios between the two reconstructed daughter cells of the zygote ranging from 60:40 to 93:7. Asymmetries pervade subsequent generations and can differ between tissues in the same individual. The phylogenies resolve the spatial embryonic patterning of tissues, revealing contiguous patches of, on average, 301 crypts in the adult colonic epithelium derived from a most recent embryonic cell and also a spatial effect in brain development. Using data from ten additional men, we investigated the developmental split between soma and germline, with results suggesting an extraembryonic contribution to primordial germ cells. This research demonstrates that, despite reaching the same ultimate tissue patterns, early bottlenecks and lineage commitments lead to substantial variation in embryonic patterns both within and between individuals.


Asunto(s)
Linaje de la Célula/genética , Embrión de Mamíferos/citología , Embrión de Mamíferos/metabolismo , Desarrollo Embrionario/genética , Mutación , Encéfalo/metabolismo , Cromosomas Humanos Y/genética , Células Clonales/metabolismo , Mutación de Línea Germinal/genética , Humanos , Masculino , Mosaicismo , Especificidad de Órganos/genética , Polimorfismo de Nucleótido Simple/genética
4.
Nature ; 598(7881): 473-478, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34646017

RESUMEN

The progression of chronic liver disease to hepatocellular carcinoma is caused by the acquisition of somatic mutations that affect 20-30 cancer genes1-8. Burdens of somatic mutations are higher and clonal expansions larger in chronic liver disease9-13 than in normal liver13-16, which enables positive selection to shape the genomic landscape9-13. Here we analysed somatic mutations from 1,590 genomes across 34 liver samples, including healthy controls, alcohol-related liver disease and non-alcoholic fatty liver disease. Seven of the 29 patients with liver disease had mutations in FOXO1, the major transcription factor in insulin signalling. These mutations affected a single hotspot within the gene, impairing the insulin-mediated nuclear export of FOXO1. Notably, six of the seven patients with FOXO1S22W hotspot mutations showed convergent evolution, with variants acquired independently by up to nine distinct hepatocyte clones per patient. CIDEB, which regulates lipid droplet metabolism in hepatocytes17-19, and GPAM, which produces storage triacylglycerol from free fatty acids20,21, also had a significant excess of mutations. We again observed frequent convergent evolution: up to fourteen independent clones per patient with CIDEB mutations and up to seven clones per patient with GPAM mutations. Mutations in metabolism genes were distributed across multiple anatomical segments of the liver, increased clone size and were seen in both alcohol-related liver disease and non-alcoholic fatty liver disease, but rarely in hepatocellular carcinoma. Master regulators of metabolic pathways are a frequent target of convergent somatic mutation in alcohol-related and non-alcoholic fatty liver disease.


Asunto(s)
Hepatopatías/genética , Hepatopatías/metabolismo , Hígado/metabolismo , Mutación/genética , Transporte Activo de Núcleo Celular/genética , Proteínas Reguladoras de la Apoptosis/genética , Línea Celular Tumoral , Enfermedad Crónica , Estudios de Cohortes , Ácidos Grasos no Esterificados/metabolismo , Femenino , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Humanos , Resistencia a la Insulina , Hepatopatías Alcohólicas/genética , Hepatopatías Alcohólicas/metabolismo , Masculino , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Triglicéridos/metabolismo
5.
Nature ; 597(7876): 381-386, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34433962

RESUMEN

Over the course of an individual's lifetime, normal human cells accumulate mutations1. Here we compare the mutational landscape in 29 cell types from the soma and germline using multiple samples from the same individuals. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types, but their absolute and relative contributions varied substantially. SBS18, which potentially reflects oxidative damage2, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The rate of mutation was lowest in spermatogonia, the stem cells from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutational processes and may be partially attributable to a low rate of cell division in basal spermatogonia. These results highlight similarities and differences in the maintenance of the germline and soma.


Asunto(s)
Células Germinativas/metabolismo , Mutación de Línea Germinal , Tasa de Mutación , Especificidad de Órganos/genética , Anciano , Células Clonales/metabolismo , Femenino , Salud , Humanos , Masculino , Microdisección , Persona de Mediana Edad , Estrés Oxidativo , Espermatogonias/metabolismo
6.
Nature ; 580(7805): 640-646, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32350471

RESUMEN

All normal somatic cells are thought to acquire mutations, but understanding of the rates, patterns, causes and consequences of somatic mutations in normal cells is limited. The uterine endometrium adopts multiple physiological states over a lifetime and is lined by a gland-forming epithelium1,2. Here, using whole-genome sequencing, we show that normal human endometrial glands are clonal cell populations with total mutation burdens that increase at about 29 base substitutions per year and that are many-fold lower than those of endometrial cancers. Normal endometrial glands frequently carry 'driver' mutations in cancer genes, the burden of which increases with age and decreases with parity. Cell clones with drivers often originate during the first decades of life and subsequently progressively colonize the epithelial lining of the endometrium. Our results show that mutational landscapes differ markedly between normal tissues-perhaps shaped by differences in their structure and physiology-and indicate that the procession of neoplastic change that leads to endometrial cancer is initiated early in life.


Asunto(s)
Análisis Mutacional de ADN , Endometrio/citología , Endometrio/metabolismo , Epitelio/metabolismo , Salud , Mutación , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Carcinogénesis/genética , Células Clonales/citología , Neoplasias Endometriales/genética , Endometrio/patología , Células Epiteliales/citología , Células Epiteliales/metabolismo , Células Epiteliales/patología , Epitelio/patología , Femenino , Humanos , Persona de Mediana Edad , Paridad/genética , Factores de Tiempo , Adulto Joven
7.
Nature ; 574(7779): 538-542, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31645727

RESUMEN

The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes1-7. Stem cells from normal livers have a low mutational burden and limited diversity of signatures8, which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation. Here, by sequencing whole genomes of 482 microdissections of 100-500 hepatocytes from 5 normal and 9 cirrhotic livers, we show that cirrhotic liver has a higher mutational burden than normal liver. Although rare in normal hepatocytes, structural variants, including chromothripsis, were prominent in cirrhosis. Driver mutations, such as point mutations and structural variants, affected 1-5% of clones. Clonal expansions of millimetres in diameter occurred in cirrhosis, with clones sequestered by the bands of fibrosis that surround regenerative nodules. Some mutational signatures were universal and equally active in both non-malignant hepatocytes and HCCs; some were substantially more active in HCCs than chronic liver disease; and others-arising from exogenous exposures-were present in a subset of patients. The activity of exogenous signatures between adjacent cirrhotic nodules varied by up to tenfold within each patient, as a result of clone-specific and microenvironmental forces. Synchronous HCCs exhibited the same mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease.


Asunto(s)
Células Clonales/citología , Células Clonales/patología , Fibrosis/genética , Fibrosis/patología , Hígado/citología , Hígado/metabolismo , Mutación , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Células Clonales/metabolismo , Análisis Mutacional de ADN , Hepatocitos/citología , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Hígado/patología , Masculino , Persona de Mediana Edad , Filogenia , Células Madre/citología , Células Madre/metabolismo , Células Madre/patología
8.
Nature ; 574(7779): 532-537, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31645730

RESUMEN

The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer1. However, our understanding of the earliest phases of colorectal neoplastic changes-which may occur in morphologically normal tissue-is comparatively limited, as for most cancer types. Here we use whole-genome sequencing to analyse hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed; some of these were ubiquitous and continuous, whereas others were only found in some individuals, in some crypts or during certain periods of life. Probable driver mutations were present in around 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium. Colorectal cancers exhibit substantially increased mutational burdens relative to normal cells. Sequencing normal colorectal cells provides quantitative insights into the genomic and clonal evolution of cancer.


Asunto(s)
Colon/citología , Células Epiteliales/citología , Células Epiteliales/metabolismo , Mutación , Síntomas Prodrómicos , Recto/citología , Adenoma/genética , Adenoma/patología , Anciano , Proteína Axina/genética , Carcinoma/genética , Carcinoma/patología , Transformación Celular Neoplásica , Células Clonales/citología , Células Clonales/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN , Femenino , Humanos , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Células Madre/citología , Células Madre/metabolismo
9.
Br J Cancer ; 122(12): 1803-1810, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32249277

RESUMEN

BACKGROUND: In colorectal and breast cancer, the density and localisation of immune infiltrates provides strong prognostic information. We asked whether similar automated quantitation and combined analysis of immune infiltrates could refine prognostic information in high-grade serous ovarian carcinoma (HGSOC) and tested associations between patterns of immune response and genomic driver alterations. METHODS: Epithelium and stroma were semi-automatically segmented and the infiltration of CD45RO+, CD8+ and CD68+ cells was automatically quantified from images of 332 HGSOC patient tissue microarray cores. RESULTS: Epithelial CD8 [p = 0.027, hazard ratio (HR) = 0.83], stromal CD68 (p = 3 × 10-4, HR = 0.44) and stromal CD45RO (p = 7 × 10-4, HR = 0.76) were positively associated with survival and remained so when averaged across the tumour and stromal compartments. Using principal component analysis, we identified optimised multiparameter survival models combining information from all immune markers (p = 0.016, HR = 0.88). There was no significant association between PTEN expression, type of TP53 mutation or presence of BRCA1/BRCA2 mutations and immune infiltrate densities or principal components. CONCLUSIONS: Combining measures of immune infiltration provided improved survival modelling and evidence for the multiple effects of different immune factors on survival. The presence of stromal CD68+ and CD45RO+ populations was associated with survival, underscoring the benefits evaluating stromal immune populations may bring for prognostic immunoscores in HGSOC.


Asunto(s)
Cistadenocarcinoma Seroso/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Ováricas/inmunología , Cistadenocarcinoma Seroso/mortalidad , Cistadenocarcinoma Seroso/patología , Femenino , Humanos , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Pronóstico , Microambiente Tumoral/inmunología
11.
Int J Gynecol Cancer ; 26(8): 1386-9, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27552403

RESUMEN

OBJECTIVES: The aim of this study was to assess the frequency of appendiceal pathology in women undergoing surgery for mucinous ovarian neoplasm and to evaluate whether appendicectomy is necessary. METHODS: This single-institution retrospective study reviewed prevalence of appendiceal lesions in all patients operated on at our institution from 2002 to 2013 with the final diagnosis of mucinous tumor of the ovary. Clinicopathological data were analyzed. RESULTS: One hundred twenty-three cases were identified. These included 45 (37%) benign mucinous ovarian neoplasms, 63 (51%) borderline, and 11 (9%) invasive mucinous ovarian tumors. In addition, 4 (3%) cases of metastatic tumors to the ovary were also identified. Appendiceal pathology was found in association with all types of mucinous ovarian tumors (benign, borderline, and malignant). In 24% of cases, appendix was macroscopically abnormal at the time of the surgery, prompting the surgical removal. Regardless of the gross findings, microscopic abnormality in the appendix was seen in 24% of all cases. The prevalence of significant occult microscopic appendiceal pathology, that is, when the appendix was grossly normal, was 6%. CONCLUSIONS: Given the prevalence of coexisting appendiceal pathology found in this study and the reported low rates of complications associated with the procedure, an appendicectomy is recommended in the management of all mucinous ovarian neoplasms.


Asunto(s)
Adenocarcinoma Mucinoso/epidemiología , Neoplasias del Apéndice/epidemiología , Neoplasias Ováricas/epidemiología , Adenocarcinoma Mucinoso/sangre , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Mucinoso/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Apendicectomía/estadística & datos numéricos , Neoplasias del Apéndice/sangre , Neoplasias del Apéndice/patología , Neoplasias del Apéndice/cirugía , Antígeno Ca-125/sangre , Femenino , Humanos , Proteínas de la Membrana/sangre , Persona de Mediana Edad , Neoplasias Ováricas/sangre , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Prevalencia , Estudios Retrospectivos , Reino Unido/epidemiología , Adulto Joven
12.
Nat Commun ; 15(1): 2026, 2024 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-38467600

RESUMEN

Timely detection of Barrett's esophagus, the pre-malignant condition of esophageal adenocarcinoma, can improve patient survival rates. The Cytosponge-TFF3 test, a non-endoscopic minimally invasive procedure, has been used for diagnosing intestinal metaplasia in Barrett's. However, it depends on pathologist's assessment of two slides stained with H&E and the immunohistochemical biomarker TFF3. This resource-intensive clinical workflow limits large-scale screening in the at-risk population. To improve screening capacity, we propose a deep learning approach for detecting Barrett's from routinely stained H&E slides. The approach solely relies on diagnostic labels, eliminating the need for expensive localized expert annotations. We train and independently validate our approach on two clinical trial datasets, totaling 1866 patients. We achieve 91.4% and 87.3% AUROCs on discovery and external test datasets for the H&E model, comparable to the TFF3 model. Our proposed semi-automated clinical workflow can reduce pathologists' workload to 48% without sacrificing diagnostic performance, enabling pathologists to prioritize high risk cases.


Asunto(s)
Adenocarcinoma , Esófago de Barrett , Aprendizaje Profundo , Neoplasias Esofágicas , Humanos , Esófago de Barrett/diagnóstico , Esófago de Barrett/patología , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/patología , Adenocarcinoma/diagnóstico , Adenocarcinoma/patología , Metaplasia
13.
J Clin Invest ; 134(2)2024 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-37934611

RESUMEN

BACKGROUNDPhase 1 study of ATRinhibition alone or with radiation therapy (PATRIOT) was a first-in-human phase I study of the oral ATR (ataxia telangiectasia and Rad3-related) inhibitor ceralasertib (AZD6738) in advanced solid tumors.METHODSThe primary objective was safety. Secondary objectives included assessment of antitumor responses and pharmacokinetic (PK) and pharmacodynamic (PD) studies. Sixty-seven patients received 20-240 mg ceralasertib BD continuously or intermittently (14 of a 28-day cycle).RESULTSIntermittent dosing was better tolerated than continuous, which was associated with dose-limiting hematological toxicity. The recommended phase 2 dose of ceralasertib was 160 mg twice daily for 2 weeks in a 4-weekly cycle. Modulation of target and increased DNA damage were identified in tumor and surrogate PD. There were 5 (8%) confirmed partial responses (PRs) (40-240 mg BD), 34 (52%) stable disease (SD), including 1 unconfirmed PR, and 27 (41%) progressive disease. Durable responses were seen in tumors with loss of AT-rich interactive domain-containing protein 1A (ARID1A) and DNA damage-response defects. Treatment-modulated tumor and systemic immune markers and responding tumors were more immune inflamed than nonresponding.CONCLUSIONCeralasertib monotherapy was tolerated at 160 mg BD intermittently and associated with antitumor activity.TRIAL REGISTRATIONClinicaltrials.gov: NCT02223923, EudraCT: 2013-003994-84.FUNDINGCancer Research UK, AstraZeneca, UK Department of Health (National Institute for Health Research), Rosetrees Trust, Experimental Cancer Medicine Centre.


Asunto(s)
Morfolinas , Neoplasias , Pirimidinas , Sulfonamidas , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Indoles , Inflamación/tratamiento farmacológico , Genómica , Proteínas de la Ataxia Telangiectasia Mutada/genética
14.
Nat Genet ; 55(2): 246-254, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36702998

RESUMEN

APOBEC mutational signatures SBS2 and SBS13 are common in many human cancer types. However, there is an incomplete understanding of its stimulus, when it occurs in the progression from normal to cancer cell and the APOBEC enzymes responsible. Here we whole-genome sequenced 342 microdissected normal epithelial crypts from the small intestines of 39 individuals and found that SBS2/SBS13 mutations were present in 17% of crypts, more frequent than most other normal tissues. Crypts with SBS2/SBS13 often had immediate crypt neighbors without SBS2/SBS13, suggesting that the underlying cause of SBS2/SBS13 is cell-intrinsic. APOBEC mutagenesis occurred in an episodic manner throughout the human lifespan, including in young children. APOBEC1 mRNA levels were very high in the small intestine epithelium, but low in the large intestine epithelium and other tissues. The results suggest that the high levels of SBS2/SBS13 in the small intestine are collateral damage from APOBEC1 fulfilling its physiological function of editing APOB mRNA.


Asunto(s)
Apolipoproteínas B , Citidina Desaminasa , Niño , Humanos , Preescolar , Apolipoproteínas B/genética , Citidina Desaminasa/genética , Mutagénesis/genética , ARN Mensajero/genética , Desaminasas APOBEC-1/genética , Intestino Delgado
15.
Clin Microbiol Infect ; 28(8): 1066-1075, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35339672

RESUMEN

BACKGROUND: Many postmortem studies address the cardiovascular effects of COVID-19 and provide valuable information, but are limited by their small sample size. OBJECTIVES: The aim of this systematic review is to better understand the various aspects of the cardiovascular complications of COVID-19 by pooling data from a large number of autopsy studies. DATA SOURCES: We searched the online databases Ovid EBM Reviews, Ovid Embase, Ovid Medline, Scopus, and Web of Science for concepts of autopsy or histopathology combined with COVID-19, published between database inception and February 2021. We also searched for unpublished manuscripts using the medRxiv services operated by Cold Spring Harbor Laboratory. STUDY ELIGIBILITY CRITERIA: Articles were considered eligible for inclusion if they reported human postmortem cardiovascular findings among individuals with a confirmed SARS coronavirus type 2 (CoV-2) infection. PARTICIPANTS: Confirmed COVID-19 patients with post-mortem cardiovascular findings. INTERVENTIONS: None. METHODS: Studies were individually assessed for risk of selection, detection, and reporting biases. The median prevalence of different autopsy findings with associated interquartile ranges (IQRs). RESULTS: This review cohort contained 50 studies including 548 hearts. The median age of the deceased was 69 years. The most prevalent acute cardiovascular findings were myocardial necrosis (median: 100.0%; IQR, 20%-100%; number of studies = 9; number of patients = 64) and myocardial oedema (median: 55.5%; IQR, 19.5%-92.5%; number of studies = 4; number of patients = 46). The median reported prevalence of extensive, focal active, and multifocal myocarditis were all 0.0%. The most prevalent chronic changes were myocyte hypertrophy (median: 69.0%; IQR, 46.8%-92.1%) and fibrosis (median: 35.0%; IQR, 35.0%-90.5%). SARS-CoV-2 was detected in the myocardium with median prevalence of 60.8% (IQR 40.4-95.6%). CONCLUSIONS: Our systematic review confirmed the high prevalence of acute and chronic cardiac pathologies in COVID-19 and SARS-CoV-2 cardiac tropism, as well as the low prevalence of myocarditis in COVID-19.


Asunto(s)
COVID-19 , Miocarditis , Anciano , Autopsia , Humanos , Pulmón , Miocarditis/epidemiología , SARS-CoV-2
16.
Cell Stem Cell ; 28(7): 1262-1274.e5, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-33657416

RESUMEN

Clonal dynamics and mutation burden in healthy human prostate epithelium are relevant to prostate cancer. We sequenced whole genomes from 409 microdissections of normal prostate epithelium across 8 donors, using phylogenetic reconstruction with spatial mapping in a 59-year-old man's prostate to reconstruct tissue dynamics across the lifespan. Somatic mutations accumulate steadily at ∼16 mutations/year/clone, with higher rates in peripheral than peri-urethral regions. The 24-30 independent glandular subunits are established as rudimentary ductal structures during fetal development by 5-10 embryonic cells each. Puberty induces formation of further side and terminal branches by local stem cells disseminated throughout the rudimentary ducts during development. During adult tissue maintenance, clonal expansions have limited geographic scope and minimal migration. Driver mutations are rare in aging prostate epithelium, but the one driver we did observe generated a sizable intraepithelial clonal expansion. Leveraging unbiased clock-like mutations, we define prostate stem cell dynamics through fetal development, puberty, and aging.


Asunto(s)
Envejecimiento , Próstata , Adulto , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Filogenia , Células Madre
17.
Nat Protoc ; 16(2): 841-871, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33318691

RESUMEN

Somatic mutations accumulate in healthy tissues as we age, giving rise to cancer and potentially contributing to ageing. To study somatic mutations in non-neoplastic tissues, we developed a series of protocols to sequence the genomes of small populations of cells isolated from histological sections. Here, we describe a complete workflow that combines laser-capture microdissection (LCM) with low-input genome sequencing, while circumventing the use of whole-genome amplification (WGA). The protocol is subdivided broadly into four steps: tissue processing, LCM, low-input library generation and mutation calling and filtering. The tissue processing and LCM steps are provided as general guidelines that might require tailoring based on the specific requirements of the study at hand. Our protocol for low-input library generation uses enzymatic rather than acoustic fragmentation to generate WGA-free whole-genome libraries. Finally, the mutation calling and filtering strategy has been adapted from previously published protocols to account for artifacts introduced via library creation. To date, we have used this workflow to perform targeted and whole-genome sequencing of small populations of cells (typically 100-1,000 cells) in thousands of microbiopsies from a wide range of human tissues. The low-input DNA protocol is designed to be compatible with liquid handling platforms and make use of equipment and expertise standard to any core sequencing facility. However, obtaining low-input DNA material via LCM requires specialized equipment and expertise. The entire protocol from tissue reception through whole-genome library generation can be accomplished in as little as 1 week, although 2-3 weeks would be a more typical turnaround time.


Asunto(s)
Captura por Microdisección con Láser/métodos , Análisis de Secuencia de ADN/métodos , Secuenciación Completa del Genoma/métodos , ADN/genética , Perfilación de la Expresión Génica/métodos , Biblioteca de Genes , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Mutación/genética , Flujo de Trabajo
18.
Nat Genet ; 53(10): 1434-1442, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34594041

RESUMEN

Mutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε and Pol δ replicate DNA during cell division. However, in some cancers, defective proofreading due to acquired POLE/POLD1 exonuclease domain mutations causes markedly elevated somatic mutation burdens with distinctive mutational signatures. Germline POLE/POLD1 mutations cause familial cancer predisposition. Here, we sequenced normal tissue and tumor DNA from individuals with germline POLE/POLD1 mutations. Increased mutation burdens with characteristic mutational signatures were found in normal adult somatic cell types, during early embryogenesis and in sperm. Thus human physiology can tolerate ubiquitously elevated mutation burdens. Except for increased cancer risk, individuals with germline POLE/POLD1 mutations do not exhibit overt features of premature aging. These results do not support a model in which all features of aging are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.


Asunto(s)
ADN Polimerasa III/genética , ADN Polimerasa II/genética , Mutación de Línea Germinal/genética , Adolescente , Adulto , Anciano , Desarrollo Embrionario/genética , Genoma Humano/genética , Humanos , Neoplasias Intestinales/patología , Intestinos/patología , Persona de Mediana Edad , Mutagénesis/genética , Filogenia , Células Madre/patología , Adulto Joven
19.
Nat Genet ; 53(12): 1698-1711, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34857954

RESUMEN

The endometrium, the mucosal lining of the uterus, undergoes dynamic changes throughout the menstrual cycle in response to ovarian hormones. We have generated dense single-cell and spatial reference maps of the human uterus and three-dimensional endometrial organoid cultures. We dissect the signaling pathways that determine cell fate of the epithelial lineages in the lumenal and glandular microenvironments. Our benchmark of the endometrial organoids reveals the pathways and cell states regulating differentiation of the secretory and ciliated lineages both in vivo and in vitro. In vitro downregulation of WNT or NOTCH pathways increases the differentiation efficiency along the secretory and ciliated lineages, respectively. We utilize our cellular maps to deconvolute bulk data from endometrial cancers and endometriotic lesions, illuminating the cell types dominating in each of these disorders. These mechanistic insights provide a platform for future development of treatments for common conditions including endometriosis and endometrial carcinoma.


Asunto(s)
Endometrio/fisiología , Ciclo Menstrual , Diferenciación Celular , Linaje de la Célula , Microambiente Celular , Neoplasias Endometriales/patología , Endometrio/embriología , Endometrio/patología , Femenino , Hormonas Esteroides Gonadales/metabolismo , Humanos , Técnicas In Vitro , Organoides , Receptores Notch/metabolismo , Transducción de Señal , Análisis Espacio-Temporal , Técnicas de Cultivo de Tejidos , Transcriptoma , Útero/patología , Proteínas Wnt/metabolismo
20.
J Clin Pathol ; 73(12): 840-844, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32605920

RESUMEN

Here, we report the pathological findings of nine complete autopsies of individuals who died in community settings in the UK, three of which were positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), three tested negative for SARS-CoV-2 but are likely false negatives, and three died of other respiratory infections. Autopsy revealed firm, consolidated lungs or lobar pneumonia. Histology of the lungs showed changes of diffuse alveolar damage with fibrin membrane formation, thickened alveolar walls and interstitium with lymphocytic infiltrate, and type 2 pneumocyte hyperplasia with shedding into the alveolar space. This series is the first in the world to describe autopsy findings in individuals dying suddenly in the community, not previously known to have COVID-19 infection, and the first autopsy series in the UK. During a time when testing in the UK is currently primarily offered to patients in hospital or symptomatic key workers, with limited testing available in community settings, it highlights the importance of testing for COVID-19 at autopsy. Two deaths occurred in care homes where a diagnosis of COVID-19 allowed the health protection team to provide support in that 'closed setting' to reduce the risks of onward transmission. This work highlights the need for frequent COVID-19 testing in the management of patients in community settings. Comprehensive virology and microbiology assessment is pivotal to correctly identify the cause of death, including those due to COVID-19 infection, and to derive accurate death statistics.


Asunto(s)
Autopsia , Prueba de COVID-19 , COVID-19/patología , Pulmón/patología , Miocardio/patología , SARS-CoV-2 , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/diagnóstico , COVID-19/mortalidad , Causas de Muerte , Infecciones Comunitarias Adquiridas/diagnóstico , Infecciones Comunitarias Adquiridas/mortalidad , Infecciones Comunitarias Adquiridas/patología , Reacciones Falso Positivas , Femenino , Humanos , Masculino , SARS-CoV-2/aislamiento & purificación , Reino Unido/epidemiología
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