RESUMO
Telomere length control is critical for cellular lifespan and tumor suppression. Telomerase is transiently activated in the inner cell mass of the developing blastocyst to reset telomere reserves. Its silencing upon differentiation leads to gradual telomere shortening in somatic cells. Here, we report that transcriptional regulation through cis-regulatory elements only partially accounts for telomerase activation in pluripotent cells. Instead, developmental control of telomerase is primarily driven by an alternative splicing event, centered around hTERT exon 2. Skipping of exon 2 triggers hTERT mRNA decay in differentiated cells, and conversely, its retention promotes telomerase accumulation in pluripotent cells. We identify SON as a regulator of exon 2 alternative splicing and report a patient carrying a SON mutation and suffering from insufficient telomerase and short telomeres. In summary, our study highlights a critical role for hTERT alternative splicing in the developmental regulation of telomerase and implicates defective splicing in telomere biology disorders.
Assuntos
Processamento Alternativo , Proteínas de Ligação a DNA/genética , Elementos Facilitadores Genéticos , Antígenos de Histocompatibilidade Menor/genética , Telomerase/genética , Homeostase do Telômero , Telômero/metabolismo , Blastocisto/metabolismo , Blastocisto/patologia , Diferenciação Celular , Pré-Escolar , Proteínas de Ligação a DNA/deficiência , Feminino , Células-Tronco Embrionárias Humanas/metabolismo , Células-Tronco Embrionárias Humanas/patologia , Humanos , Linhagem , Células-Tronco Pluripotentes/metabolismo , Células-Tronco Pluripotentes/patologia , Cultura Primária de Células , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Telomerase/deficiência , Telômero/patologiaRESUMO
Missense driver mutations in cancer are concentrated in a few hotspots1. Various mechanisms have been proposed to explain this skew, including biased mutational processes2, phenotypic differences3-6 and immunoediting of neoantigens7,8; however, to our knowledge, no existing model weighs the relative contribution of these features to tumour evolution. We propose a unified theoretical 'free fitness' framework that parsimoniously integrates multimodal genomic, epigenetic, transcriptomic and proteomic data into a biophysical model of the rate-limiting processes underlying the fitness advantage conferred on cancer cells by driver gene mutations. Focusing on TP53, the most mutated gene in cancer1, we present an inference of mutant p53 concentration and demonstrate that TP53 hotspot mutations optimally solve an evolutionary trade-off between oncogenic potential and neoantigen immunogenicity. Our model anticipates patient survival in The Cancer Genome Atlas and patients with lung cancer treated with immunotherapy as well as the age of tumour onset in germline carriers of TP53 variants. The predicted differential immunogenicity between hotspot mutations was validated experimentally in patients with cancer and in a unique large dataset of healthy individuals. Our data indicate that immune selective pressure on TP53 mutations has a smaller role in non-cancerous lesions than in tumours, suggesting that targeted immunotherapy may offer an early prophylactic opportunity for the former. Determining the relative contribution of immunogenicity and oncogenic function to the selective advantage of hotspot mutations thus has important implications for both precision immunotherapies and our understanding of tumour evolution.
Assuntos
Carcinogênese , Evolução Molecular , Neoplasias Pulmonares , Mutação , Carcinogênese/genética , Carcinogênese/imunologia , Conjuntos de Dados como Assunto , Genes p53 , Aptidão Genética , Genômica , Voluntários Saudáveis , Humanos , Imunoterapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Mutação/genética , Mutação de Sentido Incorreto , Reprodutibilidade dos TestesRESUMO
The choice to postpone treatment while awaiting genetic testing can result in significant delay in definitive therapies in patients with severe pancytopenia. Conversely, the misdiagnosis of inherited bone marrow failure (BMF) can expose patients to ineffectual and expensive therapies, toxic transplant conditioning regimens, and inappropriate use of an affected family member as a stem cell donor. To predict the likelihood of patients having acquired or inherited BMF, we developed a 2-step data-driven machine-learning model using 25 clinical and laboratory variables typically recorded at the initial clinical encounter. For model development, patients were labeled as having acquired or inherited BMF depending on their genomic data. Data sets were unbiasedly clustered, and an ensemble model was trained with cases from the largest cluster of a training cohort (n = 359) and validated with an independent cohort (n = 127). Cluster A, the largest group, was mostly immune or inherited aplastic anemia, whereas cluster B comprised underrepresented BMF phenotypes and was not included in the next step of data modeling because of a small sample size. The ensemble cluster A-specific model was accurate (89%) to predict BMF etiology, correctly predicting inherited and likely immune BMF in 79% and 92% of cases, respectively. Our model represents a practical guide for BMF diagnosis and highlights the importance of clinical and laboratory variables in the initial evaluation, particularly telomere length. Our tool can be potentially used by general hematologists and health care providers not specialized in BMF, and in under-resourced centers, to prioritize patients for genetic testing or for expeditious treatment.
Assuntos
Anemia Aplástica , Doenças da Medula Óssea , Pancitopenia , Humanos , Doenças da Medula Óssea/diagnóstico , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/terapia , Diagnóstico Diferencial , Anemia Aplástica/diagnóstico , Anemia Aplástica/genética , Anemia Aplástica/terapia , Transtornos da Insuficiência da Medula Óssea/diagnóstico , Pancitopenia/diagnósticoRESUMO
Short telomeres are a principal defining feature of telomere biology disorders, such as dyskeratosis congenita (DC), for which there are no effective treatments. Here, we report that primary fibroblasts from DC patients and late generation telomerase knockout mice display lower nicotinamide adenine dinucleotide (NAD) levels, and an imbalance in the NAD metabolome that includes elevated CD38 NADase and reduced poly(ADP-ribose) polymerase and SIRT1 activities, respectively, affecting many associated biological pathways. Supplementation with the NAD precursor, nicotinamide riboside, and CD38 inhibition improved NAD homeostasis, thereby alleviating telomere damage, defective mitochondrial biosynthesis and clearance, cell growth retardation, and cellular senescence of DC fibroblasts. These findings reveal a direct, underlying role of NAD dysregulation when telomeres are short and underscore its relevance to the pathophysiology and interventions of human telomere-driven diseases.
Assuntos
Disceratose Congênita/genética , Disceratose Congênita/metabolismo , Fibroblastos/metabolismo , NAD/metabolismo , Telomerase/genética , Telômero/metabolismo , ADP-Ribosil Ciclase 1/genética , Animais , Encéfalo/patologia , Linhagem Celular , Senescência Celular , Disceratose Congênita/patologia , Feminino , Homeostase , Humanos , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Niacinamida/análogos & derivados , Niacinamida/metabolismo , Fenótipo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Compostos de Piridínio/metabolismo , Telomerase/metabolismoRESUMO
Severe aplastic anaemia (SAA) is a rare and life-threatening bone marrow failure disorder. We used data from the transplant outcomes in aplastic anaemia study to characterize mosaic chromosomal alterations (mCAs) in the peripheral blood of 738 patients with acquired SAA and evaluate their associations with telomere length (TL) and survival post-haematopoietic cell transplant (HCT). The median age at HCT was 20.4 years (range = 0.2-77.4). Patients with SAA had shorter TL than expected for their age (median TL percentile for age: 35.7th; range <1-99.99). mCAs were detected in 211 patients (28.6%), with chr6p copy-neutral loss of heterozygosity (6p-CNLOH) in 15.9% and chr7 loss in 3.0% of the patients; chrX loss was detected in 4.1% of female patients. Negative correlations between mCA cell fraction and measured TL (r = -0.14, p = 0.0002), and possibly genetically predicted TL (r = -0.07, p = 0.06) were noted. The post-HCT 3-year survival probability was low in patients with chr7 loss (39% vs. 72% in patients with chr6-CNLOH, 60% in patients with other mCAs and 70% in patients with no mCAs; p-log rank = 0.001). In multivariable analysis, short TL (p = 0.01), but not chr7 loss (p = 0.29), was associated with worse post-HCT survival. TL may guide clinical decisions in patients with SAA.
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Li-Fraumeni syndrome (LFS), linked to heterozygous germline pathogenic/likely pathogenic variants in TP53, confers exceptionally high cancer risk, including core cancers (sarcoma, breast, adrenocortical, and brain cancer) among many other cancer types.1 Colorectal cancer (CRC) is most common after the core and hematologic cancers, accounting for â¼2.8% of diagnoses. Stomach and esophageal cancers constitute another 1.3% (TP53 Database; R20, July 2019: https://tp53.isb-cgc.org).2.
Assuntos
Neoplasias Gastrointestinais , Síndrome de Li-Fraumeni , Humanos , Síndrome de Li-Fraumeni/complicações , Síndrome de Li-Fraumeni/genética , Proteína Supressora de Tumor p53/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Neoplasias Gastrointestinais/epidemiologia , Neoplasias Gastrointestinais/etiologiaRESUMO
BACKGROUND AND AIMS: Dyskeratosis congenita (DC) and related telomere biology disorders (TBD) are characterized by very short telomeres and multisystem organ involvement including liver disease. Our study aimed to characterize baseline hepatic abnormalities in patients with DC/TBD and determine risk factors associated with liver disease progression. APPROACH AND RESULTS: A retrospective review was performed on a cohort of 58 patients (39 males) with DC/TBD who were prospectively evaluated at a single institute from 2002 to 2019. The median age at initial assessment was 18 (1.4-67.6) years, and median follow-up duration was 6 (1.4-8.2) years. Patients with autosomal or X-linked recessive inheritance and those with heterozygous TINF2 DC were significantly younger, predominantly male, and more likely to have DC-associated mucocutaneous triad features and severe bone marrow failure compared with autosomal dominant-non- TINF2 DC/TBD patients. Liver abnormality (defined at baseline assessment by laboratory and/or radiological findings) was present in 72.4% of patients with predominantly cholestatic pattern of liver enzyme elevation. Clinically significant liver disease and portal hypertension developed in 17.2% of patients during the 6-year follow-up; this progression was mainly seen in patients with recessive or TINF2 -associated DC. Significant risk factors associated with progression included the presence of pulmonary or vascular disease. CONCLUSIONS: Our experience shows a high prevalence of cholestatic pattern of liver abnormality with progression to portal hypertension in patients with DC/TBD. Presence of pulmonary and/or vascular disease in patients with recessive or TINF2 DC was an important predictor of liver disease progression, suggesting the need for increased vigilance and monitoring for complications in these patients.
Assuntos
Doenças do Sistema Digestório , Disceratose Congênita , Hipertensão Portal , Telomerase , Doenças Vasculares , Humanos , Masculino , Feminino , Disceratose Congênita/complicações , Disceratose Congênita/genética , Telômero/metabolismo , Hipertensão Portal/genética , Hipertensão Portal/complicações , Doenças Vasculares/complicações , Progressão da Doença , Biologia , Mutação , Telomerase/genética , Telomerase/metabolismoRESUMO
Dyskeratosis congenita related telomere biology disorders (DC/TBDs) are characterized by very short telomeres caused by germline pathogenic variants in telomere biology genes. Clinical presentations can affect all organs, and inheritance patterns include autosomal dominant (AD), autosomal recessive (AR), X-linked (XLR), or de novo. This study examined the associations between mode of inheritance with phenotypes and long-term clinical outcomes. Two hundred thirty-one individuals with DC/TBDs (144 male, 86.6% known genotype, median age at diagnosis 19.4 years [range 0 to 71.6]), enrolled in the National Cancer Institute's Inherited Bone Marrow Failure Syndrome Study, underwent detailed clinical assessments and longitudinal follow-up (median follow-up 5.2 years [range 0 to 36.7]). Patients were grouped by inheritance pattern, considering AD-nonTINF2, AR/XLR, and TINF2 variants separately. Severe bone marrow failure (BMF), severe liver disease, and gastrointestinal telangiectasias were more prevalent in AR/XLR or TINF2 disease, whereas pulmonary fibrosis developed predominantly in adults with AD disease. After adjusting for age at DC/TBD diagnosis, we observed the highest cancer risk in AR/XLR individuals. At last follow-up, 42% of patients were deceased with a median overall survival (OS) of 52.8 years (95% confidence interval [CI] 45.5-57.6), and the hematopoietic cell or solid organ transplant-free median survival was 45.3 years (95% CI 37.4-52.1). Significantly better OS was present in AD vs AR/XLR/TINF2 disease (P < .01), while patients with AR/XLR and TINF2 disease had similar survival probabilities. This long-term study of the clinical manifestations of DC/TBDs creates a foundation for incorporating the mode of inheritance into evidence-based clinical care guidelines and risk stratification in patients with DC/TBDs. This trial was registered at www.clinicaltrials.gov as #NCT00027274.
Assuntos
Disceratose Congênita , Telomerase , Biologia , Progressão da Doença , Disceratose Congênita/genética , Disceratose Congênita/terapia , Humanos , Masculino , Telomerase/genética , Telomerase/metabolismo , Telômero/genética , Telômero/metabolismo , Encurtamento do TelômeroRESUMO
Patients with severe aplastic anemia (SAA) can have an unrecognized inherited bone marrow failure syndrome (IBMFS) because of phenotypic heterogeneity. We curated germline genetic variants in 104 IBMFS-associated genes from exome sequencing performed on 732 patients who underwent hematopoietic cell transplant (HCT) between 1989 and 2015 for acquired SAA. Patients with pathogenic or likely pathogenic (P/LP) variants fitting known disease zygosity patterns were deemed unrecognized IBMFS. Carriers were defined as patients with a single P/LP variant in an autosomal recessive gene or females with an X-linked recessive P/LP variant. Cox proportional hazard models were used for survival analysis with follow-up until 2017. We identified 113 P/LP single-nucleotide variants or small insertions/deletions and 10 copy number variants across 42 genes in 121 patients. Ninety-one patients had 105 in silico predicted deleterious variants of uncertain significance (dVUS). Forty-eight patients (6.6%) had an unrecognized IBMFS (33% adults), and 73 (10%) were carriers. No survival difference between dVUS and acquired SAA was noted. Compared with acquired SAA (no P/LP variants), patients with unrecognized IBMFS, but not carriers, had worse survival after HCT (IBMFS hazard ratio [HR], 2.13; 95% confidence interval[CI], 1.40-3.24; P = .0004; carriers HR, 0.96; 95% CI, 0.62-1.50; P = .86). Results were similar in analyses restricted to patients receiving reduced-intensity conditioning (n = 448; HR IBMFS = 2.39; P = .01). The excess mortality risk in unrecognized IBMFS attributed to death from organ failure (HR = 4.88; P < .0001). Genetic testing should be part of the diagnostic evaluation for all patients with SAA to tailor therapeutic regimens. Carriers of a pathogenic variant in an IBMFS gene can follow HCT regimens for acquired SAA.
Assuntos
Anemia Aplástica , Transplante de Células-Tronco Hematopoéticas , Adulto , Anemia Aplástica/diagnóstico , Anemia Aplástica/genética , Anemia Aplástica/terapia , Síndrome Congênita de Insuficiência da Medula Óssea , Feminino , Testes Genéticos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Condicionamento Pré-Transplante/métodosRESUMO
Telomeres are the nucleoprotein complex at chromosome ends essential in genomic stability. Baseline telomere length (TL) is determined by rare and common germline genetic variants but shortens with age and is susceptible to certain environmental exposures. Cellular senescence or apoptosis are normally triggered when telomeres reach a critically short length, but cancer cells overcome these protective mechanisms and continue to divide despite chromosomal instability. Rare germline variants in telomere maintenance genes cause exceedingly short telomeres for age (< 1st percentile) and the telomere biology disorders, which are associated with elevated risks of bone marrow failure, myelodysplastic syndrome, acute myeloid leukemia, and squamous cell carcinoma of the head/neck and anogenital regions. Long telomeres due to rare germline variants in the same or different telomere maintenance genes are associated with elevated risks of other cancers, such as chronic lymphocytic leukemia or sarcoma. Early epidemiology studies of TL in the general population lacked reproducibility but new methods, including creation of a TL polygenic score using common variants, have found longer telomeres associated with excess risks of renal cell carcinoma, glioma, lung cancer, and others. It has become clear that when it comes to TL and cancer etiology, not too short, not too long, but "just right" telomeres are important in minimizing cancer risk.
Assuntos
Neoplasias , Telomerase , Humanos , Reprodutibilidade dos Testes , Telômero/genética , Encurtamento do Telômero , Senescência Celular , Instabilidade Genômica , Telomerase/genética , Neoplasias/genética , Neoplasias/patologiaRESUMO
People with transient epileptic amnesia (TEA) experience deficits in memory, however, little is known about their everyday experience of this, and no memory intervention studies have been conducted within this group. Using a two-part qualitative method, this study explored the lived experience of people with TEA and possible avenues for memory intervention. Fourteen people with TEA participated in either a focus group (n = 7) or an online survey (n = 7) to answer questions regarding their memory difficulties, impact on their lives, and strategies to mitigate these problems. Perceived barriers and facilitators to participating in a group memory intervention program were discussed. Thematic content analysis identified key themes regarding impacts on the individual and their relationships. Although some positive outcomes regarding family support and personal acceptance were described, most participants described negative impacts on relationships and mood. A range of strategies to mitigate memory problems were reported, although some people did not use any. Participants identified practical and socio-emotional advantages to memory intervention, with perceived barriers around individual applicability, preferences, and ability to engage. While individual preferences need to be considered, a group-based memory intervention may help address cognitive and mental health concerns, particularly for those newly diagnosed with TEA.
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Severe aplastic anemia (SAA) is a rare disorder characterized by hypoplastic bone marrow and progressive pancytopenia. The etiology of acquired SAA is not understood but is likely related to abnormal immune responses and environmental exposures. We conducted a genome-wide association study of individuals with SAA genetically matched to healthy controls in discovery (359 cases, 1,396 controls) and validation sets (175 cases, 1,059 controls). Combined analyses identified linked SNPs in distinct blocks within the major histocompatibility complex on 6p21. The top SNP encodes p.Met76Val in the P4 binding pocket of the HLA class II gene HLA-DPB1 (rs1042151A>G, odds ratio [OR] 1.75, 95% confidence interval [CI] 1.50-2.03, p = 1.94 × 10-13) and was associated with HLA-DP cell surface expression in healthy individuals (p = 2.04 × 10-6). Phylogenetic analyses indicate that Val76 is not monophyletic and likely occurs in conjunction with different HLA-DP binding groove conformations. Imputation of HLA-DPB1 alleles revealed increased risk of SAA associated with Val76-encoding alleles DPB1∗03:01, (OR 1.66, p = 1.52 × 10-7), DPB1∗10:01 (OR 2.12, p = 0.0003), and DPB1∗01:01 (OR 1.60, p = 0.0008). A second SNP near HLA-B, rs28367832G>A, reached genome-wide significance (OR 1.49, 95% CI 1.22-1.78, p = 7.27 × 10-9) in combined analyses; the association remained significant after excluding cases with clonal copy-neutral loss-of-heterozygosity affecting class I HLA genes (8.6% of cases and 0% of controls). SNPs in the HLA class II gene HLA-DPB1 and possibly class I (HLA-B) are associated with SAA. The replacement of Met76 to Val76 in certain HLA-DPB1 alleles might influence risk of SAA through mechanisms involving DP peptide binding specificity, expression, and/or other factors affecting DP function.
Assuntos
Anemia Aplástica/etiologia , Marcadores Genéticos , Predisposição Genética para Doença , Cadeias beta de HLA-DP/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Anemia Aplástica/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Filogenia , Fatores de Risco , Índice de Gravidade de Doença , Adulto JovemRESUMO
Individuals with telomere biology disorders (TBDs) have very short telomeres, high risk of bone marrow failure (BMF), and reduced survival. Using data from TBD patients, a mean leukocyte Southern blot telomere length (TL) of 5 kilobases (kb) was estimated as the 'telomere brink' at which human survival is markedly reduced. However, the shortest telomere, not the mean TL, signals replicative senescence. We used the Telomere Shortest Length Assay (TeSLA) to tally TL of all 46 chromosomes in blood-derived DNA and examined its relationship with TBDs. Patients (n = 18) had much shorter mean TL (TeSmTL) (2.54 ± 0.41 kb vs. 4.48 ± 0.52 kb, p < 0.0001) and more telomeres <3 kb than controls (n = 22) (70.43 ± 8.76% vs. 33.05 ± 6.93%, p < 0.0001). The proportion of ultrashort telomeres (<1.6 kb) was also higher in patients than controls (39.29 ± 10.69% vs. 10.40 ± 4.09%, p < 0.0001). TeS <1.6 kb was associated with severe (n = 11) compared with non-severe (n = 7) BMF (p = 0.027). Patients with multi-organ manifestations (n = 10) had more telomeres <1.6 kb than those with one affected organ system (n = 8) (p = 0.029). Findings suggest that TBD clinical manifestations are associated with a disproportionately higher number of haematopoietic cell telomeres reaching a telomere brink, whose length at the single telomere level is yet to be determined.
Assuntos
Transtornos da Insuficiência da Medula Óssea , Disceratose Congênita , Pancitopenia , Humanos , Biologia , Disceratose Congênita/genética , Telômero/genética , Encurtamento do TelômeroRESUMO
De novo mutations (DNMs) are increasingly recognized as rare disease causal factors. Identifying DNM carriers will allow researchers to study the likely distinct molecular mechanisms of DNMs. We developed Famdenovo to predict DNM status (DNM or familial mutation [FM]) of deleterious autosomal dominant germline mutations for any syndrome. We introduce Famdenovo.TP53 for Li-Fraumeni syndrome (LFS) and analyze 324 LFS family pedigrees from four US cohorts: a validation set of 186 pedigrees and a discovery set of 138 pedigrees. The concordance index for Famdenovo.TP53 prediction was 0.95 (95% CI: [0.92, 0.98]). Forty individuals (95% CI: [30, 50]) were predicted as DNM carriers, increasing the total number from 42 to 82. We compared clinical and biological features of FM versus DNM carriers: (1) cancer and mutation spectra along with parental ages were similarly distributed; (2) ascertainment criteria like early-onset breast cancer (age 20-35 yr) provides a condition for an unbiased estimate of the DNM rate: 48% (23 DNMs vs. 25 FMs); and (3) hotspot mutation R248W was not observed in DNMs, although it was as prevalent as hotspot mutation R248Q in FMs. Furthermore, we introduce Famdenovo.BRCA for hereditary breast and ovarian cancer syndrome and apply it to a small set of family data from the Cancer Genetics Network. In summary, we introduce a novel statistical approach to systematically evaluate deleterious DNMs in inherited cancer syndromes. Our approach may serve as a foundation for future studies evaluating how new deleterious mutations can be established in the germline, such as those in TP53.
Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Síndrome de Li-Fraumeni/genética , Neoplasias Ovarianas/genética , Adulto , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/diagnóstico , Família , Feminino , Humanos , Linhagem , Proteína Supressora de Tumor p53/genética , Adulto JovemRESUMO
Telomeres are DNA-protein structures at the ends of chromosomes essential in maintaining chromosomal stability. Observational studies have identified associations between telomeres and elevated cancer risk, including hematologic malignancies; but biologic mechanisms relating telomere length to cancer etiology remain unclear. Our study sought to better understand the relationship between telomere length and cancer risk by evaluating genetically-predicted telomere length (gTL) in relation to the presence of clonal somatic copy number alterations (SCNAs) in peripheral blood leukocytes. Genotyping array data were acquired from 431,507 participants in the UK Biobank and used to detect SCNAs from intensity information and infer telomere length using a polygenic risk score (PRS) of variants previously associated with leukocyte telomere length. In total, 15,236 (3.5%) of individuals had a detectable clonal SCNA on an autosomal chromosome. Overall, higher gTL value was positively associated with the presence of an autosomal SCNA (OR = 1.07, 95% CI = 1.05-1.09, P = 1.61×10-15). There was high consistency in effect estimates across strata of chromosomal event location (e.g., telomeric ends, interstitial or whole chromosome event; Phet = 0.37) and strata of copy number state (e.g., gain, loss, or neutral events; Phet = 0.05). Higher gTL value was associated with a greater cellular fraction of clones carrying autosomal SCNAs (ß = 0.004, 95% CI = 0.002-0.007, P = 6.61×10-4). Our population-based examination of gTL and SCNAs suggests inherited components of telomere length do not preferentially impact autosomal SCNA event location or copy number status, but rather likely influence cellular replicative potential.
Assuntos
Evolução Clonal/genética , Neoplasias/sangue , Homeostase do Telômero/genética , Telômero/genética , Adulto , Idoso , Divisão Celular/genética , Variações do Número de Cópias de DNA/genética , Feminino , Genética Populacional , Humanos , Leucócitos/metabolismo , Leucócitos/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/genética , Reino Unido/epidemiologiaRESUMO
Word retraining techniques can improve picture naming of treated items in people with semantic dementia (SD). The utility of this, however, has been questioned given the propensity for under- and overgeneralization errors in naming in SD. Few studies have investigated the occurrence of such errors. This study examined whether, following tailored word retraining: (1) misuse of words increases, (2) the type of naming errors changes, and/or (3) clarity of communication is reduced. Performance on trained and untrained word naming from nine participants with SD who completed a word retraining programme were analysed. Responses from baseline and post-intervention assessments were coded for misuse (i.e., trained word produced for another target item), error type, and communication clarity. All participants showed significant improvement for trained vocabulary. There was no significant increase in misuse of words, with such errors occurring rarely. At a group level, there was an increased tendency toward omission errors for untrained items, and a reduction in semantically related responses. However, this did not impact on clarity scores with no consistent change across participants. In sum, we found no negative impacts following tailored word retraining, providing further evidence of the benefit of these programmes for individuals with SD.
Assuntos
Demência Frontotemporal , Vocabulário , Humanos , Comunicação , SemânticaRESUMO
Word retraining programs have been shown to improve naming ability post-stroke and in progressive aphasias. Here, we investigated benefits for a 22-year-old Danish man (DJ), whose difficulties followed brain damage from heavy alcohol misuse. Using a multiple baseline-across-behaviours design (target behaviour: retrieval of word list items), DJ completed a 4-week "Look, Listen, Repeat" program on a computer. Ninety personally relevant target words were selected to create three matched lists. List 1 was trained for 10 sessions over 2 weeks, followed by 9 sessions for List 2 over 2 weeks, while the third list remained untrained. Naming performance was evaluated at baseline, during the intervention, and at 1 and 4 months post-training. Naming improved following each intervention block (p < .001), with only one data point overlapping between the baseline and treatment phases for trained items. Untrained words remained unchanged (p = 1.00), with 50% of data points non-overlapping across baseline to treatment phases. Performance was maintained over time, and appeared to generalize, with DJ naming more trained objects in their natural setting (85%) than untrained items (64%). While more evidence is needed, brief (20-minute), intensive (5-day/week) word retraining programs may assist word retrieval for people with brain damage associated with alcohol misuse.
Assuntos
Alcoolismo , Afasia , Lesões Encefálicas , Acidente Vascular Cerebral , Masculino , Humanos , Adulto Jovem , Adulto , Projetos de Pesquisa , Alcoolismo/complicações , Afasia/complicações , Acidente Vascular Cerebral/complicações , Lesões Encefálicas/complicações , EncéfaloRESUMO
Next-generation sequencing (NGS) is a valuable tool, but has limitations in sequencing through repetitive runs of single nucleotides (homopolymers). Pathogenic germline variants in WRAP53 encoding telomere Cajal body protein 1 (TCAB1) are a known cause of dyskeratosis congenita. We identified a significant NGS error in WRAP53, c.1562dup, p.Ala522Glyfs*8 (rs755116516 G>-/GG/GGG) that did not validate by Sanger sequencing. This error occurs because rs755116516 G>-/GG/GGG (Chr17:7,606,714) is polymorphic, and variants at this site challenge the ability of NGS to accurately call the correct number of nucleotides in a homopolymer run. This was further complicated by the fact that chr17:7,606,721 (rs769202794) is multiallelic G>A, C, T, and that chr17:7,606,722 is also multiallelic (rs7640C>A/G/T and rs373064567C>delC). In addition to the expert interpretation of potentially clinically actionable variants, it recommended that all variants in regions of the genome with homopolymers be validated by Sanger sequencing before clinical action.
Assuntos
Cromossomos Humanos Par 17 , Disceratose Congênita , Chaperonas Moleculares , Telomerase , Humanos , Cromossomos Humanos Par 17/genética , Disceratose Congênita/genética , Variação Genética , Mutação em Linhagem Germinativa/genética , Sequenciamento de Nucleotídeos em Larga Escala , Análise de Sequência de DNA , Chaperonas Moleculares/genética , Telomerase/genéticaRESUMO
PURPOSE: Women with Li-Fraumeni Syndrome (LFS) often consider risk-reducing mastectomy (RRM) due to extremely high risk of breast cancer at early ages. Data on uptake of RRM in LFS are scarce, and are inferred from experience in women with pathogenic variants (PVs) in BRCA1/2, despite differences in cancer risks. This study evaluated RRM uptake in a cohort of women with LFS. METHODS: Women (n = 205) with LFS enrolled in NCI's LFS study reported lifetime cancer diagnoses and mastectomies and completed questionnaires regarding reproductive history, cancer worry and risk perceptions. A subset of women participating in an annual cancer screening study received counseling regarding RRM. RESULTS: 65% (n = 71) of women diagnosed with presumed unilateral breast cancer (n = 109) underwent contralateral RRM over their lifetime. Nearly half (49%, n = 25) of the women who did not complete contralateral RRM within one year of their breast cancer diagnosis (n = 51) developed contralateral breast cancer (median interval = 6 years). Only 18.5% (n = 15) of women without breast cancer history (n = 81) underwent bilateral RRM. Median age at bilateral RRM of 39 years was sub-optimal for breast cancer risk reduction. Contralateral RRM was associated with early genetic diagnosis, participation in the screening study, and fewer prior cancers. Bilateral RRM uptake was associated with having had children, having breastfed, and high cancer worry. CONCLUSION: Uptake of contralateral RRM is high in women with LFS. The frequency of contralateral breast cancer necessitates active discussion of benefits of contralateral RRM and counseling regarding bilateral RRM should be tailored to the early age at risk of breast cancer onset in LFS. There is a need for research into the survival and long-term benefits of RRM in LFS.