medRxiv (Cold Spring Harbor Laboratory)最新文献

{"title":"The maintenance of complex visual scenes in working memory may require activation of working memory manipulation circuits in the dlPFC.","authors":"Frederick Nitchie, Abigail Casalvera, Marta Teferi, Milan Patel, Kevin G Lynch, Walid Makhoul, Yvette I Sheline, Nicholas L Balderston","doi":"10.1101/2023.11.11.23298415","DOIUrl":"https://doi.org/10.1101/2023.11.11.23298415","url":null,"abstract":"Past research has shown that the bilateral dorsolateral prefrontal cortices (dlPFC) are implicated in both emotional processing as well as cognitive processing, in addition to working memory Exactly how these disparate processes interact with one another within the dlPFC is less understood. To explore this, researchers designed an experiment that looked at working memory performance during fMRI under both emotional and non-emotional task conditions. Participants were asked to complete three tasks (letters, neutral images, emotional images) of the Sternberg Sorting Task under one of two trial conditions (sort or maintain). Regions of interest consisted of the left and right dlPFC as defined by brain masks based on NeuroSynth. Results showed a significant main effect of the sort condition on reaction speed for all three trial types, as well as a main effect of task type (letters) on accuracy. In addition, a significant interaction was found between trial type (sort) and task type (letters), but not for either of the picture tasks. These results reveal a discrepancy between BOLD signal and behavioral data, with no significant difference in BOLD activity during image trials being displayed, despite longer response times for every condition. While these results show that the dlPFC is clearly implicated in non-emotional cognitive processing, more research is needed to explain the lack of BOLD activation seen here for similar emotionally valanced tasks, possibly indicating involvement of other brain networks.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"19 3","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136346628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Navigating the Nexus of Food Insecurity, Anxiety, and Depression in the Face of Climate Change: A Longitudinal Study in Rural Kenya","authors":"Michael L Goodman, Lauren Raimer-Goodman, Heidi McPherson, Shreela Sharma, Ryan Ramphul, Dawit Woldu, Fridah Mukiri","doi":"10.1101/2023.11.13.23298460","DOIUrl":"https://doi.org/10.1101/2023.11.13.23298460","url":null,"abstract":"Objective: To investigate the temporal relationships between food insecurity, anxiety, and depression among adult participants in a community-based empowerment program in Meru County, Kenya. Methods: A cross-lagged panel analysis was conducted using data from 362 adult participants in a community-based empowerment program in Meru County, Kenya. Participants completed self-report measures of food insecurity, anxiety, and depression at two-time points, 11 weeks apart. Results: Food insecurity (T1) predicted subsequent anxiety and depression (T2), controlling for within-variable, within-time, and control-variable correlations. Village-level food insecurity (T1) was correlated with significantly higher anxiety (T2). Additionally, anxiety (T1) predicted higher subsequent food insecurity (T2). Conclusion: Food insecurity and anxiety have a complex bidirectional relationship. Interventions that address food security, mental health, and the psychosocial factors that promote adaptation to food-insecure environments are essential for promoting the well-being of individuals and communities in the face of climate change.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"49 19","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136281487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping the Interplay of Atrial Fibrillation, Brain Structure and Cognitive Dysfunction","authors":"Marvin Petersen, Celeste Chevalier, Felix L. Naegele, Thies Ingwersen, Amir Omidvarnia, Felix Hoffstaedter, Kaustubh Patil, Simon B. Eickhoff, Renate B. Schnabel, Paulus Kirchhof, Eckhard Schlemm, Bastian Cheng, Goetz Thomalla, Maerit Jensen","doi":"10.1101/2023.11.13.23298431","DOIUrl":"https://doi.org/10.1101/2023.11.13.23298431","url":null,"abstract":"Atrial fibrillation (AF) is associated with an elevated risk of cognitive impairment and dementia. The investigation of the cognitive sequelae and alterations of brain structure linked to AF is crucial to help address ensuing health care needs. In this study, we conducted a comprehensive neuropsychological and neuroimaging analysis of 1335 stroke-free individuals with AF (30% women, average age 69.1 years) and compared them with 2683 demographically and cardiovascular risk-matched controls (31% women, average age 69.1 years). Primary study outcomes were neuropsychological test scores and advanced magnetic resonance imaging (MRI) measures of gray matter morphology, gray and white matter microstructure, and white matter hyperintensity (WMH) load. Our analysis identified deficits in attention/executive function, information processing speed and reasoning in individuals with AF. These cognitive impairments were accompanied by a complex imaging profile suggestive of small vessel pathology: (1) reduced cortical thickness and gray matter volume in areas including primary motor, somatosensory and visual cortices as well as the orbitofrontal, lateral prefrontal, posterior insular, and temporal cortices; (2) increased extracellular free-water content in the anterior cingulate, insula, medial prefrontal cortex, medial temporal lobe, and precuneus; (3) widespread microstructural anomalies in the cerebral white matter, marked by lower fractional anisotropy (FA), higher mean diffusivity (MD) and extracellular free-water, and a higher burden of markers of small vessel disease (WMH load and peak width of skeletonized mean diffusivity). Crucially, brain structural differences statistically mediated the link between AF and cognitive performance. By integrating a multimodal analysis approach with extensive clinical and MRI data, our study highlights small vessel pathology as a possible unifying link between AF, cognitive decline and abnormal brain structure. These insights can inform diagnostic approaches and motivate the ongoing implementation of effective therapeutic strategies.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"48 10","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136282553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Somatic RIT1 indels identified in arteriovenous malformations hyperactivate RAS-MAPK signaling and are amenable to MEK inhibition","authors":"Friedrich G Kapp, Farhad Bazgir, Nagi Mahammadzade, Erik Vassella, Yvonne Doring, Annegret Holm, Axel Karow, Caroline Seebauer, Natascha Platz Batista da Silva, Walter A Wohlgemuth, Pia Kroning, Charlotte M Niemeyer, Denny Schanze, Martin Zenker, Whitney Eng, Mohammad Reza Ahmadian, Iris Baumgartner, Jochen Roessler","doi":"10.1101/2023.11.13.23298448","DOIUrl":"https://doi.org/10.1101/2023.11.13.23298448","url":null,"abstract":"Arteriovenous malformations (AVM) are benign vascular anomalies prone to pain, bleeding, and progressive growth. Treatment is often difficult and relapse after therapy is common. AVM are mainly caused by somatic mosaicism with pathogenic variants of the RAS-MAPK pathway. However, a causative variant is not identified in all patients. Using ultra-deep next generation sequencing we identified novel somatic RIT1 indel variants in lesional tissue of three AVM patients. RIT1 - not previously implicated in AVM development - encodes a RAS-like protein that can modulate RAS-MAPK signaling. For biochemical characterization, we expressed RIT1 variants in HEK293T cells, which led to a strong increase in ERK1/2 phosphorylation. Endothelial-specific mosaic overexpression of the RIT1 indels in zebrafish embryos induced AVM formation, highlighting the functional importance in vascular development. Both ERK1/2 hyperactivation in vitro and AVM formation in vivo could be suppressed by pharmacological MEK inhibition. Targeted treatment with the MEK inhibitor trametinib led to a significant decrease in bleeding episodes and AVM size in one patient. Our findings expand the genetic spectrum of AVM by identifying RIT1 as a novel gene involved in AVM formation and pave the way for targeted treatment and clinical trials in patients with AVM.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"68 4","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136348405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic analyses of inflammatory polyneuropathy and chronic inflammatory demyelinating polyradiculoneuropathy identified candidate genes.","authors":"Zhaohui Du, Samuel Lessard, Tejaswi Iyyanki, Michael Chao, Timothy Hammond, Dimitry Ofengeim, Katherine Klinger, Emanuele de Rinaldis, Shameer Khader, Clement Chatelain","doi":"10.1101/2023.11.13.23298433","DOIUrl":"https://doi.org/10.1101/2023.11.13.23298433","url":null,"abstract":"Objective: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare, immune-mediated disorder in which an aberrant immune response causes demyelination and axonal damage of the peripheral nerves. Genetic contribution to CIDP is unclear and no genome-wide association study (GWAS) has been reported so far. In this study, we aimed to identify CIDP-related risk loci, genes and pathways. Methods: To increase power, we first included all patients with a diagnosis of inflammatory polyneuropathy (IP) as cases. We performed a GWAS study using FinnGen R10 individual data and combined the results with GWAS from UK biobank (UKBB) using a fixed-effect meta-analysis. A total of 1,261 IP cases and 823,730 controls were included in the analysis. The second GWAS focused on CIDP patients and a total of 516 CIDP cases and 403,545 controls were included in the analysis. Stratified analyses by gender were also performed for both IP and CIDP. We performed gene-level analyses using transcriptome-wide mendelian randomization (TWMR) analysis, colocalization analysis, transcriptome-wide association study (TWAS) using S-PrediXcan and MAGMA to identify genes associated with IP and CIDP. Gene-set analyses were conducted using MAGMA to identify pathways that are related to IP and CIDP. Results: In GWAS study, we identified one genome-wide significant loci at 20q13.33 for CIDP risk among women; the top variant located at the intron region of gene CDH4. TWMR, colocalization and S-PrediXcan analyses identified DGKQ, GLDC, IDUA, SLAMF9 and TMEM175 as candidate pathogenic genes for IP; genes DIRAS1, GNG7, and SLC39A3 for CIDP; genes DIRAS1, DCTN1, and ME1 for IP among males; and genes DIRAS1 and ME1 for IP among women. MAGMA gene-set analyses identified a total of 18 pathways related to IP or CIDP. Conclusion: Our study identified suggestive risk genes and pathways for IP and CIDP. Functional analysis should be conducted to further confirm these associations.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"71 4","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136348691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prosthetic Visual Acuity with the PRIMA System in Patients with Atrophic Age-related Macular Degeneration at 4 years follow-up","authors":"MAHIUL MK MUQIT, YANNICK LE MER, LISA C OLMOS DE KOO, FRANK G HOLZ, JOSE A SAHEL, Daniel Palanker","doi":"10.1101/2023.11.12.23298227","DOIUrl":"https://doi.org/10.1101/2023.11.12.23298227","url":null,"abstract":"Objective: To assess the efficacy and safety of the PRIMA subretinal neurostimulation system 48-months post-implantation for improving visual acuity (VA) in patients with geographic atrophy (GA) due to age-related macular degeneration (AMD) at 48-months post-implantation. Design: First-in-human clinical trial of the PRIMA subretinal prosthesis in patients with atrophic AMD, measuring best-corrected ETDRS VA (Clinicaltrials.gov NCT03333954 ). Subjects: Five patients with GA, no foveal light perception and VA of logMAR 1.3 to 1.7 in their worse-seeing study eye. Methods: In patients implanted with a subretinal photovoltaic neurostimulation array containing 378 pixels of 100 μm in size, the VA was measured with and without the PRIMA system using ETDRS charts at 1 meter. The systems external components: augmented reality glasses and pocket computer, provide image processing capabilities, including zoom. Main Outcome Measures: VA using ETDRS charts with and without the system. Light sensitivity in the central visual field, as measured by Octopus perimetry. Anatomical outcomes demonstrated by fundus photography and optical coherence tomography up to 48-months post-implantation. Results: All five subjects met the primary endpoint of light perception elicited by the implant in the scotoma area. In one patient the implant was incorrectly inserted into the choroid. One subject died 18-months post-implantation due to study-unrelated reason. ETDRS VA results for the remaining three subjects are reported herein. Without zoom, VA closely matched the pixel size of the implant: 1.17 +/- 0.13 pixels, corresponding to mean logMAR 1.39, or Snellen 20/500, ranging from 20/438 to 20/565. Using zoom at 48 months, subjects improved their VA by 32 ETDRS letters versus baseline (SE 5.1) 95% CI[13.4,49.9], p<0.0001. Natural peripheral visual function in the treated eye did not decline after surgery compared to the fellow eye (p=0.08) during the 48 months follow-up period. Conclusions: Subretinal implantation of PRIMA in subjects with GA suffering from profound vision loss due to AMD is feasible and well tolerated, with no reduction of natural peripheral vision up to 48-months. Using prosthetic central vision through photovoltaic neurostimulation, patients reliably recognized letters and sequences of letters,and with zoom it provided a clinically meaningful improvement in VA of up to eight ETDRS lines.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"66 13","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136282637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Misclassification of yellow fever vaccination status revealed through hierarchical Bayesian modeling","authors":"Quan Minh Tran, Alex Perkins","doi":"10.1101/2023.11.12.23298434","DOIUrl":"https://doi.org/10.1101/2023.11.12.23298434","url":null,"abstract":"Vaccination coverage estimates are crucial inputs to decisions about investments in vaccination, yet they can be prone to inaccuracies. At the individual level, inaccuracies can be described in terms of the sensitivity and specificity of vaccination status. We estimated these quantities using a hierarchical Bayesian analysis of data from a test-negative study design with reported yellow fever vaccination status as the exposure. Our analysis accounted for the possibility of misclassification of both the exposure and the test at the country level. Across all countries, our median estimates of the sensitivity and specificity of vaccination status were 0.69 (95% credible interval [CrI]: 0.21-0.98) and 0.70 (95% CrI: 0.21-0.98), respectively. Median estimates at the country level ranged from 0.06 (95% CrI: 0.04-0.09) to 0.96 (95% CrI: 0.94-0.98) for sensitivity, and from 0.15 (95% CrI: 0.09-0.23) to 0.98 (95% CrI: 0.90-1.00) for specificity. This suggests that there is substantial misclassification of yellow fever vaccination status in general and extensive variation in misclassification across countries. Taking into account misclassification in vaccination status, we made adjustments to reported vaccination coverage and showed that reported coverage may be significantly underestimated in 10 out of 20 countries and significantly overestimated in 5 out of 20.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"61 29","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136283772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comparative medical genomics approach may facilitate the interpretation of rare missense variation","authors":"Bushra Haque, George Guirguis, Meredith Curtis, Hera Mohsin, Susan Walker, Michelle M Morrow, Gregory Costain","doi":"10.1101/2023.11.13.23298179","DOIUrl":"https://doi.org/10.1101/2023.11.13.23298179","url":null,"abstract":"Purpose: To determine the degree to which likely causal missense variants of single-locus traits in non-human livestock and domestic species have features suggestive of pathogenicity in a human genomic context. Methods: We extracted missense variants from the Online Mendelian Inheritance in Animals database for nine animals (cat, cattle, chicken, dog, goat, horse, pig, rabbit, sheep), mapped coordinates to the human reference genome, and annotated variants using standard genome analysis tools. We also searched a private commercial laboratory database of genetic testing results from >400,000 individuals with suspected rare disorders. Results: Of the 339 variants that were mappable to the human genome and impacted identical residues, 56 had been previously classified with respect to pathogenicity: 31 (55.4%) pathogenic/likely pathogenic, 1 (1.8%) benign/likely benign, and 24 (42.9%) uncertain/other. The odds ratio for a pathogenic/likely pathogenic classification in ClinVar was 7.0 (95% confidence interval: 4.1-12.0, p<0.0001), compared to all other germline missense variants in these same 220 genes. The remaining 283 variants disproportionately had allele frequencies and REVEL scores that supported pathogenicity. Conclusion: Cross-species comparisons could facilitate the interpretation of rare missense variation. These results provide further support for comparative medical genomics approaches that connect big data initiatives in human and veterinary genetics.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"74 4","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136347991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human enteric nervous system progenitor transplantation restores functional responses in Hirschsprung Disease patient-derived tissue","authors":"Benjamin Jevans, Fay Cooper, Yuliia Fatieieva, Antigoni Gogolou, Yi-Ning Kang, Restuadi Restuadi, Pieter Vanden Berghe, Igor Adameyko, Nikhil Thapar, Peter W Andrews, Paolo De Coppi, Anestis Tsakiridis, Conor J McCann","doi":"10.1101/2023.11.13.23298455","DOIUrl":"https://doi.org/10.1101/2023.11.13.23298455","url":null,"abstract":"Objective: Hirschsprung disease (HSCR) is a severe congenital disorder affecting 1:5000 live births. HSCR results from failure of enteric nervous system (ENS) progenitors to fully colonise the gastrointestinal tract during embryonic development. This leads to aganglionosis in the distal bowel, resulting in disrupted motor activity and impaired peristalsis. Currently, the only viable treatment option is surgical resection of the aganglionic bowel. However, patients frequently suffer debilitating, lifelong symptoms, with multiple surgical procedures often necessary. Hence, alternative treatment options are crucial. An attractive strategy involves the transplantation of ENS progenitors generated from human pluripotent stem cells (hPSCs). Design: ENS progenitors were generated from hPSCs using an accelerated protocol and characterised, in detail, through a combination of single cell RNA-sequencing, protein expression analysis and calcium imaging. We tested ENS progenitors' capacity to integrate and restore functional responses in HSCR colon, after ex vivo transplantation to organotypically cultured patient-derived colonic tissue, using organ bath contractility. Results: We found that our protocol consistently gives rise to high yields of cell populations exhibiting transcriptional and functional hallmarks of early ENS progenitors. Following transplantation, hPSC-derived ENS progenitors integrate, migrate and form neurons within explanted human HSCR colon samples. Importantly, the transplanted HSCR tissue displayed increased basal contractile activity and increased responses to electrical stimulation compared to control tissue. Conclusion: Our findings demonstrate, for the first time, the potential of hPSC-derived ENS progenitors to repopulate and restore functional responses in human HSCR patient colonic tissue.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"66 7","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136348269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and validation of multivariate predictors of primary endocrine resistance to tamoxifen and aromatase inhibitors in luminal breast cancer reveal drug-specific differences","authors":"Guokun Zhang, Vindi Jurinovic, Stephan Bartels, Matthias Christgen, Henriette Christgen, Leonie Donata Kandt, Mieke Raap, Janin Klein, Anna-Lena Katzke, Winfried Hofmann, Doris Steinemann, Ron Kates, Oleg Gluz, Monika Graeser, Sherko Kuemmel, Ulrike Nitz, Christoph Plass, Ulrich Lehmann, Ulrich Mansmann, Clarissa Gerhauser, Nadia Harbeck, Hans H. Kreipe","doi":"10.1101/2023.11.13.23298466","DOIUrl":"https://doi.org/10.1101/2023.11.13.23298466","url":null,"abstract":"Background : Endocrine therapy is highly effective in blocking the estrogen receptor pathway in HR+/HER2- early breast cancer (EBC). However, up to 40% of patients experience relapse during or after adjuvant endocrine therapy. Here, we investigate molecular mechanisms associated with primary resistance to endocrine therapy and develop predictive models. Patients and Methods : In the WSG-ADAPT trial ( NCT01779206 ), HR+/HER2- EBC patients underwent pre-operative short-term endocrine therapy (pET). Treatment response was determined by immunohistochemical in-situ labeling of cycling cells (G1 to M-phase) with Ki67 before and after pET. We performed targeted next generation sequencing and Infinium MethylationEPIC-based DNA methylation analysis post-pET in a discovery cohort (n=364, responder (R) and non-responder (NR) pairs matched for clinicopathologic features) and a validation cohort (n=270, unmatched). Predictive indices of endocrine resistance under both treatments were constructed using lasso penalized logistic regression. A subset of breast cancers from The Cancer Genome Atlas project (TCGA-BRCA) was used for external validation. Results : TP53 mutations were prominently associated with primary resistance to both tamoxifen (TAM) and aromatase inhibitors (AI), with AI non-responders exhibiting resistance in up to 32% of cases. Additionally, we identified distinct DNA methylation patterns in TAM and AI non-responders, with TAM non-responders showing global DNA methylation loss, associated with KRAS signaling, apical junctions and epithelial-mesenchymal transition (EMT). Conversely, we observed methylation gain in AI non-responders affecting developmental transcription factors, hypoxia and estrogen signaling. TAM or AI resistance was associated with increased methylation-inferred proportions of immune cells and decreased proportions of endothelial cells. Based on these findings and patient age, we developed the Predictive Endocrine ResistanCe Index (PERCI). PERCI stratified NR and R cases in both treatment groups and cohorts with high accuracy (ROC AUC TAM discovery 93.9%, validation 83%; AI discovery 98.6%, validation 76.9%). A simplified PERCI efficiently predicted progression-free survival in the TCGA-BRCA sub-cohort (Kaplan-Meier log-rank p-value = 0.03 between low and high PERCI groups). Conclusions : We identified genomic and epigenomic features associated with primary resistance to TMA and AI. By combining information on genomic alterations, patient age, differential methylation and tumor microenvironment (TME) composition, we developed PERCI TAM and PERCI AI as novel predictors of primary resistance, with potential additional prognostic value. Applying PERCI in a clinical setting may allow patient-specific drug selection to overcome resistance. WSG-ADAPT, NCT01779206 , Registered 2013-01-25, retrospectively registered.","PeriodicalId":478577,"journal":{"name":"medRxiv (Cold Spring Harbor Laboratory)","volume":"71 6","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136348689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}