scholarly journals Principles of ecDNA random inheritance drive rapid genome change and therapy resistance in human cancers

2021 ◽  
Author(s):  
Joshua T. Lange ◽  
Celine Y. Chen ◽  
Yuriy Pichugin ◽  
Frank Xie ◽  
Jun Tang ◽  
...  
Keyword(s):  
Copy Number ◽  
A Priori ◽  
Metabolic Stress ◽  
Therapy Resistance ◽  
Darwinian Evolution ◽  
Identity By Descent ◽  
Oncogene Amplification ◽  
Poor Outcomes ◽  
The Impact ◽  
Variation And Selection

The foundational principles of Darwinian evolution are variation, selection, and identity by descent. Oncogene amplification on extrachromosomal DNA (ecDNA) is a common event, driving aggressive tumour growth, drug resistance, and shorter survival in patients. Currently, the impact of non-chromosomal oncogene inheritance - random identity by descent - is not well understood. Neither is the impact of ecDNA on variation and selection. Here, integrating mathematical modeling, unbiased image analysis, CRISPR-based ecDNA tagging, and live-cell imaging, we identify a set of basic rules for how random ecDNA inheritance drives oncogene copy number and distribution, resulting in extensive intratumoural ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted cancer treatment. Observed ecDNAs obligatorily benefit host cell survival or growth and can change within a single cell cycle. In studies ranging from well-curated, patient-derived cancer cell cultures to clinical tumour samples from patients with glioblastoma and neuroblastoma treated with oncogene-targeted drugs, we show how these ecDNA inheritance rules can predict, a priori, some of the aggressive features of ecDNA-containing cancers. These properties are entailed by their ability to rapidly change their genomes in a way that is not possible for cancers driven by chromosomal oncogene amplification. These results shed new light on how the non-chromosomal random inheritance pattern of ecDNA underlies poor outcomes for cancer patients.

scholarly journals Comprehensive characterization and clinical relevance of the SWI/SNF copy number aberrations across human cancers

Hereditas ◽  
2021 ◽  
Vol 158 (1) ◽  
Author(s):  
Zhiwei Xing ◽  
Buhuan Ma ◽  
Weiting Sun ◽  
Yimin Sun ◽  
Caixia Liu
Keyword(s):  
Copy Number ◽  
Human Cancer ◽  
Therapy Resistance ◽  
The Cancer Genome Atlas ◽  
Dna Damage And Repair ◽  
Human Cancers ◽  
Oncogenic Pathways ◽  
Cancer Types ◽  
Tcga Dataset ◽  
The Impact

Abstract Background Alterations in genes encoding chromatin regulatory proteins are prevalent in cancers and may confer oncogenic properties and molecular changes linked to therapy resistance. However, the impact of copy number alterations (CNAs) of the SWItch/Sucrose NonFermentable (SWI/SNF) complex on the oncogenic and immunologic properties has not been systematically explored across human cancer types. Methods We comprehensively analyzed the genomic, transcriptomic and clinical data of The Cancer Genome Atlas (TCGA) dataset across 33 solid cancers. Results CNAs of the SWI/SNF components were identified in more than 25% of all queried cancers, and tumors harboring SWI/SNF CNAs demonstrated a worse overall survival (OS) than others in several cancer types. Mechanistically, the SCNA events in the SWI/SNF complex are correlated with dysregulated genomic features and oncogenic pathways, including the cell cycle, DNA damage and repair. Notably, the SWI/SNF CNAs were associated with homologous recombination deficiency (HRD) and improved clinical outcomes of platinum-treated ovarian cancer. Furthermore, we observed distinct immune infiltrating patterns and immunophenotypes associated with SWI/SNF CNAs in different cancer types. Conclusion The CNA events of the SWI/SNF components are a key process linked to oncogenesis, immune infiltration and therapeutic responsiveness across human cancers.

scholarly journals Chromosome 1q21 abnormalities in multiple myeloma

2021 ◽  
Vol 11 (4) ◽  
Author(s):  
Timothy M. Schmidt ◽  
Rafael Fonseca ◽  
Saad Z. Usmani
Keyword(s):  
Multiple Myeloma ◽  
Copy Number ◽  
Causative Factor ◽  
Genetic Abnormality ◽  
Chromosome 1Q ◽  
Early Progression ◽  
Plasma Cell Neoplasms ◽  
Poor Outcomes ◽  
The Impact ◽  
Chromosome 1Q21

AbstractGain of chromosome 1q (+1q) is one of the most common recurrent cytogenetic abnormalities in multiple myeloma (MM), occurring in approximately 40% of newly diagnosed cases. Although it is often considered a poor prognostic marker in MM, +1q has not been uniformly adopted as a high-risk cytogenetic abnormality in guidelines. Controversy exists regarding the importance of copy number, as well as whether +1q is itself a driver of poor outcomes or merely a common passenger genetic abnormality in biologically unstable disease. Although the identification of a clear pathogenic mechanism from +1q remains elusive, many genes at the 1q21 locus have been proposed to cause early progression and resistance to anti-myeloma therapy. The plethora of potential drivers suggests that +1q is not only a causative factor or poor outcomes in MM but may be targetable and/or predictive of response to novel therapies. This review will summarize our current understanding of the pathogenesis of +1q in plasma cell neoplasms, the impact of 1q copy number, identify potential genetic drivers of poor outcomes within this subset, and attempt to clarify its clinical significance and implications for the management of patients with multiple myeloma.

Circulating tumor cell (CTC) genomic signatures of hormone therapy resistance in men with metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 147-147
Author(s):  
Santosh Gupta ◽  
Susan Halabi ◽  
Gabor Kemeny ◽  
Monika Anand ◽  
David M. Nanus ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Copy Number ◽  
Clonal Evolution ◽  
Circulating Tumor Cell ◽  
Therapy Resistance ◽  
Comparative Genomic ◽  
Copy Number Alterations ◽  
Castration Resistant Prostate Cancer ◽  
Protein Assay ◽  
Poor Outcomes

147 Background: Men with CTC AR-V7 + mCRPC have very poor outcomes when treated with enzalutamide/abiraterone. However, many men lack AR-V7. Here, we determined whether baseline or post-treatment DNA alterations in CTCs from AR-V7 negative mCRPC men could provide clinical utility in predicting outcomes with these hormonal therapies. Methods: We analyzed whole-genome copy number alterations (CNA) using array-comparative genomic hybridization (aCGH) in CTCs from 48 men (45 baseline and 28 progression), and whole-exome sequencing (WES) from 11 mCRPC men treated with abi/enza, longitudinally, and focused exclusively on AR-V7 negative men (N = 40) by the Epic-AR-V7 nuclear protein assay, and comparing those men who benefit from therapy vs. who do not. Results: We observed broad heterogeneity of CNAs between patients; common genomic alterations included gain in KDM6A (44%), FOXA1 (44%), MYCN (32%), and AR (38%), and loss in BRCA1 (30%) and PTEN (25%). Men who had the clinical benefit to abi/enza (n = 23, median PFS 10 mo) were more likely to have CTCs with genomic gains of ATM, HSD17B4, or PTEN, and loss of BRAF, ABL1, or NKX3-1. Likewise, men who did not benefit from abi/enza (n = 14, median PFS 2.6 mo) had CTCs with more copy number alterations than men who had clinical benefit (median 19.5 vs. 14, p = 0.01), and were enriched for gain of BRCA2, APC, KDM5D, SPARC, MYCN, AR, and CYP11B1, and loss of PTEN, CHD1, PHLPP1, and NCOR2. After progression on abi/enza, we observed clonal evolution of CTCs harboring gain of ATM, FOXA1, KDM6A, CYP11B1, MYC, APC, and NCOR2, and loss of NCOR1, ERG, and RUNX2. Several COSMIC-validated non-synonymous pathogenic exome mutations were detected in progressed or non-responding patients’ CTC DNA; TP53 (55 vs 27% at baseline), AKAP9 (36 vs 9%), CDK12, KMT2D, and BRAF (each 36 vs 18%), and BRD4 and SPOP (each 18 vs 0%). Conclusions: We demonstrate that specific CTC genomic profiles associated with TP53, PTEN, WNT, DNA repair, epigenetic, and AR signaling, as well as lineage plasticity pathways are associated with worse clinical outcomes in AR-V7 negative men with mCRPC treated with abi/enza. Further mechanistic and validation studies are warranted. Clinical trial information: NCT02269982.

The impact of paralog genes: detection of copy number variation in spinal muscle atrophy patients

BIOCELL ◽  
2018 ◽  
Vol 42 (3) ◽  
pp. 87-91 ◽  
Author(s):  
Sergio LAURITO ◽  
Juan A. CUETO ◽  
Jimena PEREZ ◽  
Mar韆 ROQU�
Keyword(s):  
Copy Number Variation ◽  
Muscle Atrophy ◽  
Copy Number ◽  
Number Variation ◽  
The Impact

The Impact of Competitive Quasi-Market on Service Delivery in Benue State University, Makurdi Nigeria

GIS Business ◽  
2019 ◽  
Vol 14 (4) ◽  
pp. 85-98
Author(s):  
Idoko Peter
Keyword(s):  
Service Delivery ◽  
A Priori ◽  
Least Square ◽  
Secondary Source ◽  
State University ◽  
Ordinary Least Square ◽  
Negative Effect ◽  
The Impact ◽  
The Relationship

This research the impact of competitive quasi market on service delivery in Benue State University, Makurdi Nigeria. Both primary and secondary source of data and information were used for the study and questionnaire was used to extract information from the purposively selected respondents. The population for this study is one hundred and seventy three (173) administrative staff of Benue State University selected at random. The statistical tools employed was the classical ordinary least square (OLS) and the probability value of the estimates was used to tests hypotheses of the study. The result of the study indicates that a positive relationship exist between Competitive quasi marketing in Benue State University, Makurdi Nigeria (CQM) and Transparency in the service delivery (TRSP) and the relationship is statistically significant (p<0.05). Competitive quasi marketing (CQM) has a negative effect on Observe Competence in Benue State University, Makurdi Nigeria (OBCP) and the relationship is not statistically significant (p>0.05). Competitive quasi marketing (CQM) has a positive effect on Innovation in Benue State University, Makurdi Nigeria (INVO) and the relationship is statistically significant (p<0.05) and in line with a priori expectation. This means that a unit increases in Competitive quasi marketing (CQM) will result to a corresponding increase in innovation in Benue State University, Makurdi Nigeria (INVO) by a margin of 22.5%. It was concluded that government monopoly in the provision of certain types of services has greatly affected the quality of service experience in the institution. It was recommended among others that the stakeholders in the market has to be transparent so that the system will be productive to serve the society effectively

Glucose Levels and Outcome After Primary Intraventricular Hemorrhage

2019 ◽  
Vol 16 (1) ◽  
pp. 40-46
Author(s):  
Rui Guo ◽  
Ruiqi Chen ◽  
Chao You ◽  
Lu Ma ◽  
Hao Li ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Blood Glucose ◽  
Blood Glucose Level ◽  
Incidence Rate ◽  
Glucose Level ◽  
Intraventricular Hemorrhage ◽  
Laboratory Data ◽  
History Of ◽  
Poor Outcomes ◽  
The Impact

Background and Purpose: Hyperglycemia is reported to be associated with poor outcome in patients with spontaneous Intracerebral Hemorrhage (ICH), but the association between blood glucose level and outcomes in Primary Intraventricular Hemorrhage (PIVH) remains unclear. We sought to identify the parameters associated with admission hyperglycemia and analyze the impact of hyperglycemia on clinical outcome in patients with PIVH. Methods: Patients admitted to Department of Neurosurgery, West China Hospital with PIVH between 2010 and 2016 were retrospectively included in our study. Clinical, radiographic, and laboratory data were collected. Univariate and multivariate logistic regression analyses were used to identify independent predictors of poor outcomes. Results: One hundred and seventy patients were included in the analysis. Mean admission blood glucose level was 7.78±2.73 mmol/L and 10 patients (5.9%) had a history of diabetes mellitus. History of diabetes mellitus (P = 0.01; Odds Ratio [OR], 9.10; 95% Confidence Interval [CI], 1.64 to 50.54) was independent predictor of admission critical hyperglycemia defined at 8.17 mmol/L. Patients with admission critical hyperglycemia poorer outcome at discharge (P < 0.001) and 90 days (P < 0.001). After adjustment, admission blood glucose was significantly associated with discharge (P = 0.01; OR, 1.30; 95% CI, 1.06 to 1.59) and 90-day poor outcomes (P = 0.03; OR, 1.27; 95% CI, 1.03 to 1.58), as well as mortality at 90 days (P = 0.005; OR, 1.41; 95% CI, 1.11 to 1.78). In addition, admission critical hyperglycemia showed significantly increased the incidence rate of pneumonia in PIVH (P = 0.02; OR, 6.04; 95% CI 1.27 to 28.80) even after adjusting for the confounders. Conclusion: Admission blood glucose after PIVH is associated with discharge and 90-day poor outcomes, as well as mortality at 90 days. Admission hyperglycemia significantly increases the incidence rate of pneumonia in PIVH.

scholarly journals Frame me if you must: PrEP framing and the impact on adherence to HIV Pre-exposure Prophylaxis

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S439-S439
Author(s):  
Eric Ellorin ◽  
Jill Blumenthal ◽  
Sonia Jain ◽  
Xiaoying Sun ◽  
Katya Corado ◽  
...  
Keyword(s):  
A Priori ◽  
Social Groups ◽  
Continuous Measure ◽  
Gay Community ◽  
Randomized Controlled ◽  
Exposure Prophylaxis ◽  
The Impact ◽  
Actual Prevalence ◽  
Tenofovir Diphosphate

Abstract Background “PrEP whore” has been used both as a pejorative by PrEP opponents in the gay community and, reactively, by PrEP advocates as a method to reclaim the label from stigmatization and “slut-shaming.” The actual prevalence and impact of such PrEP-directed stigma on adherence have been insufficiently studied. Methods CCTG 595 was a randomized controlled PrEP demonstration project in 398 HIV-uninfected MSM and transwomen. Intracellular tenofovir-diphosphate (TFV-DP) levels at weeks 12 and 48 were used as a continuous measure of adherence. At study visits, participants were asked to describe how they perceived others’ reactions to them being on PrEP. These perceptions were categorized a priori as either “positively framed,” “negatively framed,” or both. We used Wilcoxon rank-sum to determine the association between positive and negative framing and TFV-DP levels at weeks 12 and 48. Results By week 4, 29% of participants reported perceiving positive reactions from members of their social groups, 5% negative, and 6% both. Reporting decreased over 48 weeks, but positive reactions were consistently reported more than negative. At week 12, no differences in mean TFV-DP levels were observed in participants with positively-framed reactions compared with those reporting no outcome or only negatively-framed (1338 [IQR, 1036-1609] vs. 1281 [946-1489] fmol/punch, P = 0.17). Additionally, no differences were observed in those with negative reactions vs. those without (1209 [977–1427] vs. 1303 [964–1545], P = 0.58). At week 48, mean TFV-DP levels trended toward being higher among those that report any reaction, regardless if positive (1335 [909–1665] vs. 1179 [841–1455], P = 0.09) or negative (1377 [1054–1603] vs. 1192 [838–1486], P = 0.10) than those reporting no reaction. At week 48, 46% of participants reported experiencing some form of PrEP-directed judgment, 23% reported being called “PrEP whore,” and 21% avoiding disclosing PrEP use. Conclusion Over 48 weeks, nearly half of participants reported some form of judgment or stigmatization as a consequence of PrEP use. However, individuals more frequently perceived positively framed reactions to being on PrEP than negative. Importantly, long-term PrEP adherence does not appear to suffer as a result of negative PrEP framing. Disclosures All authors: No reported disclosures.

scholarly journals Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants

2021 ◽  
Author(s):  
Elmo Christian Saarentaus ◽  
Aki Samuli Havulinna ◽  
Nina Mars ◽  
Ari Ahola-Olli ◽  
Tuomo Tapio Johannes Kiiskinen ◽  
...  
Keyword(s):  
High Risk ◽  
Educational Attainment ◽  
Household Income ◽  
Copy Number ◽  
Copy Number Variants ◽  
Well Being ◽  
Subjective Health ◽  
Polygenic Risk Score ◽  
The Impact ◽  
Health Cognition

AbstractCopy number variants (CNVs) are associated with syndromic and severe neurological and psychiatric disorders (SNPDs), such as intellectual disability, epilepsy, schizophrenia, and bipolar disorder. Although considered high-impact, CNVs are also observed in the general population. This presents a diagnostic challenge in evaluating their clinical significance. To estimate the phenotypic differences between CNV carriers and non-carriers regarding general health and well-being, we compared the impact of SNPD-associated CNVs on health, cognition, and socioeconomic phenotypes to the impact of three genome-wide polygenic risk score (PRS) in two Finnish cohorts (FINRISK, n = 23,053 and NFBC1966, n = 4895). The focus was on CNV carriers and PRS extremes who do not have an SNPD diagnosis. We identified high-risk CNVs (DECIPHER CNVs, risk gene deletions, or large [>1 Mb] CNVs) in 744 study participants (2.66%), 36 (4.8%) of whom had a diagnosed SNPD. In the remaining 708 unaffected carriers, we observed lower educational attainment (EA; OR = 0.77 [95% CI 0.66–0.89]) and lower household income (OR = 0.77 [0.66–0.89]). Income-associated CNVs also lowered household income (OR = 0.50 [0.38–0.66]), and CNVs with medical consequences lowered subjective health (OR = 0.48 [0.32–0.72]). The impact of PRSs was broader. At the lowest extreme of PRS for EA, we observed lower EA (OR = 0.31 [0.26–0.37]), lower-income (OR = 0.66 [0.57–0.77]), lower subjective health (OR = 0.72 [0.61–0.83]), and increased mortality (Cox’s HR = 1.55 [1.21–1.98]). PRS for intelligence had a similar impact, whereas PRS for schizophrenia did not affect these traits. We conclude that the majority of working-age individuals carrying high-risk CNVs without SNPD diagnosis have a modest impact on morbidity and mortality, as well as the limited impact on income and educational attainment, compared to individuals at the extreme end of common genetic variation. Our findings highlight that the contribution of traditional high-risk variants such as CNVs should be analyzed in a broader genetic context, rather than evaluated in isolation.

scholarly journals Using Unstated Cases to Correct for COVID-19 Pandemic Outbreak and Its Impact on Easing the Intervention for Qatar

Biology ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 463
Author(s):  
Narjiss Sallahi ◽  
Heesoo Park ◽  
Fedwa El Mellouhi ◽  
Mustapha Rachdi ◽  
Idir Ouassou ◽  
...  
Keyword(s):  
Public Health ◽  
A Priori ◽  
Epidemiological Models ◽  
Sir Epidemic Model ◽  
Gulf Region ◽  
Epidemiological Modeling ◽  
Public Health Policies ◽  
Sir Epidemic ◽  
The Impact ◽  
Case Data

Epidemiological Modeling supports the evaluation of various disease management activities. The value of epidemiological models lies in their ability to study various scenarios and to provide governments with a priori knowledge of the consequence of disease incursions and the impact of preventive strategies. A prevalent method of modeling the spread of pandemics is to categorize individuals in the population as belonging to one of several distinct compartments, which represents their health status with regard to the pandemic. In this work, a modified SIR epidemic model is proposed and analyzed with respect to the identification of its parameters and initial values based on stated or recorded case data from public health sources to estimate the unreported cases and the effectiveness of public health policies such as social distancing in slowing the spread of the epidemic. The analysis aims to highlight the importance of unreported cases for correcting the underestimated basic reproduction number. In many epidemic outbreaks, the number of reported infections is likely much lower than the actual number of infections which can be calculated from the model’s parameters derived from reported case data. The analysis is applied to the COVID-19 pandemic for several countries in the Gulf region and Europe.

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