Full-length isoform concatenation sequencing to resolve cancer transcriptome complexity.

BACKGROUND: Cancers exhibit complex transcriptomes with aberrant splicing that induces isoform-level differential expression compared to non-diseased tissues. Transcriptomic profiling using short-read sequencing has utility in providing a cost-effective approach for evaluating isoform expression, although short-read assembly displays limitations in the accurate inference of full-length transcripts. Long-read RNA sequencing (Iso-Seq), using the Pacific Biosciences (PacBio) platform, can overcome such limitations by providing full-length isoform sequence resolution which requires no read assembly and represents native expressed transcripts. A constraint of the Iso-Seq protocol is due to fewer reads output per instrument run, which, as an example, can consequently affect the detection of lowly expressed transcripts. To address these deficiencies, we developed a concatenation workflow, PacBio Full-Length Isoform Concatemer Sequencing (PB_FLIC-Seq), designed to increase the number of unique, sequenced PacBio long-reads thereby improving overall detection of unique isoforms. In addition, we anticipate that the increase in read depth will help improve the detection of moderate to low-level expressed isoforms. RESULTS: In sequencing a commercial reference (Spike-In RNA Variants; SIRV) with known isoform complexity we demonstrated a 3.4-fold increase in read output per run and improved SIRV recall when using the PB_FLIC-Seq method compared to the same samples processed with the Iso-Seq protocol. We applied this protocol to a translational cancer case, also demonstrating the utility of the PB_FLIC-Seq method for identifying differential full-length isoform expression in a pediatric diffuse midline glioma compared to its adjacent non-malignant tissue. Our data analysis revealed increased expression of extracellular matrix (ECM) genes within the tumor sample, including an isoform of the Secreted Protein Acidic and Cysteine Rich (SPARC) gene that was expressed 11,676-fold higher than in the adjacent non-malignant tissue. Finally, by using the PB_FLIC-Seq method, we detected several cancer-specific novel isoforms. CONCLUSION: This work describes a concatenation-based methodology for increasing the number of sequenced full-length isoform reads on the PacBio platform, yielding improved discovery of expressed isoforms. We applied this workflow to profile the transcriptome of a pediatric diffuse midline glioma and adjacent non-malignant tissue. Our findings of cancer-specific novel isoform expression further highlight the importance of long-read sequencing for characterization of complex tumor transcriptomes.

A LINE-1 mediated deletion resulting in germline retinoblastoma predisposition.

Retinoblastoma is an ocular cancer associated with genomic variation in the RB1 gene. In individuals with bilateral retinoblastoma, a germline variant in RB1 is identified in virtually all cases. We describe herein an individual with bilateral retinoblastoma for whom multiple clinical lab assays performed by outside commercial laboratories failed to identify a germline RB1 variant. Paired tumor/normal exome sequencing, long-read whole genome sequencing, and long-read isoform sequencing was performed on a translational research basis ultimately identified a germline likely de novo Long Interspersed Nuclear Element (LINE)-1 mediated deletion resulting in a premature stop of translation of RB1 as the underlying genetic cause of retinoblastoma in this individual. Based on these research findings, the LINE-1 mediated deletion was confirmed via Sanger sequencing in our clinical laboratory, and results were reported in the patient's medical record to allow for appropriate genetic counseling.

Psychological well-being and exercise addiction: The treatment effects of an REBT intervention for females.

Whilst there is growing research on the benefits of Rational Emotive Behaviour Therapy (REBT) for athletic performance and wellbeing, there has been little attention on the effectiveness of REBT for the exercising population. Recent evidence suggests that REBT may be helpful for males who show signs of exercise addiction, but the effects for females are currently unknown. The current study aims to build on the extant research by adopting a single-case research design to examine the effects of REBT on irrational beliefs, exercise addiction symptomology, psychological distress, and unconditional self-acceptance (USA) of three female exercisers. Self-report data were collected at pre-, during, and post-REBT timepoints. Visual analyses revealed reductions in irrational beliefs and psychological distress, and increases in USA, maintained two-weeks post-REBT. Exercise addiction symptomology also reduced during the intervention, and this was maintained for two out of the three exercisers post-REBT. Social validation data supported these findings. The study adds weight to the efficacy of REBT in improving exercise addiction and its comorbidities.

The effect of increased collect pump rate on collection efficiency in hematopoietic progenitor cell collection by apheresis in allogeneic adult donors-A single center analysis.

BACKGROUND: Optimizing CD34 recovery while minimizing harm to hematopoietic progenitor cell donors by apheresis (HPC(A) donors) is critical to the success of allogeneic hematopoietic cell transplantation. We examined the efficacy and safety of starting allogeneic HPC(A) donors at a collect pump rate (CPR) of 2 mL/min on the Spectra Optia regardless of the inlet flow rate and/or pre-apheresis white blood cell (WBC) count (high CPR group). STUDY DESIGN AND METHODS: A single-center retrospective study was performed on allogeneic adult donors from 10/2020 to 12/2022. From 10/2020 to 6/19/2022, all donors had CPR of ~1 mL/min (historical group). High CPR group started 6/20/2022. RESULTS: During the study period, 412 donors were in historical group versus 196 (32.2%) in high CPR group. Median CD34 collection efficiency (CE) was higher and more consistent in high CPR group (55.1% vs. 53% in historical group, p < .0001) and remained significant in multivariate analysis. Although product volume was higher in high CPR group, WBC, hematocrit, and platelet concentrations were significantly lower. No difference in engraftment outcomes in patients receiving products from two groups was observed. Moreover, no differences occurred in a significant peri-procedural adverse event or percent decrease in platelets (6.87% decrease in platelets per 100 × 106 CD34 cells collected versus 6.66% in historical group, p = .89). Furthermore, high CPR group had ~26 min less in collection time for every 100 × 106 CD34 cells collected, resulting in less positive fluid balances. CONCLUSIONS: Starting allogeneic HPC(A) donor collection at a CPR of 2 mL/min is safe and effective.

Cell Phone Radiation Exposure Limits and Engineering Solutions.

In the 1990s, the Institute of Electrical and Electronics Engineers (IEEE) restricted its risk assessment for human exposure to radiofrequency radiation (RFR) in seven ways: (1) Inappropriate focus on heat, ignoring sub-thermal effects. (2) Reliance on exposure experiments performed over very short times. (3) Overlooking time/amplitude characteristics of RFR signals. (4) Ignoring carcinogenicity, hypersensitivity, and other health conditions connected with RFR. (5) Measuring cellphone Specific Absorption Rates (SAR) at arbitrary distances from the head. (6) Averaging SAR doses at volumetric/mass scales irrelevant to health. (7) Using unrealistic simulations for cell phone SAR estimations. Low-cost software and hardware modifications are proposed here for cellular phone RFR exposure mitigation: (1) inhibiting RFR emissions in contact with the body, (2) use of antenna patterns reducing the Percent of Power absorbed in the Head (PPHead) and body and increasing the Percent of Power Radiated for communications (PPR), and (3) automated protocol-based reductions of the number of RFR emissions, their duration, or integrated dose. These inexpensive measures do not fundamentally alter cell phone functions or communications quality. A health threat is scientifically documented at many levels and acknowledged by industries. Yet mitigation of RFR exposures to users does not appear as a priority with most cell phone manufacturers.

Associations of life course obesity with endometrial cancer in the Epidemiology of Endometrial Cancer Consortium (E2C2).

BACKGROUND: Adult obesity is a strong risk factor for endometrial cancer (EC); however, associations of early life obesity with EC are inconclusive. We evaluated associations of young adulthood (18-21 years) and adulthood (at enrolment) body mass index (BMI) and weight change with EC risk in the Epidemiology of Endometrial Cancer Consortium (E2C2). METHODS: We pooled data from nine case-control and 11 cohort studies in E2C2. We performed multivariable logistic regression analyses to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for BMI (kg/m2) in young adulthood and adulthood, with adjustment for BMI in adulthood and young adulthood, respectively. We evaluated categorical changes in weight (5-kg increments) and BMI from young adulthood to adulthood, and stratified analyses by histology, menopausal status, race and ethnicity, hormone replacement therapy (HRT) use and diabetes. RESULTS: We included 14 859 cases and 40 859 controls. Obesity in adulthood (OR = 2.85, 95% CI = 2.47-3.29) and young adulthood (OR = 1.26, 95% CI = 1.06-1.50) were positively associated with EC risk. Weight gain and BMI gain were positively associated with EC; weight loss was inversely associated with EC. Young adulthood obesity was more strongly associated with EC among cases diagnosed with endometrioid histology, those who were pre/perimenopausal, non-Hispanic White and non-Hispanic Black, among never HRT users and non-diabetics. CONCLUSIONS: Young adulthood obesity is associated with EC risk, even after accounting for BMI in adulthood. Weight gain is also associated with EC risk, whereas weight loss is inversely associated. Achieving and maintaining a healthy weight over the life course is important for EC prevention efforts.

EgNRT2.3 and EgNAR2 expression are controlled by nitrogen deprivation and encode proteins that function as a two-component nitrate uptake system in oil palm.

Oil palm (Elaeis guineensis Jacq.) is an important crop for oil and biodiesel production. Oil palm plantations require extensive fertilizer additions to achieve a high yield. Fertilizer application decisions and management for oil palm farming rely on leaf tissue and soil nutrient analyses with little information available to describe the key players for nutrient uptake. A molecular understanding of how nutrients, especially nitrogen (N), are taken up in oil palm is very important to improve fertilizer use and formulation practice in oil palm plantations. In this work, two nitrate uptake genes in oil palm, EgNRT2.3 and EgNAR2, were cloned and characterized. Spatial expression analysis showed high expression of these two genes was mainly found in un-lignified young roots. Interestingly, EgNRT2.3 and EgNAR2 were up-regulated by N deprivation, but their expression pattern depended on the form of N source. Promoter analysis of these two genes confirmed the presence of regulatory elements that support these expression patterns. The Xenopus oocyte assay showed that EgNRT2.3 and EgNAR2 had to act together to take up nitrate. The results suggest that EgNRT2.3 and EgNAR2 act as a two-component nitrate uptake system in oil palm.

Pacific Biosciences Fusion and Long Isoform Pipeline for Cancer Transcriptome-Based Resolution of Isoform Complexity.

Genomic profiling using short-read sequencing has utility in detecting disease-associated variation in both DNA and RNA. However, given the frequent occurrence of structural variation in cancer, molecular profiling using long-read sequencing improves the resolution of such events. For example, the Pacific Biosciences long-read RNA-sequencing (Iso-Seq) transcriptome protocol provides full-length isoform characterization, discernment of allelic phasing, and isoform discovery, and identifies expressed fusion partners. The Pacific Biosciences Fusion and Long Isoform Pipeline (PB_FLIP) incorporates a suite of RNA-sequencing software analysis tools and scripts to identify expressed fusion partners and isoforms. In addition, sequencing of a commercial reference (Spike-In RNA Variants) with known isoform complexity was performed and demonstrated high recall of the Iso-Seq and PB_FLIP workflow to benchmark our protocol and analysis performance. This study describes the utility of Iso-Seq and PB_FLIP analysis in improving deconvolution of complex structural variants and isoform detection within an institutional pediatric and adolescent/young adult translational cancer research cohort. The exemplar case studies demonstrate that Iso-Seq and PB_FLIP discover novel expressed fusion partners, resolve complex intragenic alterations, and discriminate between allele-specific expression profiles.

Leveraging gene therapy to achieve long-term continuous or controllable expression of biotherapeutics.

T cells redirected to cancer cells either via a chimeric antigen receptor (CAR-T) or a bispecific molecule have been breakthrough technologies; however, CAR-T cells require individualized manufacturing and bispecifics generally require continuous infusions. We created an off-the-shelf, single-dose solution for achieving prolonged systemic serum levels of protein immunotherapeutics via adeno-associated virus (AAV) gene transfer. We demonstrate proof of principle in a CD19+ lymphoma xenograft model using a single intravenous dose of AAV expressing a secreted version of blinatumomab, which could serve as a universal alternative for CD19 CAR-T cell therapy. In addition, we created an inducible version using an exon skipping strategy and achieved repeated, on-demand expression up to at least 36 weeks after AAV injection. Our system could be considered for short-term and/or repeated expression of other transgenes of interest for noncancer applications.

Detection of brain somatic variation in epilepsy-associated developmental lesions.

OBJECTIVE: Epilepsy-associated developmental lesions, including malformations of cortical development and low-grade developmental tumors, represent a major cause of drug-resistant seizures requiring surgical intervention in children. Brain-restricted somatic mosaicism has been implicated in the genetic etiology of these lesions; however, many contributory genes remain unidentified. METHODS: We enrolled 50 children who were undergoing epilepsy surgery into a translational research study. Resected tissue was divided for clinical neuropathologic evaluation and genomic analysis. We performed exome and RNA sequencing to identify somatic variation and we confirmed our findings using high-depth targeted DNA sequencing. RESULTS: We uncovered candidate disease-causing somatic variation affecting 28 patients (56%), as well as candidate germline variants affecting 4 patients (8%). In agreement with previous studies, we identified somatic variation affecting solute carrier family 35 member A2 (SLC35A2) and mechanistic target of rapamycin kinase (MTOR) pathway genes in patients with focal cortical dysplasia. Somatic gains of chromosome 1q were detected in 30% (3 of 10) of patients with Type I focal cortical dysplasia (FCD)s. Somatic variation in mitogen-activated protein kinase (MAPK) pathway genes (i.e., fibroblast growth factor receptor 1 [FGFR1], FGFR2, B-raf proto-oncogene, serine/threonine kinase [BRAF], and KRAS proto-oncogene, GTPase [KRAS]) was associated with low-grade epilepsy-associated developmental tumors. RNA sequencing enabled the detection of somatic structural variation that would have otherwise been missed, and which accounted for more than one-half of epilepsy-associated tumor diagnoses. Sampling across multiple anatomic regions revealed that somatic variant allele fractions vary widely within epileptogenic tissue. Finally, we identified putative disease-causing variants in genes not yet associated with focal cortical dysplasia. SIGNIFICANCE: These results further elucidate the genetic basis of structural brain abnormalities leading to focal epilepsy in children and point to new candidate disease genes.

The OncoSim-Breast Cancer Microsimulation Model.

BACKGROUND: OncoSim-Breast is a Canadian breast cancer simulation model to evaluate breast cancer interventions. This paper aims to describe the OncoSim-Breast model and how well it reproduces observed breast cancer trends. METHODS: The OncoSim-Breast model simulates the onset, growth, and spread of invasive and ductal carcinoma in situ tumours. It combines Canadian cancer incidence, mortality, screening program, and cost data to project population-level outcomes. Users can change the model input to answer specific questions. Here, we compared its projections with observed data. First, we compared the model's projected breast cancer trends with the observed data in the Canadian Cancer Registry and from Vital Statistics. Next, we replicated a screening trial to compare the model's projections with the trial's observed screening effects. RESULTS: OncoSim-Breast's projected incidence, mortality, and stage distribution of breast cancer were close to the observed data in the Canadian Cancer Registry and from Vital Statistics. OncoSim-Breast also reproduced the breast cancer screening effects observed in the UK Age trial. CONCLUSIONS: OncoSim-Breast's ability to reproduce the observed population-level breast cancer trends and the screening effects in a randomized trial increases the confidence of using its results to inform policy decisions related to early detection of breast cancer.

Expanding the clinical phenotype of FGFR1 internal tandem duplication.

Closed spinal dysraphism (SD) is a type of neural tube defect originating during early embryonic development whereby the neural tissue of the spinal defect remains covered by skin, often coinciding with markers of cutaneous stigmata. It is hypothesized that these events are caused by multifactorial processes, including genetic and environmental causes. We present an infant with a unique congenital midline lesion associated with a closed SD. Through comprehensive molecular profiling of the intraspinal lesion and contiguous skin lesion, an internal tandem duplication (ITD) of the kinase domain of the fibroblast growth factor receptor 1 (FGFR1) gene was found. This ITD variant is somatic mosaic in nature as supported by a diminished variant allele frequency in the lesional tissue and by its absence in peripheral blood. FGFR1 ITD results in constitutive activation of the receptor tyrosine kinase to promote cell growth, differentiation, and survival through RAS/MAPK signaling. Identification of FGFR1 ITD outside of central nervous system tumors is exceedingly rare, and this report broadens the phenotypic spectrum of somatic mosaic FGFR1-related disease.

Immune Activity and Response Differences of Oncolytic Viral Therapy in Recurrent Glioblastoma: Gene Expression Analyses of a Phase IB Study.

PURPOSE: Previously, clinical trials of experimental virotherapy for recurrent glioblastoma multiforme (GBM) demonstrated that inoculation with a conditionally replication-competent Δγ134.5 oncolytic herpes simplex virus (oHSV), G207, was safe. Following the initial safety study, a phase Ib trial enrolled 6 adult patients diagnosed with GBM recurrence from which tumor tissue was banked for future studies. PATIENTS AND METHODS: Here, we analyzed tumor RNA sequencing (RNA-seq) data obtained from pre- and posttreatment (collected 2 or 5 days after G207 injection) biopsies from the phase Ib study patients. RESULTS: Using a Spearman rank-order correlation analysis, we identified approximately 500 genes whose expression pattern correlated with survival duration. Many of these genes were enriched for the intrinsic IFN-mediated antiviral and adaptive immune functional responses, including immune cell chemotaxis and antigen presentation to T-cells. Furthermore, we show that the expression of several T-cell-related genes was highest in the patient with the longest survival after G207 inoculation. CONCLUSIONS: Our data support that the oHSV-induced type I IFN production and the subsequent recruitment of an adaptive immune response differed between enrolled patients and showed association with survival duration in patients with recurrent malignant glioma after treatment with an early generation oHSV.

Fenretinide inhibits vitamin A formation from ß-carotene and regulates carotenoid levels in mice.

N-[4-hydroxyphenyl]retinamide, commonly known as fenretinide, a synthetic retinoid with pleiotropic benefits for human health, is currently utilized in clinical trials for cancer, cystic fibrosis, and COVID-19. However, fenretinide reduces plasma vitamin A levels by interacting with retinol-binding protein 4 (RBP4), which often results in reversible night blindness in patients. Cell culture and in vitro studies show that fenretinide binds and inhibits the activity of ß-carotene oxygenase 1 (BCO1), the enzyme responsible for endogenous vitamin A formation. Whether fenretinide inhibits vitamin A synthesis in mammals, however, remains unknown. The goal of this study was to determine if the inhibition of BCO1 by fenretinide affects vitamin A formation in mice fed ß-carotene. Our results show that wild-type mice treated with fenretinide for ten days had a reduction in tissue vitamin A stores accompanied by a two-fold increase in ß-carotene in plasma (P < 0.01) and several tissues. These effects persisted in RBP4-deficient mice and were independent of changes in intestinal ß-carotene absorption, suggesting that fenretinide inhibits vitamin A synthesis in mice. Using Bco1-/- and Bco2-/- mice we also show that fenretinide regulates intestinal carotenoid and vitamin E uptake by activating vitamin A signaling during short-term vitamin A deficiency. This study provides a deeper understanding of the impact of fenretinide on vitamin A, carotenoid, and vitamin E homeostasis, which is crucial for the pharmacological utilization of this retinoid.

Discovery of clinically relevant fusions in pediatric cancer.

BACKGROUND: Pediatric cancers typically have a distinct genomic landscape when compared to adult cancers and frequently carry somatic gene fusion events that alter gene expression and drive tumorigenesis. Sensitive and specific detection of gene fusions through the analysis of next-generation-based RNA sequencing (RNA-Seq) data is computationally challenging and may be confounded by low tumor cellularity or underlying genomic complexity. Furthermore, numerous computational tools are available to identify fusions from supporting RNA-Seq reads, yet each algorithm demonstrates unique variability in sensitivity and precision, and no clearly superior approach currently exists. To overcome these challenges, we have developed an ensemble fusion calling approach to increase the accuracy of identifying fusions. RESULTS: Our Ensemble Fusion (EnFusion) approach utilizes seven fusion calling algorithms: Arriba, CICERO, FusionMap, FusionCatcher, JAFFA, MapSplice, and STAR-Fusion, which are packaged as a fully automated pipeline using Docker and Amazon Web Services (AWS) serverless technology. This method uses paired end RNA-Seq sequence reads as input, and the output from each algorithm is examined to identify fusions detected by a consensus of at least three algorithms. These consensus fusion results are filtered by comparison to an internal database to remove likely artifactual fusions occurring at high frequencies in our internal cohort, while a "known fusion list" prevents failure to report known pathogenic events. We have employed the EnFusion pipeline on RNA-Seq data from 229 patients with pediatric cancer or blood disorders studied under an IRB-approved protocol. The samples consist of 138 central nervous system tumors, 73 solid tumors, and 18 hematologic malignancies or disorders. The combination of an ensemble fusion-calling pipeline and a knowledge-based filtering strategy identified 67 clinically relevant fusions among our cohort (diagnostic yield of 29.3%), including RBPMS-MET, BCAN-NTRK1, and TRIM22-BRAF fusions. Following clinical confirmation and reporting in the patient's medical record, both known and novel fusions provided medically meaningful information. CONCLUSIONS: The EnFusion pipeline offers a streamlined approach to discover fusions in cancer, at higher levels of sensitivity and accuracy than single algorithm methods. Furthermore, this method accurately identifies driver fusions in pediatric cancer, providing clinical impact by contributing evidence to diagnosis and, when appropriate, indicating targeted therapies.

Gastroblastoma with a novel EWSR1-CTBP1 fusion presenting in adolescence.

Gastroblastomas are rare tumors with a biphasic epithelioid/spindle cell morphology that typically present in early adulthood and have recurrent MALAT1-GLI1 fusions. We describe an adolescent patient with Wiskott-Aldrich syndrome who presented with a large submucosal gastric tumor with biphasic morphology. Despite histologic features consistent with gastroblastoma, a MALAT1-GLI1 fusion was not found in this patient's tumor; instead, comprehensive molecular profiling identified a novel EWSR1-CTBP1 fusion and no other significant genetic alterations. The tumor also overexpressed NOTCH and FGFR by RNA profiling. The novel fusion and expression profile suggest a role for epithelial-mesenchymal transition in this tumor, with potential implications for the pathogenesis of biphasic gastric tumors such as gastroblastoma.

Estimating the future cancer management costs attributable to modifiable risk factors in Canada.

OBJECTIVES: An estimated 33-37% of incident cancers in Canada are attributable to modifiable risk factors. Interventions targeting these risk factors would minimize the substantial health and economic burdens Canadians face due to cancer. We estimate the future health and economic burden of cancer in Canada by incorporating data from the Canadian Population Attributable Risk of Cancer (ComPARe) study into OncoSim, a web-based microsimulation tool. METHODS: Using the integrated OncoSim population attributable risk and population impact measures, we evaluated risk factor-targeted intervention scenarios implemented in 2020, assuming the targeted risk factor prevalence reduction would be achieved by 2032 with a 12-year latency period. RESULTS: We estimate that smoking will be the largest contributor to cancer-related costs, with a cost of CAD $44.4 billion between 2032 and 2044. An estimated CAD $3.3 billion of the cost could be avoided with a 30% reduction in smoking prevalence by 2022. Following smoking, the next highest cancer management costs are associated with inadequate physical activity and excess body weight, accounting for CAD $10.7 billion ($2.7 billion avoidable) and CAD $9.8 billion ($3.2 billion avoidable), respectively. Avoidable costs for other risk factors range from CAD $90 million to CAD $2.5 billion. CONCLUSION: Interventions targeting modifiable cancer risk factors could prevent a substantial number of incident cancer cases and billions of dollars in cancer management costs. With limited budgets and rising costs in cancer care in Canada, these simulation models and results are valuable for researchers and policymakers to inform decisions and prioritize and evaluate intervention programs.

RéSUMé: OBJECTIFS: Il est estimé que de 33 % à 37 % des cancers incidents au Canada sont imputables à des facteurs de risque modifiables. Des interventions ciblant ces facteurs de risque réduiraient le fardeau sanitaire et économique considérable du cancer dans la population canadienne. Nous avons estimé le futur fardeau sanitaire et économique du cancer au Canada en intégrant les données de l'étude ComPARe (Canadian Population Attributable Risk of Cancer) dans l'outil de microsimulation en ligne OncoSim. MéTHODE: À l'aide des indicateurs d'impact dans la population et du risque attribuable dans la population intégrés dans OncoSim, nous avons évalué des scénarios d'intervention mis en œuvre en 2020 axés sur les facteurs de risque, en partant de l'hypothèse que la réduction de la prévalence des facteurs de risque ciblés serait atteinte d'ici 2032 avec une période de latence de 12 ans. RéSULTATS: Nous estimons que le tabagisme sera le facteur qui contribuera le plus aux coûts du cancer, avec un coût de 44,4 milliards $ CA entre 2032 et 2044. Il est estimé qu'une part de 3,3 milliards $ CA de ce coût pourrait être évitée en réduisant de 30 % la prévalence du tabagisme d'ici 2022. Après le tabagisme, les coûts de prise en charge du cancer les plus élevés sont associés à l'inactivité physique et au surpoids, qui représentent respectivement 10,7 milliard $ CA (dont 2,7 milliards $ évitables) et 9,8 milliards $ CA (dont 3,2 milliards $ évitables). Les coûts évitables pour d'autres facteurs de risque vont de 90 millions $ CA à 2,5 milliards $ CA. CONCLUSION: Des interventions ciblant les facteurs de risque de cancer modifiables pourraient prévenir un nombre considérable de cas de cancers incidents et épargner des milliards de dollars en coûts de prise en charge du cancer. Avec les budgets serrés et la hausse des coûts des soins du cancer au Canada, ces modèles de simulation et leurs résultats permettent aux chercheurs et aux responsables des politiques d'éclairer les décisions et de hiérarchiser et d'évaluer les programmes d'intervention.

Estimates of future cancer mortality attributable to modifiable risk factors in Canada.

OBJECTIVES: Modifiable lifestyle, environmental, and infectious risk factors associated with cancer impact both cancer incidence and mortality at the population level. Most studies estimating this burden focus on cancer incidence. However, because these risk factors are associated with cancers of disparate mortality rates, the burden associated with cancer incidence could differ from cancer mortality. Therefore, estimating the cancer mortality attributable to these risk factors provides additional insight into cancer prevention. Here, we estimated future cancer deaths and the number of avoidable deaths in Canada due to modifiable risk factors. METHODS: The projected cancer mortality data came from OncoSim, a web-based microsimulation tool. These data were applied to the methodological framework that we previously used to estimate the population attributable risks and the potential impact fractions of modifiable risk factors on Canadian cancer incidence. RESULTS: We estimated that most cancer deaths will be attributed to tobacco smoking with an average of 27,900 deaths annually from 2024 to 2047. If Canada's current trends in excess body weight continue, cancer deaths attributable to excess body weight would double from 2786 deaths in 2024 to 5604 deaths in 2047, becoming the second leading modifiable cause of cancer death. Applying targets to reduce these risk factors, up to 34,600 cancer deaths could be prevented from 2024 to 2047. CONCLUSION: Our simulated results complement our previous findings on the cancer incidence burden since decreasing the overall burden of cancer will be accelerated through a combination of decreasing cancer incidence and improving survival outcomes through improved treatments.

RéSUMé: OBJECTIFS: Les facteurs de risque modifiables associés au cancer (liés au mode de vie, à l'environnement, aux maladies infectieuses) ont des effets à la fois sur l'incidence du cancer et sur la mortalité par cancer à l'échelle de la population. La plupart des études qui estiment ce fardeau portent sur l'incidence du cancer. Cependant, comme les facteurs de risque susmentionnés sont associés à des cancers dont les taux de mortalité sont disparates, le fardeau associé à l'incidence du cancer pourrait différer de la mortalité par cancer. En conséquence, l'estimation de la mortalité par cancer imputable à ces facteurs de risque pourrait éclairer la prévention du cancer. Nous estimons ici les décès futurs par cancer et le nombre de décès évitables au Canada dus à des facteurs de risque modifiables. MéTHODE: Les données projetées sur la mortalité par cancer proviennent d'OncoSim, un outil de microsimulation en ligne. Elles ont été appliquées au cadre méthodologique que nous avions déjà utilisé pour estimer les risques attribuables dans la population et les fractions de l'incidence potentielle des facteurs de risque modifiables sur l'incidence canadienne du cancer. RéSULTATS: Selon nos estimations, entre 2024 et 2047, la plupart des décès par cancer seront imputés au tabagisme, qui causera en moyenne 27 900 décès par année. Si les tendances actuelles au Canada en matière de surpoids se maintiennent, les décès par cancer attribuables au surpoids doubleraient, passant de 2 786 décès en 2024 à 5 604 en 2047, et le surpoids deviendrait la deuxième cause modifiable de décès par cancer. En appliquant des cibles de réduction de ces facteurs de risque, jusqu'à 34 600 décès par cancer pourraient être évités entre 2024 et 2047. CONCLUSION: Les résultats de notre simulation confirment nos constatations antérieures sur le fardeau de l'incidence du cancer, car la diminution du fardeau global du cancer sera accélérée par une combinaison de la diminution de l'incidence du cancer et de l'amélioration des résultats de survie grâce à l'amélioration des traitements.

PTEN somatic mutations contribute to spectrum of cerebral overgrowth.

Phosphatase and tensin homologue (PTEN) regulates cell growth and survival through inhibition of the mammalian target of rapamycin (MTOR) signalling pathway. Germline genetic variation of PTEN is associated with autism, macrocephaly and PTEN hamartoma tumour syndromes. The effect of developmental PTEN somatic mutations on nervous system phenotypes is not well understood, although brain somatic mosaicism of MTOR pathway genes is an emerging cause of cortical dysplasia and epilepsy in the paediatric population. Here we report two somatic variants of PTEN affecting a single patient presenting with intractable epilepsy and hemimegalencephaly that varied in clinical severity throughout the left cerebral hemisphere. High-throughput sequencing analysis of affected brain tissue identified two somatic variants in PTEN. The first variant was present in multiple cell lineages throughout the entire hemisphere and associated with mild cerebral overgrowth. The second variant was restricted to posterior brain regions and affected the opposite PTEN allele, resulting in a segmental region of more severe malformation, and the only neurons in which it was found by single-nuclei RNA-sequencing had a unique disease-related expression profile. This study reveals brain mosaicism of PTEN as a disease mechanism of hemimegalencephaly and furthermore demonstrates the varying effects of single- or bi-allelic disruption of PTEN on cortical phenotypes.

Dairy foods, calcium, and risk of breast cancer overall and for subtypes defined by estrogen receptor status: a pooled analysis of 21 cohort studies.

BACKGROUND: Epidemiologic studies examining the relations between dairy product and calcium intakes and breast cancer have been inconclusive, especially for tumor subtypes. OBJECTIVE: To evaluate the associations between intakes of specific dairy products and calcium and risk of breast cancer overall and for subtypes defined by estrogen receptor (ER) status. METHOD: We pooled the individual-level data of over 1 million women who were followed for a maximum of 8-20 years across studies. Associations were evaluated for dairy product and calcium intakes and risk of incident invasive breast cancer overall (n = 37,861 cases) and by subtypes defined by ER status. Study-specific multivariable hazard ratios (HRs) were estimated and then combined using random-effects models. RESULTS: Overall, no clear association was observed between the consumption of specific dairy foods, dietary (from foods only) calcium, and total (from foods and supplements) calcium, and risk of overall breast cancer. Although each dairy product showed a null or very weak inverse association with risk of overall breast cancer (P, test for trend >0.05 for all), differences by ER status were suggested for yogurt and cottage/ricotta cheese with associations observed for ER-negative tumors only (pooled HR = 0.90, 95% CI: 0.83, 0.98 comparing ≥60 g/d with <1 g/d of yogurt and 0.85, 95% CI: 0.76, 0.95 comparing ≥25 g/d with <1 g/d of cottage/ricotta cheese). Dietary calcium intake was only weakly associated with breast cancer risk (pooled HR = 0.98, 95% CI: 0.97, 0.99 per 350 mg/d). CONCLUSION: Our study shows that adult dairy or calcium consumption is unlikely to associate with a higher risk of breast cancer and that higher yogurt and cottage/ricotta cheese intakes were inversely associated with the risk of ER-negative breast cancer, a less hormonally dependent subtype with poor prognosis. Future studies on fermented dairy products, earlier life exposures, ER-negative breast cancer, and different racial/ethnic populations may further elucidate the relation.