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1.
J. optom. (Internet) ; 14(1): 86-91, ene.-mar. 2021. tab, graf
Artigo em Inglês | IBECS-Express | IBECS | ID: ibc-ET6-1900

RESUMO

PURPOSE: While there are numerous studies comparing open-view autorefractors to subjective refraction or other open-view autorefractors, most studies between closed and open-view autorefraction tend to focus on children rather than young adults. The aim of this study was to determine the concordance in non-cycloplegic refractive error between two modern objective autorefractors: the closed-view monocular Topcon TRK-2P and the binocular open-view Grand Seiko WR-5500. METHODS: Fifty young adults aged 20-29 years (mean age 22 ± 1.6 years) underwent non-cycloplegic autorefraction using the Grand Seiko WAM-5500 (open view) and Topcon TRK-2P (closed-view) autorefractors on both eyes. Findings were expressed as the isolated spherical component and were also converted from clinical to vector notation: Mean Spherical Error (MSE) and the astigmatic components J0 and J45. RESULTS: Mean MSE ± SD was -1.00 ± 2.40D for the Grand Seiko WAM-5500 compared to -1.23 ± 2.29D for the Topcon TRK-2P. Up to seventy-six percent of the cohort had mean spherical errors from the Topcon TRK-2P which fell within ±0.50D of the Grand Seiko reading and 58% fell within ±0.25D. Mean differences between the two instruments were statistically significant for all components (J0, spherical, and MSE) (p < 0.01), except J45 (p > 0.05). CONCLUSIONS: The differences in non-cycloplegic MSE between these two instruments are small, but statistically significant. From a clinical perspective the Topcon TRK-2P may serve as a useful starting point for subjective refraction, but additional work is needed to help further minimise differences between the instruments


No disponible

2.
Gut ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33632709

RESUMO

OBJECTIVE: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. DESIGN: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. RESULTS: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. CONCLUSION: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.

3.
J Natl Cancer Inst ; 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33528005

RESUMO

BACKGROUND: Aspirin-use reduces colorectal cancer (CRC) incidence, but there is limited evidence regarding associations of aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) with CRC-specific survival. METHODS: This prospective analysis includes women and men from the Cancer Prevention Study-II Nutrition Cohort who were cancer-free at baseline (1992 or 1993) and diagnosed with CRC during incidence follow-up through 2015. Detailed information on aspirin and non-aspirin NSAID-use was self-reported on questionnaires at baseline, in 1997, and every 2 years thereafter. Pre- and post-diagnosis data were available for 2,686 and 1,931 participants without distant-metastases, respectively, among whom 512 and 251 died from CRC during mortality follow-up through 2016. Secondary analyses examined associations between pre-diagnosis aspirin-use and stage at diagnosis (distant-metastatic versus localized or regional). All statistical tests were two-sided. RESULTS: Long-term regular use of aspirin (>15 times per month) before diagnosis was associated with lower CRC-specific mortality (multivariable-adjusted hazard ratio (HR)= 0.69; 95% CI = 0.52-0.92). Post-diagnosis regular aspirin use was not statistically significantly associated with risk of CRC-specific mortality overall (HR = 0.82; 95% CI = 0.62-1.09), although participants who began regular aspirin use only after their diagnosis were at lower risk than participants who did not use aspirin at both the pre-and post-diagnosis periods (HR = 0.60; 95% CI = 0.36-0.98). Long-term aspirin use before diagnosis was also associated with lower odds of diagnosis with distant metastases (multivariable-adjusted odds ratio = 0.73; 95% CI = 0.53-0.99). CONCLUSIONS: Our results suggest that long-term aspirin use before a diagnosis of non-metastatic colorectal cancer may be associated with lower CRC-specific mortality after diagnosis, consistent with possible inhibition of micro-metastases before diagnosis.

5.
Nat Protoc ; 16(2): 841-871, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33318691

RESUMO

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.

6.
Environ Toxicol Chem ; 2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33315280

RESUMO

recent industrial developments have resulted in an increase in use of so-called technology-critical elements (TCEs), for which the potential impacts on aquatic biota remain to be evaluated. In the present study, quantitative ion character activity relationships (QICARs) have been developed to relate intrinsic metal properties to their toxicity towards freshwater aquatic organisms. In total, 23 metal properties were tested as predictors of acute ec50 values for 12 data-rich metals, for algae, daphnids and fish (with and without species distinction). Simple and multiple linear regressions were developed using the toxicological data expressed as a function of the total dissolved metal concentrations. The best regressions were then tested by comparing the predicted ec50 values for the tces (germanium, indium, gold, rhenium and platinum group elements - pges - which include iridium, platinum, palladium, rhodium, and ruthenium) with the few measured values that are available. The eight 'best' QICAR models (adjusted r2 > 0.6) used χm 2 r as the predictor. For a given metal ion, this composite parameter, also known as the covalent index, is a measure of the importance of covalent interactions relative to ionic interactions. The toxicity of the tces was reasonably well predicted for most of the TCEs, with values falling within the 95 percent prediction intervals for the regressions of the measured versus predicted ec50 values. Exceptions included au(i) (all test organisms), au(iii) (algae and fish), pt(ii) (algae, daphnids), ru(iii) (daphnids) and rh(iii) (daphnids, fish). We conclude that qicars show potential as a screening tool to review toxicity data and flag 'outliers', which might need further scrutiny, and as an interpolating or extrapolating tool to predict TCE toxicity. This article is protected by copyright. All rights reserved.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33354812

RESUMO

PURPOSE: In the UK, most referrals to the hospital eye service (HES) originate from community optometrists (CO). This audit investigates the quality of referrals, replies, and communication between CO and the HES. METHODS: Optometric referrals and replies were extracted from three practices in England. If no reply letter was found, the records were searched at each local HES unit, and additional replies or records copied. De-identified referrals, replies and records were audited by a panel against established standards to evaluate whether the referrals were necessary, accurate and directed to the appropriate professional. The referral rate (RR) and referral reply rate (RRR) were calculated. RESULTS: A total of 459 de-identified referrals were extracted. The RR ranged from 3.6%-8.7%. The proportion of referred patients who were seen in the HES unit was 63%-76%. From the CO perspective, the proportion of referrals for which they received replies ranged from 26%-49%. Adjusting the number of referrals for cases when it would be reasonable to expect an HES reply, RRR becomes 38%-62%. Patients received a copy of the reply in 3%-21% of cases. Referrals were made to the appropriate service in over 95% of cases, were judged necessary in 93%-97% and were accurate in 81%-98% of cases. The referral reply addressed the reason for the referral in 93%-97% and was meaningful in 94%-99% of cases. The most common conditions referred were glaucoma, cataract, anterior segment lesions, and neurological/ocular motor anomalies. The CO/HES dyad (pairing) in the area with the lowest average household income had the highest RR. CONCLUSIONS: In contrast with the Royal College of Ophthalmologists/College of Optometrists joint statement on sharing patient information, CO referrals often do not elicit a reply to the referring CO. Replies from the HES to COs are important for patient care, benefitting patients and clinicians, and minimising unnecessary HES appointments.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33318029

RESUMO

BACKGROUND: Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk. METHODS: Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N = 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N = 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls). RESULTS: Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03-1.13; OR: 3.33, 95% CI, 2.46-4.50; and OR: 1.15, 95% CI, 1.02-1.29, respectively). CONCLUSIONS: MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin's reduction of metastasis. IMPACT: Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.

9.
Nature ; 2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33361815

RESUMO

Focal chromosomal amplification contributes to the initiation of cancer by mediating overexpression of oncogenes1-3, and to the development of cancer therapy resistance by increasing the expression of genes whose action diminishes the efficacy of anti-cancer drugs. Here we used whole-genome sequencing of clonal cell isolates that developed chemotherapeutic resistance to show that chromothripsis is a major driver of circular extrachromosomal DNA (ecDNA) amplification (also known as double minutes) through mechanisms that depend on poly(ADP-ribose) polymerases (PARP) and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). Longitudinal analyses revealed that a further increase in drug tolerance is achieved by structural evolution of ecDNAs through additional rounds of chromothripsis. In situ Hi-C sequencing showed that ecDNAs preferentially tether near chromosome ends, where they re-integrate when DNA damage is present. Intrachromosomal amplifications that formed initially under low-level drug selection underwent continuing breakage-fusion-bridge cycles, generating amplicons more than 100 megabases in length that became trapped within interphase bridges and then shattered, thereby producing micronuclei whose encapsulated ecDNAs are substrates for chromothripsis. We identified similar genome rearrangement profiles linked to localized gene amplification in human cancers with acquired drug resistance or oncogene amplifications. We propose that chromothripsis is a primary mechanism that accelerates genomic DNA rearrangement and amplification into ecDNA and enables rapid acquisition of tolerance to altered growth conditions.

10.
Artigo em Inglês | MEDLINE | ID: mdl-33188634

RESUMO

The scientific knowledge produced by academic research can be valued in all sectors of human activity, including private sector. The ROVALTAIN Foundation organized a round-table during its scientific day in 2019. It crossed the points of view of academic scientists and industrial partners, addressing five main topics. The first one concerned the validation of a common definition of the academic research/private partners interface. Then, the group discussed the place for academic expertise in the corporate world; the advantages of involving academic researchers in expertise for the private sector; and the limits of this model. To conclude, the need of a third party, like the ROVALTAIN Foundation, as a catalyzer in building the interface between academic research and private partners has been discussed.

12.
Haematologica ; Online ahead of print2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-33054126

RESUMO

Nodal peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) remains a diagnosis encompassing a heterogenous group of PTCL cases not fitting criteria for more homogeneous subtypes. They are characterized by a poor clinical outcome when treated with anthracycline-containing regimens. A better understanding of their biology could improve prognostic stratification and foster the development of novel therapeutic approaches. Recent targeted and whole exome sequencing studies have shown recurrent copy number abnormalities (CNAs) with prognostic significance. Here, investigating 5 formalin-fixed, paraffin embedded cases of PTCL-NOS by whole genome sequencing (WGS), we found a high prevalence of structural variants and complex events, such as chromothripsis likely responsible for the observed CNAs. Among them, CDKN2A and PTEN deletions emerged as the most frequent aberration, as confirmed in a final cohort of 143 patients with nodal PTCL. The incidence of CDKN2A and PTEN deletions among PTCL-NOS was 46% and 26%, respectively. Furthermore, we found that co-occurrence of CDKN2A and PTEN deletions is an event associated with PTCL-NOS with absolute specificity. In contrast, these deletions were rare and never co-occurred in angioimmunoblastic and anaplastic lymphomas. CDKN2A deletion was associated with shorter overall survival in multivariate analysis corrected by age, IPI, transplant eligibility and GATA3 expression (adjusted HR =2.53; 95% CI 1.006-6.3; p=0.048). These data suggest that CDKN2A deletions may be relevant for refining the prognosis of PTCL-NOS and their significance should be evaluated in prospective trials.

13.
eNeuro ; 7(6)2020.
Artigo em Inglês | MEDLINE | ID: mdl-33097488

RESUMO

Retinofugal synapses serve as models for understanding how sensory signals from the periphery are relayed to the brain. Past studies have focused primarily on understanding the postsynaptic glutamatergic receptor subtypes involved in signal transmission, but the mechanisms underlying glutamate release at presynaptic retinal terminals remains largely unknown. Here we explored how different calcium (Ca2+) channel subtypes regulate glutamatergic excitatory synaptic transmission in two principal retinorecipient targets, the dorsal lateral geniculate nucleus (dLGN) and superior colliculus (SC) of the mouse. We used an in vitro slice preparation to record the synaptic responses of dLGN and SC neurons evoked by the electrical stimulation of optic tract (OT) fibers before and during the application of selective Ca2+ channel blockers. We found that synaptic responses to paired or repetitive OT stimulation were highly sensitive to extracellular levels of Ca2+ and to selective antagonists of voltage gated Ca2+ channels, indicating that these channels regulate the presynaptic release of glutamate at retinal synapses in both dLGN and SC. Bath application of selective Ca2+ channel blockers revealed that P/Q-type Ca2+ channels primarily operate to regulate glutamate release at retinal synapses in dLGN, while N-type Ca2+ channels dominate release in the SC.

14.
Int J Cancer ; 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-33038280

RESUMO

Obesity is considered a chronic inflammatory state characterized by continued secretion of adipokines and cytokines. Experimental and epidemiological evidence indicates that circulating adipokines may be associated with the development of obesity-related cancers, but it is unclear if these associations are causal or confounded. We examined potential causal associations of specific adipokines (adiponectin, leptin, soluble leptin receptor [sOB-R] and plasminogen activator inhibitor-1 [PAI-1]) with five obesity-related cancers (colorectal, pancreatic, renal cell carcinoma [RCC], ovarian and endometrial) using Mendelian randomization (MR) methods. We used summary-level data from large genetic consortia for 114 530 cancer cases and 245 284 controls. We constructed genetic instruments using 18 genetic variants for adiponectin, 2 for leptin and 4 for both sOB-R and PAI-1 (P value for inclusion<5 × 10-8 ). Causal estimates were obtained using two-sample MR methods. In the inverse-variance weighted models, we found an inverse association between adiponectin and risk of colorectal cancer (odds ratio per 1 µg/mL increment in adiponectin concentration: 0.90 [95% confidence interval = 0.84-0.97]; P = .01); but, evidence of horizontal pleiotropy was detected and the association was not present when this was taken into consideration. No association was found for adiponectin and risks of pancreatic cancer, RCC, ovarian cancer and endometrial cancer. Leptin, sOB-R and PAI-1 were also similarly unrelated to risk of obesity-related cancers. Despite the large sample size, our MR analyses do not support causal effects of circulating adiponectin, leptin, sOB-R and PAI-1 concentrations on the development of five obesity-related cancers.

15.
Gastroenterology ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33058866

RESUMO

BACKGROUND AND AIMS: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes. METHODS: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted. RESULTS: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10-6, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis. CONCLUSIONS: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.

16.
Nat Genet ; 52(11): 1178-1188, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33020667

RESUMO

Somatic mutations in driver genes may ultimately lead to the development of cancer. Understanding how somatic mutations accumulate in cancer genomes and the underlying factors that generate somatic mutations is therefore crucial for developing novel therapeutic strategies. To understand the interplay between spatial genome organization and specific mutational processes, we studied 3,000 tumor-normal-pair whole-genome datasets from 42 different human cancer types. Our analyses reveal that the change in somatic mutational load in cancer genomes is co-localized with topologically-associating-domain boundaries. Domain boundaries constitute a better proxy to track mutational load change than replication timing measurements. We show that different mutational processes lead to distinct somatic mutation distributions where certain processes generate mutations in active domains, and others generate mutations in inactive domains. Overall, the interplay between three-dimensional genome organization and active mutational processes has a substantial influence on the large-scale mutation-rate variations observed in human cancers.

17.
Nat Commun ; 11(1): 5040, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028839

RESUMO

Bringing together cancer genomes from different projects increases power and allows the investigation of pan-cancer, molecular mechanisms. However, working with whole genomes sequenced over several years in different sequencing centres requires a framework to compare the quality of these sequences. We used the Pan-Cancer Analysis of Whole Genomes cohort as a test case to construct such a framework. This cohort contains whole cancer genomes of 2832 donors from 18 sequencing centres. We developed a non-redundant set of five quality control (QC) measurements to establish a star rating system. These QC measures reflect known differences in sequencing protocol and provide a guide to downstream analyses and allow for exclusion of samples of poor quality. We have found that this is an effective framework of quality measures. The implementation of the framework is available at: https://dockstore.org/containers/quay.io/jwerner_dkfz/pancanqc:1.2.2 .


Assuntos
Genoma Humano/genética , Genômica/normas , Neoplasias/genética , Controle de Qualidade , Mapeamento Cromossômico/normas , Cromossomos Humanos/genética , Análise Mutacional de DNA/normas , Feminino , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/normas , Humanos , Masculino , Mutação , Software , Sequenciamento Completo do Genoma/normas
18.
Science ; 370(6512): 75-82, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33004514

RESUMO

The extent of somatic mutation and clonal selection in the human bladder remains unknown. We sequenced 2097 bladder microbiopsies from 20 individuals using targeted (n = 1914 microbiopsies), whole-exome (n = 655), and whole-genome (n = 88) sequencing. We found widespread positive selection in 17 genes. Chromatin remodeling genes were frequently mutated, whereas mutations were absent in several major bladder cancer genes. There was extensive interindividual variation in selection, with different driver genes dominating the clonal landscape across individuals. Mutational signatures were heterogeneous across clones and individuals, which suggests differential exposure to mutagens in the urine. Evidence of APOBEC mutagenesis was found in 22% of the microbiopsies. Sequencing multiple microbiopsies from five patients with bladder cancer enabled comparisons with cancer-free individuals and across histological features. This study reveals a rich landscape of mutational processes and selection in normal urothelium with large heterogeneity across clones and individuals.


Assuntos
Genes Neoplásicos , Mutagênese , Seleção Genética , Neoplasias da Bexiga Urinária/genética , Bexiga Urinária/patologia , Urotélio/patologia , Desaminases APOBEC/genética , Adulto , Idoso , Biópsia , Montagem e Desmontagem da Cromatina/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutagênicos/análise , Mutação
19.
J Pathol ; 252(4): 433-440, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32866294

RESUMO

The rare benign giant cell tumour of bone (GCTB) is defined by an almost unique mutation in the H3.3 family of histone genes H3-3A or H3-3B; however, the same mutation is occasionally found in primary malignant bone tumours which share many features with the benign variant. Moreover, lung metastases can occur despite the absence of malignant histological features in either the primary or metastatic lesions. Herein we investigated the genetic events of 17 GCTBs including benign and malignant variants and the methylation profiles of 122 bone tumour samples including GCTBs. Benign GCTBs possessed few somatic alterations and no other known drivers besides the H3.3 mutation, whereas all malignant tumours harboured at least one additional driver mutation and exhibited genomic features resembling osteosarcomas, including high mutational burden, additional driver event(s), and a high degree of aneuploidy. The H3.3 mutation was found to predate the development of aneuploidy. In contrast to osteosarcomas, malignant H3.3-mutated tumours were enriched for a variety of alterations involving TERT, other than amplification, suggesting telomere dysfunction in the transformation of benign to malignant GCTB. DNA sequencing of the benign metastasising GCTB revealed no additional driver alterations; polyclonal seeding in the lung was identified, implying that the metastatic lesions represent an embolic event. Unsupervised clustering of DNA methylation profiles revealed that malignant H3.3-mutated tumours are distinct from their benign counterpart, and other bone tumours. Differential methylation analysis identified CCND1, encoding cyclin D1, as a plausible cancer driver gene in these tumours because hypermethylation of the CCND1 promoter was specific for GCTBs. We report here the genomic and methylation patterns underlying the rare clinical phenomena of benign metastasising and malignant transformation of GCTB and show how the combination of genomic and epigenomic findings could potentially distinguish benign from malignant GCTBs, thereby predicting aggressive behaviour in challenging diagnostic cases. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

20.
BMC Med ; 18(1): 229, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32878631

RESUMO

BACKGROUND: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex. METHODS: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10-8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study. RESULTS: The associations between circulating UCB levels and CRC risk differed by sex (Pheterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (Pheterogeneity ≥ 0.2). CONCLUSIONS: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.

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