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The zinc-finger protein Zelda (Zld) is a key activator of zygotic transcription in early Drosophila embryos. Here, we study Zld-dependent regulation of the seven-striped pattern of the pair-rule gene even-skipped (eve). Individual stripes are regulated by discrete enhancers that respond to broadly distributed activators; stripe boundaries are formed by localized repressors encoded by the gap genes. The strongest effects of Zld are on stripes 2, 3 and 7, which are regulated by two enhancers in a 3.8â kb genomic fragment that includes the eve basal promoter. We show that Zld facilitates binding of the activator Bicoid and the gap repressors to this fragment, consistent with its proposed role as a pioneer protein. To test whether the effects of Zld are direct, we mutated all canonical Zld sites in the 3.8â kb fragment, which reduced expression but failed to phenocopy the abolishment of stripes caused by removing Zld in trans. We show that Zld also indirectly regulates the eve stripes by establishing specific gap gene expression boundaries, which provides the embryonic spacing required for proper stripe activation.
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Proteínas de Drosophila , Animais , Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Proteínas de Drosophila/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/metabolismo , Regiões Promotoras Genéticas/genética , Fatores de Transcrição/metabolismoRESUMO
The K50 (lysine at amino acid position 50) homeodomain (HD) protein Orthodenticle (Otd) is critical for anterior patterning and brain and eye development in most metazoans. In Drosophila melanogaster, another K50HD protein, Bicoid (Bcd), has evolved to replace Otd's ancestral function in embryo patterning. Bcd is distributed as a long-range maternal gradient and activates transcription of a large number of target genes, including otd Otd and Bcd bind similar DNA sequences in vitro, but how their transcriptional activities are integrated to pattern anterior regions of the embryo is unknown. Here we define three major classes of enhancers that are differentially sensitive to binding and transcriptional activation by Bcd and Otd. Class 1 enhancers are initially activated by Bcd, and activation is transferred to Otd via a feed-forward relay (FFR) that involves sequential binding of the two proteins to the same DNA motif. Class 2 enhancers are activated by Bcd and maintained by an Otd-independent mechanism. Class 3 enhancers are never bound by Bcd, but Otd binds and activates them in a second wave of zygotic transcription. The specific activities of enhancers in each class are mediated by DNA motif variants preferentially bound by Bcd or Otd and the presence or absence of sites for cofactors that interact with these proteins. Our results define specific patterning roles for Bcd and Otd and provide mechanisms for coordinating the precise timing of gene expression patterns during embryonic development.
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Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/embriologia , Drosophila melanogaster/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Transativadores/genética , Transativadores/metabolismo , Motivos de Aminoácidos , Animais , Padronização Corporal/genética , Drosophila melanogaster/metabolismo , Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Embrionário/genética , Elementos Facilitadores Genéticos/genética , Ligação ProteicaRESUMO
Histone acetyltransferases (HATs) are implicated as both oncogene and nononcogene dependencies in diverse human cancers. Acetyl-CoA-competitive HAT inhibitors have emerged as potential cancer therapeutics and the first clinical trial for this class of drugs is ongoing (NCT04606446). Despite these developments, the potential mechanisms of therapeutic response and evolved drug resistance remain poorly understood. Having discovered that multiple regulators of de novo coenzyme A (CoA) biosynthesis can modulate sensitivity to CBP/p300 HAT inhibition (PANK3, PANK4 and SLC5A6), we determined that elevated acetyl-CoA concentrations can outcompete drug-target engagement to elicit acquired drug resistance. This not only affects structurally diverse CBP/p300 HAT inhibitors, but also agents related to an investigational KAT6A/B HAT inhibitor that is currently in Phase 1 clinical trials. Altogether, this work uncovers CoA metabolism as an unexpected liability of anticancer HAT inhibitors and will therefore buoy future efforts to optimize the efficacy of this new form of targeted therapy.
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Histona Acetiltransferases , Neoplasias , Humanos , Histona Acetiltransferases/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo , Acetilcoenzima A/metabolismo , Ligação ProteicaRESUMO
OBJECTIVE: To provide an understanding of the role of common genetic variations in colorectal cancer (CRC) risk, we report an updated field synopsis and comprehensive assessment of evidence to catalogue all genetic markers for CRC (CRCgene2). DESIGN: We included 869 publications after parallel literature review and extracted data for 1063 polymorphisms in 303 different genes. Meta-analyses were performed for 308 single nucleotide polymorphisms (SNPs) in 158 different genes with at least three independent studies available for analysis. Scottish, Canadian and Spanish data from genome-wide association studies (GWASs) were incorporated for the meta-analyses of 132 SNPs. To assess and classify the credibility of the associations, we applied the Venice criteria and Bayesian False-Discovery Probability (BFDP). Genetic associations classified as 'positive' and 'less-credible positive' were further validated in three large GWAS consortia conducted in populations of European origin. RESULTS: We initially identified 18 independent variants at 16 loci that were classified as 'positive' polymorphisms for their highly credible associations with CRC risk and 59 variants at 49 loci that were classified as 'less-credible positive' SNPs; 72.2% of the 'positive' SNPs were successfully replicated in three large GWASs and the ones that were not replicated were downgraded to 'less-credible' positive (reducing the 'positive' variants to 14 at 11 loci). For the remaining 231 variants, which were previously reported, our meta-analyses found no evidence to support their associations with CRC risk. CONCLUSION: The CRCgene2 database provides an updated list of genetic variants related to CRC risk by using harmonised methods to assess their credibility.
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Neoplasias Colorretais/genética , Polimorfismo de Nucleotídeo Único , Proteínas Adaptadoras de Transdução de Sinal/genética , Antígenos CD/genética , Proteína Morfogenética Óssea 2/genética , Caderinas/genética , DNA Glicosilases/genética , Estudos de Associação Genética , Loci Gênicos , Humanos , Proteína Smad7/genética , Telomerase/genética , Fator de Crescimento Transformador beta1/genéticaRESUMO
Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.
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Cromossomos Humanos Par 13 , Cromossomos Humanos Par 20 , Neoplasias da Bexiga Urinária/genética , População Branca/genética , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Neoplasias da Bexiga Urinária/etnologiaRESUMO
Myeloma is one of the most common malignancies that results in osteolytic lesions of the spine. Complications, including pathological fractures of the vertebrae and spinal cord compression, may cause severe pain, deformity and neurological sequelae. They may also have significant consequences for quality of life and prognosis for patients. For patients with known or newly diagnosed myeloma presenting with persistent back or radicular pain/weakness, early diagnosis of spinal myeloma disease is therefore essential to treat and prevent further deterioration. Magnetic resonance imaging is the initial imaging modality of choice for the evaluation of spinal disease. Treatment of the underlying malignancy with systemic chemotherapy together with supportive bisphosphonate treatment reduces further vertebral damage. Additional interventions such as cement augmentation, radiotherapy, or surgery are often necessary to prevent, treat and control spinal complications. However, optimal management is dependent on the individual nature of the spinal involvement and requires careful assessment and appropriate intervention throughout. This article reviews the treatment and management options for spinal myeloma disease and highlights the value of defined pathways to enable the proper management of patients affected by it.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Difosfonatos/uso terapêutico , Imageamento por Ressonância Magnética , Mieloma Múltiplo , Neoplasias da Coluna Vertebral , Feminino , Humanos , Masculino , Mieloma Múltiplo/diagnóstico por imagem , Mieloma Múltiplo/tratamento farmacológico , Radiografia , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias da Coluna Vertebral/tratamento farmacológicoRESUMO
Adolescent idiopathic scoliosis (AIS) affects between 0.5% and 5.2% of adolescents and is progressive in two-thirds of cases. Bracing is an effective non-operative treatment for AIS and has been shown to prevent up to 72% of curves from requiring surgery. This paper explores the presentation of AIS in the UK and identifies who would be suitable for bracing, as per guidelines published by the Scoliosis Research Society (SRS) and British Scoliosis Society (BSS), through curve severity and skeletal maturity at presentation. There were 526 patients with AIS eligible for inclusion across three tertiary referral centres in the UK. The study period was individualised to each centre, between January 2012 and December 2021. Only 10% were appropriate for bracing via either SRS or BSS criteria. The rest were either too old, skeletally mature or had a curve size too large to benefit. By the end of data collection, 38% had undergone surgery for their scoliosis. In the UK, bracing for AIS is only suitable for a small number at presentation. Future efforts to minimise delays in specialist review and intervention will increase the number of those with AIS suitable for bracing and reduce the number and burden of operative interventions for AIS in the UK.
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Introduction: Tomita En-bloc spondylectomy of L5 is one of the most challenging techniques in radical oncological spine surgery. A 42-year-old female was referred with lower back pain and L5 radiculopathy with a background of right shoulder liposarcoma excision. CT-PET confirmed a solitary L5 oligometastasis. MRI showed thecal sac indentation hence wasn't suitable for Stereotactic Ablative Radiotherapy (SABR) alone. The seeding nature of sarcoma prevents the indication of separation surgery hence excisional surgery is considered for radical curative treatment. This case report demonstrates dual-staged modified TES including the utilisation of novel techniques to allow for maximum radical oncological control in the era of SABR and lesser invasive surgery. Methods: First-stage: Carbonfibre pedicle screws planned from L2 to S2AI-Pelvis, aligned, to her patient-specific rods. Radiofrequency ablation of L5 pedicles prior to osteotomy was performed to prevent sarcoma cell seeding. Microscope-assisted thecal sac tumour separation and L5 nerve root dissection was performed. Novel surgical navigation of the ultrasonic bone-cutter assisted inferior L4 and superior S1 endplate osteotomies. Second-stage: Vascular-assisted retroperitoneal approach at L4-S1 was undertaken protecting the great vessels. Completion of osteotomies at L4 and S1 to En-bloc L5: (L4 inferior endplate, L4/5 disc, L5 body, L5/S1 disc and S1 superior endplate). Anterior reconstruction used an expandable PEEK cage obviating the need for a third posterior stage. Reinforced with a patient-specific carbon plate L4-S1 promontory. Results: Patient rehabilitated well and was discharged after 42 days. Cyberknife of 30Gy in 5 fractions was delivered two months post-op. Despite left foot drop, she's walking independently 9 months post-op. Conclusion: These are challenging cases require a truly multi-disciplinary team approach. We share this technique for a dual stage TES and metal-free construct with post adjuvant SABR to achieve maximum local control in spinal oligometastatic disease. This case promotes our modified TES technique in the era of SABR and separation surgery in carefully selected cases.
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STUDY DESIGN: A retrospective analysis of oncologist-provided prognoses vs actual survival outcomes of patients referred with Metastatic spinal cord compression (MSCC) to a supra-regional multidisciplinary team (MDT). OBJECTIVES: Prognostic scoring systems, such as the revised Tokuhashi, are commonly used to help guide the treatment of MSCC. However, scoring systems do not accommodate for the improved outcomes of contemporary cancer therapy. Oncologist-provided prognoses play an important role in real world rapid decision making. There is a paucity of evidence assessing the accuracy of the oncologist-provided prognosis. We conducted a retrospective study to evaluate this. METHODS: Data was captured between January 2015 and December 2018. Patients were split into 2 groups: Group 1 (prognosis estimated <6 months) and Group 2 (prognosis estimated >6 months). Median overall survival (mOS) and hazard ratio for death (HR) was assessed. Receiver operating characteristic (ROC) analysis was performed to assess the accuracy of the oncologist's prognosis. RESULTS: 829 patients were included. mOS in Group 1 was 5.8 months (95% CI 4.2-7.4 m), and in Group 2 mOS was not reached. Log rank test gave a Chi2 of 131 (P < .001). Cox regression analysis revealed a HR of .30 (P < .001). Area under the ROC curve was 78%. CONCLUSIONS: Oncologist-provided prognosis is accurate in this cohort of unselected, consecutive MSCC patients. It reduced reliance on scoring systems that can become outdated. Given the rapid progress in cancer treatment, the oncologist's prognostic prediction is integral in efficient and effective MSCC management to help rapidly determine surgical candidacy.
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Transcriptional co-regulators have been widely pursued as targets for disrupting oncogenic gene regulatory programs. However, many proteins in this target class are universally essential for cell survival, which limits their therapeutic window. Here we unveil a genetic interaction between histone deacetylase 1 (HDAC1) and HDAC2, wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal deletions that occur in diverse solid and hematological malignancies, including neuroblastoma and multiple myeloma. Using genetic disruption or dTAG-mediated degradation, we show that targeting HDAC2 suppresses the growth of HDAC1-deficient neuroblastoma in vitro and in vivo. Mechanistically, we find that targeted degradation of HDAC2 in these cells prompts the degradation of several members of the nucleosome remodeling and deacetylase (NuRD) complex, leading to diminished chromatin accessibility at HDAC2-NuRD-bound sites of the genome and impaired control of enhancer-associated transcription. Furthermore, we reveal that several of the degraded NuRD complex subunits are dependencies in neuroblastoma and multiple myeloma, providing motivation to develop paralog-selective HDAC1 or HDAC2 degraders that could leverage HDAC1/2 synthetic lethality to target NuRD vulnerabilities. Altogether, we identify HDAC1/2 collateral synthetic lethality as a potential therapeutic target and reveal an unexplored mechanism for targeting NuRD-associated cancer dependencies.
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Mieloma Múltiplo , Neuroblastoma , Humanos , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo , Mieloma Múltiplo/genética , Regulação da Expressão Gênica , Nucleossomos , Neuroblastoma/genética , Histona Desacetilase 2/genética , Histona Desacetilase 2/metabolismoRESUMO
BACKGROUND: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC. OBJECTIVES: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. METHODS: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). RESULTS: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. CONCLUSIONS: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.
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Neoplasias Colorretais , Ácido Fólico , Humanos , Ácido Fólico/metabolismo , Fatores de Risco , Neoplasias Colorretais/genética , Estudos de Casos e Controles , Suplementos NutricionaisRESUMO
BACKGROUND: Genomic regions identified by genome-wide association studies (GWAS) for bladder cancer risk provide new insights into etiology. OBJECTIVE: To identify new susceptibility variants for bladder cancer in a meta-analysis of new and existing genome-wide genotype data. DESIGN, SETTING, AND PARTICIPANTS: Data from 32 studies that includes 13,790 bladder cancer cases and 343,502 controls of European ancestry were used for meta-analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Log-additive associations of genetic variants were assessed using logistic regression models. A fixed-effects model was used for meta-analysis of the results. Stratified analyses were conducted to evaluate effect modification by sex and smoking status. A polygenic risk score (PRS) was generated on the basis of known and novel susceptibility variants and tested for interaction with smoking. RESULTS AND LIMITATIONS: Multiple novel bladder cancer susceptibility loci (6p.22.3, 7q36.3, 8q21.13, 9p21.3, 10q22.1, 19q13.33) as well as improved signals in three known regions (4p16.3, 5p15.33, 11p15.5) were identified, bringing the number of independent markers at genome-wide significance (p < 5 × 10-8) to 24. The 4p16.3 (FGFR3/TACC3) locus was associated with a stronger risk for women than for men (p-interaction = 0.002). Bladder cancer risk was increased by interactions between smoking status and genetic variants at 8p22 (NAT2; multiplicative p value for interaction [pM-I] = 0.004), 8q21.13 (PAG1; pM-I = 0.01), and 9p21.3 (LOC107987026/MTAP/CDKN2A; pM-I = 0.02). The PRS based on the 24 independent GWAS markers (odds ratio per standard deviation increase 1.49, 95% confidence interval 1.44-1.53), which also showed comparable results in two prospective cohorts (UK Biobank, PLCO trial), revealed an approximately fourfold difference in the lifetime risk of bladder cancer according to the PRS (e.g., 1st vs 10th decile) for both smokers and nonsmokers. CONCLUSIONS: We report novel loci associated with risk of bladder cancer that provide clues to its biological underpinnings. Using 24 independent markers, we constructed a PRS to stratify lifetime risk. The PRS combined with smoking history, and other established risk factors, has the potential to inform future screening efforts for bladder cancer. PATIENT SUMMARY: We identified new genetic markers that provide biological insights into the genetic causes of bladder cancer. These genetic risk factors combined with lifestyle risk factors, such as smoking, may inform future preventive and screening strategies for bladder cancer.
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Arilamina N-Acetiltransferase , Neoplasias da Bexiga Urinária , Masculino , Humanos , Feminino , Estudo de Associação Genômica Ampla , Estudos Prospectivos , Fatores de Risco , Genótipo , Neoplasias da Bexiga Urinária/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Proteínas Associadas aos Microtúbulos , Proteínas de Membrana , Proteínas Adaptadoras de Transdução de SinalRESUMO
AIMS: Vertebral body tethering (VBT) is a non-fusion technique to correct scoliosis. It allows correction of scoliosis through growth modulation (GM) by tethering the convex side to allow concave unrestricted growth similar to the hemiepiphysiodesis concept. The other modality is anterior scoliosis correction (ASC) where the tether is able to perform most of the correction immediately where limited growth is expected. METHODS: We conducted a retrospective analysis of clinical and radiological data of 20 patients aged between 9 and 17 years old, (with a 19 female: 1 male ratio) between January 2014 to December 2016 with a mean five-year follow-up (4 to 7). RESULTS: There were ten patients in each group with a total of 23 curves operated on. VBT-GM mean age was 12.5 years (9 to 14) with a mean Risser classification of 0.63 (0 to 2) and VBT-ASC was 14.9 years (13 to 17) with a mean Risser classification of 3.66 (3 to 5). Mean preoperative VBT-GM Cobb was 47.4° (40° to 58°) with a Fulcrum unbend of 17.4 (1° to 41°), compared to VBT-ASC 56.5° (40° to 79°) with 30.6 (2° to 69°)unbend. Postoperative VBT-GM was 20.3° and VBT-ASC Cobb angle was 11.2°. The early postoperative correction rate was 54.3% versus 81% whereas Fulcrum Bending Correction Index (FBCI) was 93.1% vs 146.6%. The last Cobb angle on radiograph at mean five years' follow-up was 19.4° (VBT-GM) and 16.5° (VBT-ASC). Patients with open triradiate cartilage (TRC) had three over-corrections. Overall, 5% of patients required fusion. This one patient alone had a over-correction, a second-stage tether release, and final conversion to fusion. CONCLUSION: We show a high success rate (95%) in helping children avoid fusion at five years post-surgery. VBT is a safe technique for correction of scoliosis in the skeletally immature patient. This is the first report at five years that shows two methods of VBT can be employed depending on the skeletal maturity of the patient: GM and ASC. Cite this article: Bone Jt Open 2022;3(2):123-129.
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BACKGROUND: In the management of a trauma patient with cervical spine injury, the need for accurate diagnostic imaging is key to ensure correct management. Different classification systems have been developed including the Subaxial Injury Classification (SLIC) system and AO cervical spine fracture classification. Through a multicentre study, we have identified a group of cases where the use of CT alone to classify fractures by either SLIC or AO score may be deficient and the use of dynamic cervical spine radiographs could help identify instability. METHODS: Three level 1 trauma centers retrospectively reviewed patients with cervical spine injuries. Cervical spine radiographs (AP and lateral) were undertaken in collar, in all patients with suspected cervical spine injury within 2 weeks, followed by reanalysis of scoring systems. RESULTS: Eleven cases were identified in total, and 72% were male with a mean age of 65 years, with approximately 54% being older than 70 years. All patients reported their pain as severe using the Visual Analogue Scale scale. The predynamic radiograph mean SLIC score was 0.73, which is in contrast to the postdynamic radiograph mean SLIC score of 6. The statistical significance (P = 0.004) was found using the Wilcoxon signed-rank test. CONCLUSION: Supine imaging eliminates the gravitational loads normally exerted on the c-spine. The cases show assumed cervical stability based on CT, but dynamic c-spine radiographs subsequently demonstrated instability. Therefore, we suggest a combination of SLIC and AO classification using radiologic imaging to classify fracture and correlate clinical symptoms with persistent neck pain, which warrants a Miami-J collar and dynamic c-spine radiograph to assess stability with re-evaluation of scoring.
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Lesões do Pescoço , Fraturas da Coluna Vertebral , Traumatismos da Coluna Vertebral , Humanos , Masculino , Idoso , Feminino , Estudos Retrospectivos , Fraturas da Coluna Vertebral/diagnóstico por imagem , Traumatismos da Coluna Vertebral/diagnóstico por imagem , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/lesões , RadiografiaRESUMO
The XPC gene is involved in repair of bulky DNA adducts formed by carcinogenic metabolites and oxidative DNA damage, both known bladder cancer risk factors. Single nucleotide polymorphisms (SNPs) in XPC have been associated with increased bladder cancer risk. Recently, rarer genetic variants have been identified but it is difficult to ascertain which are of functional importance. During a mutation screen of XPC in DNA from 33 bladder tumour samples and matched blood samples, we identified five novel variants in the patients' germ line DNA. In a case-control study of 771 bladder cancer cases and 800 controls, c.905T>C (Phe302Ser), c.1177C>T (Arg393Trp), c.*156G>A [3' untranslated region (UTR)] and c.2251-37C>A (in an intronic C>G SNP site) were found to be rare variants, with a combined odds ratio of 3.1 (95% confidence interval 1.0-9.8, P=0.048) for carriage of one variant. The fifth variant was a 2% minor allele frequency SNP not associated with bladder cancer. The two non-synonymous coding variants were predicted to have functional effects using analytical algorithms; a reduced recruitment of GFP-tagged XPC plasmids containing either c.905T>C or c.1177C>T to sites of 408 nm wavelength laser-induced oxidative DNA damage was found in vitro. c.*156G>A appeared to be associated with reduced messenger RNA stability in an in vitro plasmid-based assay. Although the laser microbeam assay is relevant to a range of DNA repair genes, our 3' UTR assay based on Green fluorescent protein(GFP) has widespread applicability and could be used to assess any gene. These assays may be useful in determining which rare variants are functional, prior to large genotyping efforts.
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Proteínas de Ligação a DNA/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Bexiga Urinária/genética , Regiões 3' não Traduzidas/genética , Estudos de Casos e Controles , Linhagem Celular Tumoral , Humanos , MutaçãoRESUMO
OBJECTIVE: Low-grade mucinous tumors of the appendix appear to have a simple histological structure. Paradoxically, reports have suggested a greater frequency of Ki-ras gene mutation in these lesions than in more complex lesions such as benign colonic adenomas and carcinomas. We assessed several molecular genetic changes, including Ki-ras gene mutations, in a large series of low-grade mucinous tumors of the appendix. MATERIAL AND METHODS: We retrospectively ascertained low-grade mucinous tumors of the appendix from computerized pathology records. Extracted DNA was analyzed for APC and DCC gene loss of heterozygosity, microsatellite instability and for the presence of Ki-ras gene mutation using standard molecular techniques. Controls consisted of normal appendices, other appendiceal neoplasms, and ovarian mucinous cystadenomas. RESULTS: A total of 31 low-grade appendiceal mucinous tumors were identified. All were microsatellite stable and none demonstrated loss of heterozygosity for the APC or DCC genes. By contrast, all 31 lesions contained a Ki-ras gene mutation. CONCLUSIONS: The presence of a Ki-ras gene mutation in all lesions, with no other molecular changes identified, strongly suggests a possible etiological role of the Ki-ras mutation in the development of this particular lesion of the appendix. Based on other work regarding intestinal bacteria, we hypothesize a relationship between chronic inflammation of the appendix from bacterial overgrowth and Ki-ras gene mutation.
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Neoplasias do Apêndice/genética , Cistadenoma Mucinoso/genética , Genes ras/genética , Neoplasias Ovarianas/genética , Adenocarcinoma/genética , Adenoma Viloso/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Apêndice/patologia , Tumor Carcinoide/genética , Cistadenoma Mucinoso/patologia , Análise Mutacional de DNA , DNA de Neoplasias , Feminino , Genes APC , Genes DCC/genética , Humanos , Pólipos Intestinais/genética , Perda de Heterozigosidade/genética , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Adulto JovemRESUMO
PURPOSE: Current clinical and radiological methods of predicting a patient's growth potential are limited in terms of practicality, accuracy and known to differ in different races. This information influences optimal timing of bracing and surgical intervention in adolescent idiopathic scoliosis (AIS). The Luk classification was developed to mitigate limitations of existing tools. Few reliability studies are available and are limited to certain geographical regions with varying results. This study was performed to analyze reproducibility and reliability of the Luk Distal Radius and Ulna Classification in European patients. METHODS: This is a radiological study of 50 randomly selected left hand and wrist radiographs of patients with AIS referred to a tertiary referral centre. They were assessed for bone maturity using the Luk Distal Radius and Ulna Classification. Assessment was performed twice by four examiners at an interval of one month. Statistical analysis was performed using the intraclass correlation (ICC) method to determine the reliabilities within and between the examiners. RESULTS: In total, 50 radiographs (M:F = 13:37) with a mean age of 13.7 years (10 to 18) were assessed for reliability. The inter-rater ICC value was 0.918 for radius assessment and 0.939 for ulna assessment. The intra-rater ICC values for radius assessment ranged between 0.897 and 0.769 and between 0.948 and 0.786 for ulna assessment. There was near perfect correlation for both assessments. CONCLUSION: This study provides independent evidence that the Luk Distal Radius and Ulna Classification is a reliable tool for assessment of skeletal maturity for European patients. Minimal clinical experience is required to reliably utilize it. LEVEL OF EVIDENCE: IV.
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[This corrects the article DOI: 10.1093/jscr/rjaa559.].
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Transcriptional coregulators, which mediate chromatin-dependent transcriptional signaling, represent tractable targets to modulate tumorigenic gene expression programs with small molecules. Genetic loss-of-function studies have recently implicated the transcriptional coactivator, ENL, as a selective requirement for the survival of acute leukemia and highlighted an essential role for its chromatin reader YEATS domain. Motivated by these discoveries, we executed a screen of nearly 300,000 small molecules and identified an amido-imidazopyridine inhibitor of the ENL YEATS domain (IC50 = 7 µM). Improvements to the initial screening hit were enabled by adopting and expanding upon a SuFEx-based approach to high-throughput medicinal chemistry, ultimately demonstrating that it is compatible with cell-based drug discovery. Through these efforts, we discovered SR-0813, a potent and selective ENL/AF9 YEATS domain inhibitor (IC50 = 25 nM). Armed with this tool and a first-in-class ENL PROTAC, SR-1114, we detailed the biological response of AML cells to pharmacological ENL disruption for the first time. Most notably, we discovered that ENL YEATS inhibition is sufficient to selectively suppress ENL target genes, including HOXA9/10, MYB, MYC, and a number of other leukemia proto-oncogenes. Cumulatively, our study establishes YEATS domain inhibition as a viable approach to disrupt the pathogenic function of ENL in acute leukemia and provides the first thoroughly characterized chemical probe for the ENL YEATS domain.
RESUMO
Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.