Search

Chimeric antigen receptor T cell (CAR-T) therapy is a promising approach to improve survival for children and adults with relapsed/refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL), but these clinical trials might not be equally accessible to patients of low socioeconomic status (SES) or to patients from racial or ethnic minority groups. We sought to describe the sociodemographic characteristics of pediatric and adolescent and young adult (AYA) patients enrolled in CAR-T clinical trials and to compare these characteristics to those of other patients with r/r B-ALL. We conducted a multicenter retrospective cohort study at 5 pediatric consortium sites to compare the sociodemographic characteristics of patients treated and enrolled in CAR-T trials at their home institution, other patients with r/r B-ALL treated at these sites, and patients referred from an external hospital for CAR-T trials. The patients were age 0 to 27 years with r/r B-ALL treated at 1 of the consortium sites between 2012 and 2018. Clinical and demographic data were collected from the electronic health record. We calculated distance from home to treating institution and assigned SES scores based on census tract. Among the 337 patients treated for r/r B-ALL, 112 were referred from an external hospital to a consortium site and enrolled in a CAR-T trial and 225 were treated primarily at a consortium site, with 34% enrolled in a CAR-T trial. Patients treated primarily at a consortium site had similar characteristics regardless of trial enrollment. Lower proportions of Hispanic patients (37% versus 56%; P = .03), patients whose preferred language was Spanish (8% versus 22%; P = .006), and publicly insured patients (38% versus 65%; P = .001) were referred from an external hospital than were treated primarily at a consortium site and enrolled in a CAR-T trial. Patients who are Hispanic, Spanish-speaking, or publicly insured are underrepresented in referrals from external hospitals to CAR-T centers. External provider implicit bias also may influence referral of these patients. Establishing partnerships between CAR-T centers and external hospital sites may improve provider familiarity, patient referral, and patient access to CAR-T clinical trials., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Introduction: Treatment decisions in older adults with acute myeloid leukemia (AML) are challenging, particularly for those who are not candidates for intensive chemotherapy (IC), and the trade-offs patients, their families and physicians consider when choosing a treatment option are not well understood. This qualitative research explored the value of extending survival and the treatment decision-making process from a multi-stakeholder perspective., Methods: Overall, 28 patients with AML (≥ 65 years old, unsuitable for IC), 25 of their relatives and 10 independent physicians from the US, UK and Canada took part in one-on-one, 60-minute qualitative interviews., Results: Across all stakeholders, improved health-related quality of life (HRQoL), extended survival and relief of AML symptoms were recognized as most important in AML treatment decision-making. However, extending survival in 'good health' was more important than extending survival alone, particularly because of the extra time it gives patients and their relatives together, and allows patients to achieve important goals. Patients' limited understanding of available treatment options, paired with incorrect perceptions of treatment side effects, impacted their involvement in the treatment decision-making process. Patients and physicians perceived physicians to have the most influence in the decision-making process despite their priorities not always aligning., Conclusion: These findings illustrate the importance of having structured discussions which explicitly assess patients' goals and their understanding and expectations of treatments and also the need for patient friendly resources about the lived experience of AML and available treatment options. These measures will help to ensure that patients are fully involved in the shared decision-making process., (© 2022. The Author(s).)

Purpose: As immune checkpoint inhibitors (ICI) become increasingly used in frontline settings, identifying early indicators of response is needed. Recent studies suggest a role for circulating tumor DNA (ctDNA) in monitoring response to ICI, but uncertainty exists in the generalizability of these studies. Here, the role of ctDNA for monitoring response to ICI is assessed through a standardized approach by assessing clinical trial data from five independent studies., Patients and Methods: Patient-level clinical and ctDNA data were pooled and harmonized from 200 patients across five independent clinical trials investigating the treatment of patients with non-small-cell lung cancer with programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1)-directed monotherapy or in combination with chemotherapy. CtDNA levels were measured using different ctDNA assays across the studies. Maximum variant allele frequencies were calculated using all somatic tumor-derived variants in each unique patient sample to correlate ctDNA changes with overall survival (OS) and progression-free survival (PFS)., Results: We observed strong associations between reductions in ctDNA levels from on-treatment liquid biopsies with improved OS (OS; hazard ratio, 2.28; 95% CI, 1.62 to 3.20; P < .001) and PFS (PFS; hazard ratio 1.76; 95% CI, 1.31 to 2.36; P < .001). Changes in the maximum variant allele frequencies ctDNA values showed strong association across different outcomes., Conclusion: In this pooled analysis of five independent clinical trials, consistent and robust associations between reductions in ctDNA and outcomes were found across multiple end points assessed in patients with non-small-cell lung cancer treated with an ICI. Additional tumor types, stages, and drug classes should be included in future analyses to further validate this. CtDNA may serve as an important tool in clinical development and an early indicator of treatment benefit.

Purpose: Radiotherapy for childhood cancer is associated with elevated subsequent neoplasm (SN) risk, but the contribution of rare variants in DNA damage response and radiation sensitivity genes to SN risk is unknown., Patients and Methods: We conducted whole-exome sequencing in a cohort of childhood cancer survivors originally diagnosed during 1970 to 1986 (mean follow-up, 32.7 years), with reconstruction of doses to body regions from radiotherapy records. We identified patients who developed SN types previously reported to be related to radiotherapy (RT-SNs; eg, basal cell carcinoma [BCC], breast cancer, meningioma, thyroid cancer, sarcoma) and matched controls (sex, childhood cancer type/diagnosis, age, SN location, radiation dose, survival). Conditional logistic regression assessed SN risk associated with potentially protein-damaging rare variants (SnpEff, ClinVar) in 476 DNA damage response or radiation sensitivity genes with exact permutation-based P values using a Bonferroni-corrected significance threshold of P < 8.06 × 10 -5 ., Results: Among 5,105 childhood cancer survivors of European descent, 1,108 (21.7%) developed at least 1 RT-SN. Out-of-field RT-SN risk, excluding BCC, was associated with homologous recombination repair (HRR) gene variants (patient cases, 23.2%; controls, 10.8%; odds ratio [OR], 2.6; 95% CI, 1.7 to 3.9; P = 4.79 × 10 -5 ), most notably but nonsignificantly for FANCM (patient cases, 4.0%; matched controls, 0.6%; P = 9.64 × 10 -5 ). HRR variants were not associated with likely in/near-field RT-SNs, excluding BCC (patient cases, 12.7%; matched controls, 12.9%; P = .92). Irrespective of radiation dose, risk for RT-SNs was also associated with EXO1 variants (patient cases, 1.8%; controls, 0.4%; P = 3.31 × 10 -5 ), another gene implicated in DNA double-strand break repair., Conclusion: In this large-scale discovery study, we identified novel associations between RT-SN risk after childhood cancer and potentially protein-damaging rare variants in genes involved in DNA double-strand break repair, particularly HRR. With replication, these results could affect screening recommendations for childhood cancer survivors and risk-benefit assessments of treatment approaches., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/authors/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Belynda D. HicksEmployment: United Therapeutics (I) Stock and Other Ownership Interests: United Therapeutics (I) Honoraria: Roche Molecular Diagnostics Travel, Accommodations, Expenses: Roche Molecular Diagnostics, United Therapeutics (I)Susan A. SmithHonoraria: Memorial Sloan-Kettering Cancer Center Travel, Accommodations, Expenses: Memorial Sloan-Kettering Cancer CenterDiana M. MerinoTravel, Accommodations, Expenses: Aetion No other potential conflicts of interest were reported., (© 2020 by American Society of Clinical Oncology.)

Background: Diagnostic tests, including US Food and Drug Administration (FDA)-approved tests and laboratory-developed tests, are frequently used to guide care for patients with cancer, and, recently, have been the subject of several policy discussions and insurance coverage determinations. As the use of diagnostic testing has evolved, stakeholders have raised questions about the lack of standardized test performance metrics and the risk this poses to patients., Objectives: To describe the use of diagnostic testing for patients with advanced non-small-cell lung cancer (NSCLC), to analyze the utilization of FDA-approved versus laboratory-developed diagnostic tests, and to evaluate the impact of existing regulatory and coverage frameworks on diagnostic test ordering and physician treatment decision-making for patients with advanced NSCLC., Methods: We conducted a 2-part study consisting of an online survey and patient chart review from March 1, 2019, to March 25, 2019, of physicians managing patients with advanced NSCLC. Respondents qualified for this study if they managed at least 5 patients with advanced NSCLC per month and had diagnosed at least 1 patient with advanced NSCLC in the 12 months before the survey. A total of 150 physicians completed the survey; before completing the survey, they were instructed to review between 4 and 8 charts of patients with stage IV NSCLC from their list of active patients., Results: A total of 150 practicing oncologists who manage patients with advanced NSCLC responded to the survey and reviewed a total of 815 patient charts. Of these 815 patients, 812 (99.6%) were tested for at least 1 biomarker, including 73% of patients who were tested for EGFR , 70% tested for ALK , 58% tested for BRAF V600E, and 38% of patients tested for ROS1 , by FDA-approved diagnostic tests. In all, 185 (83%) patients who tested positive for EGFR and 60 (83%) patients who tested positive for ALK received an FDA-approved targeted therapy for their biomarker. A total of 98 (65%) physicians responded that the patient's insurance coverage factored into their decision to order diagnostic tests and 69 (45%) physicians responded that cost or the patient's insurance coverage could influence them not to prescribe an indicated targeted therapy., Conclusion: The survey results indicate that diagnostic testing has become routine in the treatment of patients with advanced NSCLC, the use of FDA-approved diagnostic tests has increased, and insurance coverage and cost influence patient access to diagnostic testing as well as to targeted treatment options., (Copyright © 2020 by Engage Healthcare Communications, LLC.)

Background: Tumor mutational burden (TMB), defined as the number of somatic mutations per megabase of interrogated genomic sequence, demonstrates predictive biomarker potential for the identification of patients with cancer most likely to respond to immune checkpoint inhibitors. TMB is optimally calculated by whole exome sequencing (WES), but next-generation sequencing targeted panels provide TMB estimates in a time-effective and cost-effective manner. However, differences in panel size and gene coverage, in addition to the underlying bioinformatics pipelines, are known drivers of variability in TMB estimates across laboratories. By directly comparing panel-based TMB estimates from participating laboratories, this study aims to characterize the theoretical variability of panel-based TMB estimates, and provides guidelines on TMB reporting, analytic validation requirements and reference standard alignment in order to maintain consistency of TMB estimation across platforms., Methods: Eleven laboratories used WES data from The Cancer Genome Atlas Multi-Center Mutation calling in Multiple Cancers (MC3) samples and calculated TMB from the subset of the exome restricted to the genes covered by their targeted panel using their own bioinformatics pipeline (panel TMB). A reference TMB value was calculated from the entire exome using a uniform bioinformatics pipeline all members agreed on (WES TMB). Linear regression analyses were performed to investigate the relationship between WES and panel TMB for all 32 cancer types combined and separately. Variability in panel TMB values at various WES TMB values was also quantified using 95% prediction limits., Results: Study results demonstrated that variability within and between panel TMB values increases as the WES TMB values increase. For each panel, prediction limits based on linear regression analyses that modeled panel TMB as a function of WES TMB were calculated and found to approximately capture the intended 95% of observed panel TMB values. Certain cancer types, such as uterine, bladder and colon cancers exhibited greater variability in panel TMB values, compared with lung and head and neck cancers., Conclusions: Increasing uptake of TMB as a predictive biomarker in the clinic creates an urgent need to bring stakeholders together to agree on the harmonization of key aspects of panel-based TMB estimation, such as the standardization of TMB reporting, standardization of analytical validation studies and the alignment of panel-based TMB values with a reference standard. These harmonization efforts should improve consistency and reliability of panel TMB estimates and aid in clinical decision-making., Competing Interests: Competing interests: DF: employment with Foundation Medicine and stockholder in Roche. VF: employment with NeoGenomics Inc and stockholder in NeoGenomics Inc. S-JC: employment with ACT Genomics and stockholder in ACT Genomics. JRW: founder and owner of Resphira Biosciences and paid consultant to PGDx. PW: employment with Illumina and stockholder in Illumina. JB: employment with Bristol-Myers Squibb, shareholder in Bristol-Myers Squibb and shareholder in Johnson & Johnson. JCB: employment with AstraZeneca Pharmaceuticals and stocks in AstraZeneca Pharmaceuticals. RC: employment with Thermo Fisher Scientific. WSC: employment with Caris Life Sciences. JHC: employment with ACT Genomics. DC: employment with Thermo Fisher Scientific and stockholder in Thermo Fisher Scientific. JSD: employment with Personal Genome Diagnostics. VG: employment with QIAGEN. MH: received research funding from Bristol-Myers Squibb; is paid a consultant to Merck, Bristol-Myers Squibb, AstraZeneca, Genentech/Roche, Janssen, Nektar, Syndax, Mirati and Shattuck Labs; has received travel support/honoraria from AztraZeneca and BMS and a patent has been filed by MSK related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx. EH: employment with Guardant Health Inc and stockholder in Guardant Health Inc. YL: employment with Foundation Medicine while engaged in the research project (March 2019). Currently, an employee of Thrive Sciences, Inc and stockholder of Thrive Sciences, Inc. AP: employment with QIAGEN. KJQ: employment with Guardant Health Inc and stockholder in Guardant Health Inc. NR: NR and Memorial Sloan Kettering Cancer Center have a patent filing (PCT/US2015/062208) for the use of tumor mutation burden and HLA for prediction of immunotherapy efficacy, which is licensed to Personal Genome Diagnostics. NR is a founder, shareholder and serves on the scientific advisory board of Gritstone Oncology. NR has also consulted for AbbVie, AstraZeneca, BMS, EMD Sorono, Genentech, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron. HT: employment with Caris Life Sciences. CW: employment with Bristol-Myers Squibb, shareholder in Bristol-Myers Squibb ad shareholder in Johnson & Johnson. MX: employment with AstraZeneca Pharmaceuticals. CZ: employment with Illumina and stockholder in Illumina. AS: advisory board and/or speech honoraria from: Bayer, BMS, MSD, Novartis, AstraZeneca, Roche, Seattle Genomics, Illumina, Thermo Fisher, Takeda. Research funding from: Chugai, BMS., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Tumor mutational burden (TMB) is an emerging biomarker used to identify patients who are more likely to benefit from immuno-oncology therapy. Aside from various unsettled technical aspects, biological variables such as tumor cell content and intratumor heterogeneity may play an important role in determining TMB., Methods: TMB estimates were determined applying the TruSight Oncology 500 targeted sequencing panel. Spatial and temporal heterogeneity was analyzed by multiregion sequencing (two to six samples) of 24 pulmonary adenocarcinomas and by sequencing a set of matched primary tumors, locoregional lymph node metastases, and distant metastases in five patients., Results: On average, a coding region of 1.28 Mbp was covered with a mean read depth of 609x. Manual validation of the mutation-calls confirmed a good performance, but revealed noticeable misclassification during germline filtering. Different regions within a tumor showed considerable spatial TMB variance in 30% (7 of 24) of the cases (maximum difference, 14.13 mut/Mbp). Lymph node-derived TMB was significantly lower (p = 0.016). In 13 cases, distinct mutational profiles were exclusive to different regions of a tumor, leading to higher values for simulated aggregated TMB. Combined, intratumor heterogeneity and the aggregated TMB could result in divergent TMB designation in 17% of the analyzed patients. TMB variation between primary tumor and distant metastases existed but was not profound., Conclusions: Our data show that, in addition to technical aspects such as germline filtering, the tumor content and spatially divergent mutational profiles within a tumor are relevant factors influencing TMB estimation, revealing limitations of single-sample-based TMB estimations in a clinical context., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Histological grading of choroid plexus tumors (CPTs) remains the best prognostic tool to distinguish between aggressive choroid plexus carcinoma (CPC) and the more benign choroid plexus papilloma (CPP) or atypical choroid plexus papilloma (aCPP); however, these distinctions can be challenging. Standard treatment of CPC is very aggressive and often leads to severe damage to the young child's brain. Therefore, it is crucial to distinguish between CPC and less aggressive entities (CPP or aCPP) to avoid unnecessary exposure of the young patient to neurotoxic therapy. To better stratify CPTs, we utilized DNA methylation (DNAm) to identify prognostic epigenetic biomarkers for CPCs., Methods: We obtained DNA methylation profiles of 34 CPTs using the HumanMethylation450 BeadChip from Illumina, and the data was analyzed using the Illumina Genome Studio analysis software. Validation of differentially methylated CpG sites chosen as biomarkers was performed using pyrosequencing analysis on additional 22 CPTs. Sensitivity testing of the CPC DNAm signature was performed on a replication cohort of 61 CPT tumors obtained from Neuropathology, University Hospital Münster, Germany., Results: Generated genome-wide DNAm profiles of CPTs showed significant differences in DNAm between CPCs and the CPPs or aCPPs. The prediction of clinical outcome could be improved by combining the DNAm profile with the mutational status of TP53. CPCs with homozygous TP53 mutations clustered as a group separate from those carrying a heterozygous TP53 mutation or CPCs with wild type TP53 (TP53-wt) and showed the worst survival outcome. Specific DNAm signatures for CPCs revealed AK1, PER2, and PLSCR4 as potential biomarkers for CPC that can be used to improve molecular stratification for diagnosis and treatment., Conclusions: We demonstrate that combining specific DNAm signature for CPCs with histological approaches better differentiate aggressive tumors from those that are not life threatening. These findings have important implications for future prognostic risk prediction in clinical disease management.

Characterization of tumors utilizing next-generation sequencing methods, including assessment of the number of somatic mutations (tumor mutational burden [TMB]), is currently at the forefront of the field of personalized medicine. Recent clinical studies have associated high TMB with improved patient response rates and survival benefit from immune checkpoint inhibitors; hence, TMB is emerging as a biomarker of response for these immunotherapy agents. However, variability in current methods for TMB estimation and reporting is evident, demonstrating a need for standardization and harmonization of TMB assessment methodology across assays and centers. Two uniquely placed organizations, Friends of Cancer Research (Friends) and the Quality Assurance Initiative Pathology (QuIP), have collaborated to coordinate efforts for international multistakeholder initiatives to address this need. Friends and QuIP, who have partnered with several academic centers, pharmaceutical organizations, and diagnostic companies, have adopted complementary, multidisciplinary approaches toward the goal of proposing evidence-based recommendations for achieving consistent TMB estimation and reporting in clinical samples across assays and centers. Many factors influence TMB assessment, including preanalytical factors, choice of assay, and methods of reporting. Preliminary analyses highlight the importance of targeted gene panel size and composition, and bioinformatic parameters for reliable TMB estimation. Herein, Friends and QuIP propose recommendations toward consistent TMB estimation and reporting methods in clinical samples across assays and centers. These recommendations should be followed to minimize variability in TMB estimation and reporting, which will ensure reliable and reproducible identification of patients who are likely to benefit from immune checkpoint inhibitors., (© 2019 The Authors. Genes, Chromosomes & Cancer published by Wiley Periodicals, Inc.)

Excess sarcoma risks after childhood cancer are well established, but risks among young adulthood cancer survivors are poorly understood. Using US population-based cancer registry data, we compared bone and soft-tissue sarcoma risk vs the general population among 186 351 individuals who were diagnosed with nonsarcoma first primary malignancies at ages 20-39 years from 1975 to 2014 (follow-up through 2015) and survived at least 1 year. Bone sarcomas were rare (n = 50), but risk was statistically significantly elevated overall (2.9-fold) and greater than fivefold after Hodgkin lymphoma, non-Hodgkin lymphoma, and central nervous system tumors. Soft-tissue sarcomas were more common (n = 284) and risks were statistically significantly elevated approximately twofold overall and after melanoma and carcinomas of the breast, thyroid, and testis, and greater than fourfold after Hodgkin lymphoma and central nervous system tumors. Risks varied markedly by subtype, with the highest risks (greater than fourfold) for osteosarcoma and the soft-tissue subtypes of rhabdomyosarcoma and blood vessel and nerve sheath sarcomas. These data demonstrate elevated risk for sarcoma after a range of young adulthood cancers., (Published by Oxford University Press 2019. This work is written by US Government employees and is in the public domain in the US.)

Attribution of adverse events (AEs) is critical to oncology drug development and the regulatory process. However, processes for determining the causality of AEs are often sub-optimal, unreliable, and inefficient. Thus, we conducted a toxicity-attribution workshop in Silver Springs MD to develop guidance for improving attribution of AEs in oncology clinical trials. Attribution stakeholder experts from regulatory agencies, sponsors and contract research organizations, clinical trial principal investigators, pre-clinical translational scientists, and research staff involved in capturing attribution information participated. We also included patients treated in oncology clinical trials and academic researchers with expertise in attribution. We identified numerous challenges with AE attribution, including the non-informative nature of and burdens associated with the 5-tier system of attribution, increased complexity of trial logistics, costs and time associated with AE attribution data collection, lack of training in attribution for early-career investigators, insufficient baseline assessments, and lack of consistency in the reporting of treatment-related and treatment-emergent AEs in publications and clinical scientific reports. We developed recommendations to improve attribution: we propose transitioning from the present 5-tier system to a 2-3 tier system for attribution, more complete baseline information on patients' clinical status at trial entry, and mechanisms for more rapid sharing of AE information during trials. Oncology societies should develop recommendations and training in attribution of toxicities. We call for further harmonization and synchronization of recommendations regarding causality safety reporting between FDA, EMA and other regulatory agencies. Finally, we suggest that journals maintain or develop standardized requirements for reporting attribution in oncology clinical trials., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Choroid plexus carcinoma (CPC) is a rare brain tumor that occurs most commonly in very young children and has a dismal prognosis despite intensive therapy. Improved outcomes for patients with CPC depend on a deeper understanding of the mechanisms underlying the disease. Here we developed transgenic models of CPCs by activating the Myc oncogene and deleting the Trp53 tumor suppressor gene in murine neural stem cells or progenitors. Murine CPC resembled their human counterparts at a histologic level, and like the hypodiploid subset of human CPC, exhibited multiple whole-chromosome losses, particularly of chromosomes 8, 12, and 19. Analysis of murine and human CPC gene expression profiles and copy number changes revealed altered expression of genes involved in cell cycle, DNA damage response, and cilium function. High-throughput drug screening identified small molecule inhibitors that decreased the viability of CPC. These models will be valuable tools for understanding the biology of choroid plexus tumors and for testing novel approaches to therapy. SIGNIFICANCE: This study describes new mouse models of choroid plexus carcinoma and uses them to investigate the biology and therapeutic responsiveness of this highly malignant pediatric brain tumor., (©2019 American Association for Cancer Research.)

Objective: Perceived upright depends on three main factors: vision, graviception, and the internal representation of the long axis of the body. We assessed the relative contributions of these factors in individuals with sub-acute and chronic stroke and controls using a novel tool; the Oriented Character Recognition Test (OCHART). We also considered whether individuals who displayed active pushing or had a history of pushing behaviours had different weightings than those with no signs of pushing., Method: Three participants experienced a stroke 6 months prior: eight with a history of pushing. In total, 12 participants served as healthy aged-matched controls. Visual and graviceptive cues were dissociated by orienting the visual background left, right, or upright relative to the body, or by orienting the body left, right, or upright relative to gravity. A three-vector model was used to quantify the weightings of vision, graviception, and the body to the perceptual upright., Results: The control group showed weightings of 13% vision, 25% graviception, and 62% body. Some individuals with stroke showed a similar pattern; others, particularly those with recent stroke, showed different patterns, for example, being unaffected by one of the three factors. The participant with active pushing behaviour displayed an ipsilesional perceptual bias (>30°) and was not affected by visual cues to upright., Conclusion: The results of OCHART may be used to quantify the weightings of multisensory inputs in individuals post-stroke and may help characterize perceptual sources of pushing behaviours.

Background: Childhood cancer survivors treated with chest-directed radiotherapy have substantially elevated risk for developing breast cancer. Although genetic susceptibility to breast cancer in the general population is well studied, large-scale evaluation of breast cancer susceptibility after chest-directed radiotherapy for childhood cancer is lacking., Methods: We conducted a genome-wide association study of breast cancer in female survivors of childhood cancer, pooling two cohorts with detailed treatment data and systematic, long-term follow-up: the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. The study population comprised 207 survivors who developed breast cancer and 2774 who had not developed any subsequent neoplasm as of last follow-up. Genotyping and subsequent imputation yielded 16 958 466 high-quality variants for analysis. We tested associations in the overall population and in subgroups stratified by receipt of lower than 10 and 10 or higher gray breast radiation exposure. We report P values and pooled per-allele risk estimates from Cox proportional hazards regression models. All statistical tests were two-sided., Results: Among survivors who received 10 or higher gray breast radiation exposure, a locus on 1q41 was associated with subsequent breast cancer risk (rs4342822, nearest gene PROX1 , risk allele frequency in control subjects [RAF controls ] = 0.46, hazard ratio = 1.92, 95% confidence interval = 1.49 to 2.44, P = 7.09 × 10 -9 ). Two rare variants also showed potentially promising associations (breast radiation ≥10 gray: rs74949440, 11q23, TAGLN , RAF controls = 0.02, P = 5.84 × 10 -8 ; <10 gray: rs17020562, 1q32.3, RPS6KC1 , RAF controls = 0.0005, P = 6.68 × 10 -8 ). Associations were restricted to these dose subgroups, with consistent findings in the two survivor cohorts., Conclusions: Our study provides strong evidence that germline genetics outside high-risk syndromes could modify the effect of radiation exposure on breast cancer risk after childhood cancer., (Published by Oxford University Press 2017. This work is written by US Government employees and is in the public domain in the US.)

Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.

Human bipedal balance control is achieved either reactively or predictively by a distributed network of neural areas within the central nervous system with a potential role for cerebral cortex. While the role of the cortex in reactive balance has been widely explored, only few studies have addressed the cortical activations related to predictive balance control. The present study investigated the cortical activations related to the preparation and execution of anticipatory postural adjustment (APA) that precede a step. This study also examined whether the preparatory cortical activations related to a specific movement is dependent on the context of control (postural component vs. focal component). Ground reaction forces and electroencephalographic (EEG) data were recorded from 14 healthy adults while they performed lateral weight shift and lateral stepping with and without initially preloading their weight to the stance leg. EEG analysis revealed that there were distinct movement-related potentials (MRPs) with concurrent event-related desynchronization (ERD) of mu and beta rhythms prior to the onset of APA and also to the onset of foot-off during lateral stepping in the fronto-central cortical areas. Also, the MRPs and ERD prior to the onset of APA and onset of lateral weight shift were not significantly different suggesting the comparable cortical activations for the generation of postural and focal movements. The present study reveals the occurrence of cortical activation prior to the execution of an APA that precedes a step. Importantly, this cortical activity appears independent of the context of the movement., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

DNA replication-associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutation consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (>250/Mb), which was greater than all childhood and most cancers (>7,000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerase ɛ or δ. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P < 10(-13)). Sequential tumor biopsy analysis revealed that bMMRD/polymerase-mutant cancers rapidly amass an excess of simultaneous mutations (∼600 mutations/cell division), reaching but not exceeding ∼20,000 exonic mutations in <6 months. This implies a threshold compatible with cancer-cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair.

Purpose: To investigate molecular alterations in choroid plexus tumors (CPT) using a genome-wide high-throughput approach to identify diagnostic and prognostic signatures that will refine tumor stratification and guide therapeutic options., Experimental Design: One hundred CPTs were obtained from a multi-institutional tissue and clinical database. Copy-number (CN), DNA methylation, and gene expression signatures were assessed for 74, 36, and 40 samples, respectively. Molecular subgroups were correlated with clinical parameters and outcomes., Results: Unique molecular signatures distinguished choroid plexus carcinomas (CPC) from choroid plexus papillomas (CPP) and atypical choroid plexus papillomas (aCPP); however, no significantly distinct molecular alterations between CPPs and aCPPs were observed. Allele-specific CN analysis of CPCs revealed two novel subgroups according to DNA content: hypodiploid and hyperdiploid CPCs. Hyperdiploid CPCs exhibited recurrent acquired uniparental disomy events. Somatic mutations in TP53 were observed in 60% of CPCs. Investigating the number of mutated copies of p53 per sample revealed a high-risk group of patients with CPC carrying two copies of mutant p53, who exhibited poor 5-year event-free (EFS) and overall survival (OS) compared with patients with CPC carrying one copy of mutant p53 (OS: 14.3%, 95% confidence interval, 0.71%-46.5% vs. 66.7%, 28.2%-87.8%, respectively, P = 0.04; EFS: 0% vs. 44.4%, 13.6%-71.9%, respectively, P = 0.03). CPPs and aCPPs exhibited favorable survival., Discussion: Our data demonstrate that differences in CN, gene expression, and DNA methylation signatures distinguish CPCs from CPPs and aCPPs; however, molecular similarities among the papillomas suggest that these two histologic subgroups are indeed a single molecular entity. A greater number of copies of mutated TP53 were significantly associated to increased tumor aggressiveness and a worse survival outcome in CPCs. Collectively, these findings will facilitate stratified approaches to the clinical management of CPTs., (©2014 American Association for Cancer Research.)

Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Recent evidence indicates that genetic variation in fatty acid desaturases 1 and 2 (FADS1 and FADS2) is associated with changes in plasma fatty acid profiles; however, the association with altered desaturase activity has not been examined in different ethnic populations. The present study examined whether genetic variation in the FADS gene cluster regulates desaturase activity in two populations of young Canadian adults (Caucasian and Asian) and whether altered desaturase activity was reflected in both n-3 and n-6 fatty acid profiles. FADS1 and FADS2 were genotyped in a random subset of participants (Caucasian, n=78; Asian, n=69) from the Toronto Nutrigenomics and Health study using MALDI-TOF mass spectrometry, and plasma fatty acids were measured by gas chromatography. Desaturase activities were estimated using the following fatty acid ratios: γ-linoleic acid to linoleic acid (GLA:LA), arachidonic acid to linoleic acid (AA:LA), arachidonic acid to dihomo-γ-linoleic acid (AA:DGLA), and eicosapentaneoic acid to α-linolenic acid (EPA:ALA). Nineteen single nucleotide polymorphisms (SNPs) were examined, and several SNPs (9 in Caucasians and 8 in Asians) were associated with various desaturase activities. The most significant association detected was between the FADS1 rs174547 SNP and AA:LA in both Caucasians (p=4.0 × 10(-8)) and Asians (p=5.0 × 10(-5)). Although the minor allele for this SNP differed between Caucasians (T) and Asians (C), carriers of the C allele had a lower desaturase activity than carriers of the T allele in both groups. To determine whether rs174547 was a dominant SNP in the FADS gene cluster, we constructed an additional model which included this SNP as a covariate. Only one SNP (rs498793 in FADS2) remained associated with the EPA:ALA ratio (p=1.1 × 10(-5)) in Asians. This study shows that genetic variation in the FADS gene cluster (in particular rs174547) can alter desaturase activity in subjects of Caucasians and Asian descent., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Perturbations in lipid metabolism characterize many of the chronic diseases currently plaguing our society, such as obesity, diabetes, and cardiovascular disease. Thus interventions that target plasma lipid levels remain a primary goal to manage these diseases. The determinants of plasma lipid levels are multi-factorial, consisting of both genetic and lifestyle components. Recent evidence indicates that fatty acid desaturases have an important role in defining plasma and tissue lipid profiles. This review will highlight the current state-of-knowledge regarding three desaturases (Scd-1, Fads1 and Fads2) and their potential roles in disease onset and development. Although research in rodent models has provided invaluable insight into the regulation and functions of these desaturases, the extent to which murine research can be translated to humans remains unclear. Evidence emerging from human-based research demonstrates that genetic variation in human desaturase genes affects enzyme activity and, consequently, disease risk factors. Moreover, this genetic variation may have a trans-generational effect via breastfeeding. Therefore inter-individual variation in desaturase function is attributed to both genetic and lifestyle components. As such, population-based research regarding the role of desaturases on disease risk is challenged by this complex gene-lifestyle paradigm. Unravelling the contribution of each component is paramount for understanding the inter-individual variation that exists in plasma lipid profiles, and will provide crucial information to develop personalized strategies to improve health management.

A deficiency in major seed storage proteins is associated with a nearly two-fold increase in sulfur amino acid content in genetically related lines of common bean (Phaseolus vulgaris). Their mature seed proteome was compared by an approach combining label-free quantification by spectral counting, 2-DE, and analysis of selective extracts. Lack of phaseolin, phytohemagglutinin and arcelin was mainly compensated by increases in legumin, alpha-amylase inhibitors and mannose lectin FRIL. Along with legumin, albumin-2, defensin and albumin-1 were major contributors to the elevated sulfur amino acid content. Coordinate induction of granule-bound starch synthase I, starch synthase II-2 and starch branching enzyme were associated with minor alteration of starch composition, whereas increased levels of UDP-glucose 4-epimerase were correlated with a 30% increase in raffinose content. Induction of cell division cycle protein 48 and ubiquitin suggested enhanced ER-associated degradation. This was not associated with a classical unfolded protein response as the levels of ER HSC70-cognate binding protein were actually reduced in the mutant. Repression of rab1 GTPase was consistent with decreased traffic through the secretory pathway. Collectively, these results have implications for the nutritional quality of common bean, and provide information on the pleiotropic phenotype associated with storage protein deficiency in a dicotyledonous seed., (Crown Copyright 2010. Published by Elsevier B.V. All rights reserved.)

The Balanopaceae, whose flowers were poorly known, have, in the past, been variously allocated to the Fagales, Euphorbiaceae, Salicales or other hamamelids and rosids (these groups being in Fagales, Malpighiales and Saxifragales, according to the Angiosperm Phylogeny Group). This paper attempts a clarification based on flower morphology. Female flowers and cupules were studied in Balanops vieillardii, young fruits in B. australiana. The cupules are simple involucres of bracts which are spirally arranged (according to a Fibonacci pattern) on the floral axis preceding the flower. They contrast with the complicated cupules of Fagaceae which consist of a condensed cymose ramification system of axes of several orders around the flower. Flowers appear later than most of the cupular bracts, in contrast to Fagaceae. In addition to a terminal flower there may be several smaller lateral flowers in the axil of cupular bracts, each surrounded by its own small cupule. The female flowers do not have a perianth. They consist of two to three large carpels. At anthesis, the ovary is completely septate; the syncarpous part (ovary and lower style) is completely symplicate. The carpels are free for most of their length, with the free parts once, twice or three times bifurcate, in contrast to simple in Fagales. The stigmatic surface covers the ventral side of each stigmatic branch and at the margins also spreads to the dorsal side. The stigma is wet and secretion appears holocrine. The two ovules per carpel are collateral and axile in early development. However, at anthesis they appear one above the other, because in one ovule the funicle greatly elongates. As the ovary elongates only above the placenta, the ovules appear basal at anthesis. The ovules are (weakly) crassinucellar, bitegmic (not unitegmic), anatropous, and intermediate between apotropous and epitropous (not apotropous). The ovules are mature at anthesis, in contrast to Fagales. In mature ovules the upper part of the nucellus disintegrates, and a weakly differentiated endothelium is present in the inner integument. The morphological results of this study support a position of Balanopaceae in Malpighiales, and not Fagales or other orders, and are thus in accordance with recent molecular results based on chloroplast rbcL sequences data. However, within Malpighiales, as opposed to molecular results, Balanopaceae agree more with Euphorbiaceae s.l. than with Dichapetalaceae/Trigoniaceae and Chrysobalanaceae/Euphroniaceae.