Genetic Stratification Research Articles

Genetic markers of chronic lymphocytic leukemia: a retrospective study of 312 patients from a reference center in Lebanon.

Aim: Chronic lymphocytic leukemia (CLL) is a highly heterogenous hemopathy. Genetic stratification of CLL patients has important prognostic and therapeutic values -mainly immunoglobulin heavy chain variable regiongene (IGHV) mutational status and the presence of cytogenetic abnormalities. The genetics of CLL in Lebanon is scarcely described in the literature. Patients & methods: In this work, we studied the genetic biomarkers of 312 Lebanese CLL patients. Results: Prominent IGHV genes were IGHV4-34, IGHV1-69 and IGHV3-30; and CLL #1 and #5 presented major subsets. Some similarities as well as major differences were highlighted when comparing our data with previously published data. Conclusion: The distribution of IGHV alleles in our series differed from previously described distributions, suggesting involvement of antigenic selection and regional variables in CLL pathogenesis.

GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification

Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on ‘around the clock’ glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.

Pharmacogenetics of angiotensin modulators according to APOE-ϵ4 alleles and the ACE insertion/deletion polymorphism in Alzheimer's disease.

In Alzheimer's disease (AD), angiotensin II receptor blockers (ARBs) could reduce cerebrovascular dysfunction, while angiotensin-converting enzyme inhibitors (ACEis) might increase brain amyloid-β by suppressing effects of the angiotensin-converting enzyme 1, an amyloid-β-degrading enzyme. However, ACEis could benefit patients with AD by reducing the amyloidogenic processing of the amyloid precursor protein, by central cholinergic and anti-inflammatory mechanisms, and by peripheral modulation of glucose homeostasis. We aimed to investigate whether the ACE insertion/deletion polymorphism is associated with clinical changes in patients with AD, while considering apolipoprotein E (APOE)-ϵ4 carrier status and blood pressure response to angiotensin modulators. Consecutive outpatients with late-onset AD were screened with cognitive tests and anthropometric measurements, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic associations were estimated for 1 year, taking APOE-ϵ4 carrier status and genotypes of the ACE insertion/deletion polymorphism into account, along with treatment with ACEis or ARBs. For 193 patients (67.4% women, 53.4% APOE-ϵ4 carriers), the ACE insertion/deletion polymorphism was in Hardy-Weinberg equilibrium (p = 0.281), while arterial hypertension was prevalent in 80.3% (n = 124 used an ACEi, n = 21 used an ARB). ARBs benefitted mostly APOE-ϵ4 carriers concerning caregiver burden variations, cognitive and functional decline. ACEis benefitted APOE-ϵ4 non-carriers concerning cognitive and functional decline due to improved blood pressure control in addition to possible central mechanisms. The ACE insertion/deletion polymorphism led to variable response to angiotensin modulators concerning neurological outcomes and blood pressure variations. Angiotensin modulators may be disease-modifiers in AD, while genetic stratification of samples is recommended in clinical studies.

Targeting metabolic vulnerabilities to overcome resistance to therapy in acute myeloid leukemia.

Malignant hematopoietic cells gain metabolic plasticity, reorganize anabolic mechanisms to improve anabolic output and prevent oxidative damage, and bypass cell cycle checkpoints, eventually outcompeting normal hematopoietic cells. Current therapeutic strategies of acute myeloid leukemia (AML) are based on prognostic stratification that includes mutation profile as the closest surrogate to disease biology. Clinical efficacy of targeted therapies, e.g., agents targeting mutant FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase 1 or 2, are mostly limited to the presence of relevant mutations. Recent studies have not only demonstrated that specific mutations in AML create metabolic vulnerabilities but also highlighted the efficacy of targeting metabolic vulnerabilities in combination with inhibitors of these mutations. Therefore, delineating the functional relationships between genetic stratification, metabolic dependencies, and response to specific inhibitors of these vulnerabilities is crucial for identifying more effective therapeutic regimens, understanding resistance mechanisms, and identifying early response markers, ultimately improving the likelihood of cure. In addition, metabolic changes occurring in the tumor microenvironment have also been reported as therapeutic targets. The metabolic profiles of leukemia stem cells (LSCs) differ, and relapsed/refractory LSCs switch to alternative metabolic pathways, fueling oxidative phosphorylation (OXPHOS), rendering them therapeutically resistant. In this review, we discuss the role of cancer metabolic pathways that contribute to the metabolic plasticity of AML and confer resistance to standard therapy; we also highlight the latest promising developments in the field in translating these important findings to the clinic and discuss the tumor microenvironment that supports metabolic plasticity and interplay with AML cells.

Clinical impact of the genomic landscape and leukemogenic trajectories in non-intensively treated elderly acute myeloid leukemia patients

To characterize the genomic landscape and leukemogenic pathways of older, newly diagnosed, non-intensively treated patients with AML and to study the clinical implications, comprehensive genetics analyses were performed including targeted DNA sequencing of 263 genes in 604 patients treated in a prospective Phase III clinical trial. Leukemic trajectories were delineated using oncogenetic tree modeling and hierarchical clustering, and prognostic groups were derived from multivariable Cox regression models. Clonal hematopoiesis-related genes (ASXL1, TET2, SRSF2, DNMT3A) were most frequently mutated. The oncogenetic modeling algorithm produced a tree with five branches with ASXL1, DDX41, DNMT3A, TET2, and TP53 emanating from the root suggesting leukemia-initiating events which gave rise to further subbranches with distinct subclones. Unsupervised clustering mirrored the genetic groups identified by the tree model. Multivariable analysis identified FLT3 internal tandem duplications (ITD), SRSF2, and TP53 mutations as poor prognostic factors, while DDX41 mutations exerted an exceptionally favorable effect. Subsequent backwards elimination based on the Akaike information criterion delineated three genetic risk groups: DDX41 mutations (favorable-risk), DDX41wildtype/FLT3-ITDneg/TP53wildtype (intermediate-risk), and FLT3-ITD or TP53 mutations (high-risk). Our data identified distinct trajectories of leukemia development in older AML patients and provide a basis for a clinically meaningful genetic outcome stratification for patients receiving less intensive therapies.

Genetic Diversity of Cowpea Parental Lines Assembled for Breeding in Uganda

Cowpea is a grain legume that is commonly grown in Sub-Saharan Africa (SSA) for a variety of uses including food, feed, and soil fertility enhancement through nitrogen fixation. Genetic improvement in cowpea can be accomplished by creating breeding populations from high-performing but genetically diverse parental lines. The goal of this study was to use single nucleotide polymorphic markers (SNPs) to estimate genetic diversity and population stratification among cowpea parental genotypes from five countries. A total of 2,746 SNP markers were used to analyze 62 cowpea genotypes that differed in key characteristics. Only 55% of the SNP markers were polymorphic across the 62 genotypes and met the selection requirement. The gene diversity varied from 0.52 to 0.57 with an average of 0.55, while the polymorphic information content ranged from 0.46 to 0.51 with an average of 0.49, showing that the cowpea parental lines are genetically diverse. The analysis of molecular variance (AMOVA) found high significant (p < 0.001) variation among genotypes and non-significant variation across genotypes depending on country of origin. The cluster analysis for the 62 genotypes using the unweighted pair group procedure with arithmetic mean approach divided the genotypes into two distinct groups. Genotypes from the same geographical regions tended to cluster together and there was a significant level of genetic variation among genotypes from Uganda and Nigeria. The SNP markers utilized in this study were effective at distinguishing genotypes and may be used to estimate the diversity in the cowpea core collection. The genetic diversity in this collection is important for future development of improved varieties of cowpea in Uganda.

#4434 IMPACT OF GENETIC FACTORS FOR SALT-SENSITIVE HYPERTENSION AND RENAL DAMAGE ON HOSPITALIZED COVID-19 PATIENTS

Abstract Background and Aims The coronavirus SARS-CoV-2 infects patients by binding human angiotensin-converting enzyme 2. Also, the ATP1A1 subunit of the plasma membrane Na-K-pump is critical in supporting the entry of SARS-CoV-2 into cells. Targeting of the ouabain binding site on the Na-K-pump by gene silencing or low concentrations of ouabain blocks viral infection in murine model. A recent finding demonstrated a more effective antiviral activity of digoxin and ouabain against SARS-CoV-2 infection in vitro than previously approved antiviral agents such as chloroquine and remdesivir. Moreover, cardiotonic steroids can promote renal inflammation and oxidative stress through the Na-K-pump α-1 and Src kinase signaling complex in both renal epithelial and immune cells. Arterial hypertension is one of the most common comorbidities associated with COVID-19, especially in patients with severe clinical involvement and at risk of death. The aim of this study is to evaluate the genetic aspects of pathways related to hypertension and renal failure, and to Na-K-pump activity such as endogenous ouabain and RAAS system, in order to partly dissect the wide clinical spectrum of the disease in hospitalized patients infected by SARS-CoV-2, with various degrees of symptoms. Method We investigated the relationship between three outcomes and genetic determinants in the COVID-BioB study (ClincalTrials.gov NCT04318366), a characterization of an Italian cohort of about 500 patients, a SARS-CoV-2 positive population recruited during the first wave of pandemic at San Raffaele Scientific Institute with biological samples and clinical assessment data available in an internal biobank. Targeted DNA genotyping was performed by custom arrays on TaqMan OpenArray system (ThermoFisher) for single nucleotide polymorphisms (SNPs). The genetic variants were selected as candidate for salt-sensitive hypertension and renal failure. Associations with genetic markers and outcomes were carried out with logistic regression analysis for outcome absence/presence comparison. Results COVID-19 patients were all hospitalized, with mean age 67.4±13.5 (30.2% female), pneumonia 96.9%, hypertension 51.8%, coronary arterial disease 26.8%, emergency department AKI stage 1- 11.1%, AKI stage 2- 0.4%, CKD stage&amp;gt;3 11.5%, Chronic Obstructive Pulmonary Disease 8.2%, creatinine 1.19±0.70, all at emergency department admission, in-hospital AKI 37.8%, Intensive Care unit admission 18.3%, and in-hospital death 20.6%. The main outcomes for the analysis of SNPs were in-hospital death, AKI and onset of proteinuria. The main findings for the SNP analysis concerned different genetic markers, each specific for different outcomes. A SNP in renin gene (REN), rs10900555, was associated with the in-hospital death (OR 3.84 [95%CI 1.15;12.85], P = .029). PRKG1 gene coding for the protein kinase cGMP-Dependent reported association with AKI for two different SNPs (rs1904694, OR 2.78 [95%CI 1.63;4.72], P = .0002; rs7905063, OR 2.71 [95%CI 1.72;4.23], P = .00002), with the same risk alleles previously linked to salt-sensitive hypertension. TT genotype (at risk for salt-sensitivity) in uromodulin gene (UMOD, SNP rs4293393) increases the risk of proteinuria development (OR 1.86 [95%CI 1.02;3.40], P = .044). Conclusion This genetic analysis, firstly reported on the COVID-BioB cohort, showed an intriguing relation between some polymorphisms previously associated with salt-sensitive hypertension and worst outcome or renal damage, during COVID-19. This genetic stratification may help to identify patients at risk AKI, and (directly or not) for death and renal damage (proteinuria) during COVID-19. Moreover, it may explain, at least in part, the debated relationship between hypertension and severity of COVID-19.

A scalable approach to democratizing cancer risk stratification: One healthcare system’s approach using a patient-facing digital platform.

10622 Background: Access to genetic testing and risk stratification is primarily gated by referrals from non-genetics providers for patients who meet testing criteria. The majority of Americans seek care at community hospitals that are closer to home; community hospitals are faced with the challenge of how to democratize access to precision oncology and cancer prevention. Research has shown that the establishment of such protocols is challenging, requiring organizational buy-in, capital, resources, and the involvement of multiple levels of clinical and nonclinical stakeholders. Here we highlight Sarah Cannon, the Cancer Institute of HCA Healthcare, and their programmatic approach to risk stratification using a digital platform offered universally to all patients undergoing screening mammography. Methods: From February to November in 2022, fourteen sites were assessed to have appropriate provider and facility capabilities to support the implement the CARE program. The web-based risk-stratification tool is sent to individuals before standard ambulatory appointments to assess their lifetime risk for breast cancer based on the Tyrer-Cuzick (version 8.0) risk algorithm and National Comprehensive Cancer Network (NCCN) genetic testing criteria. Testing criteria included hereditary breast, ovarian, pancreatic, and prostate cancers, Lynch syndrome, and familial adenomatous polyposis (FAP). Retrospective data was pulled from patients seen between February 2022 through January 2023. The outcome measures included percentage of individuals who completed the risk-assessment, met genetic testing criteria, pursued germline genetic testing, received a positive germline result, and/or had a breast cancer risk ≥20%. Results: During the 10 months at the 14 community hospitals a total of 25,671 individuals were invited for risk assessment through the CARE program; 19,277 (75.1%) individuals completed assessment. Overall, 5,070 (26.3%) met genetic testing criteria and 1,536 individuals had a ≥20% lifetime risk of breast cancer, for a total of 34% of patients identified as elevated risk. 23.4% (1,187) of those meeting criteria opted to proceed with germline genetic testing. An additional 126 individuals who did not meet criteria pursued genetic testing. Of the 1,313 completed genetic tests, 96 (7%) had positive genetic test results. Fifty-four of 96 (56%) positive results had an impact on medical management and cancer prevention. Conclusions: Sarah Cannon and HCA Healthcare have successfully begun implementing a comprehensive, digital risk stratification program in the community hospital setting to provide standardized access to genomic testing and risk stratification. By identifying patients with an elevated risk for cancer, the potential for increased early cancer detection and precision oncology can be observed in a scalable and sustainable program.

Genetic spectrum of familial and sporadic dilated cardiomyopathy: arrhythmic phenotypes associated with mutations in the lamin A/C (LMNA) gene

Purpose. To study the diagnostic value of cascade family screening and the spectrum of genetic variants in patients with familial and sporadic DCM, assess clinical outcomes and comparative analysis of 5-year event-free survival.Materials and methods. The study included 156 unrelated patients with verified DCM. All patients (aged 46 [34; 57] years; 125 (80%) male; LVEF 31 [24; 38]%; LV EDD 68 [61; 74] mm; follow-up period - 77 [59; 108] months) a complex of clinical and instrumental studies (ECG, ECHO, HM, MRI), cascade family screening with genetic testing (NGS+Sanger) and segregation analysis were performed.Results. Criteria for familial DCM were identified in 73 (46.8%) probands. The genetic cause of DCM was identified in 47 (64,4%) familial cases, while for sporadic form DCM pathogenic variants were detected in 19 (22,9%) patients. The dominant mutations were truncating variants in the titin gene (10,9%) and variants in the lamin A/C (LMNA) gene - 8,33%. As a result of the evaluation of cumulative event-free survival (Kaplan-Meier curves), LMNA carriers showed the poor 5-year prognosis for ventricular tachyarrhythmic events (x2=39.9; p=0,0001) and composite adverse outcomes (x2=12.1; p=0.001). Probands who had a familial DCM (log rang x2=38.5; p=0,0001) showed the worst prognosis and low cumulative survival when compared with patients of the sporadic DCM.Conclusion. Cascade clinical family screening and genetic testing in the DCM cohort increased the level of diagnosis of familial DCM from 4.5% to 46.8%. Associations of LMNA mutations with life-threatening tachyarrhythmias are defined as prognostically significant, that confirms the important role of genetic stratification of arrhythmic risk.

LSC17 score complements genetics and measurable residual disease in acute myeloid leukemia: an ALFA study

AbstractWhether the LSC17 gene expression can improve risk stratification in the context of next generation sequencing–based risk stratification and measurable residual disease (MRD) in patients with intensively treated AML has not been explored. We analyzed LSC17 in 504 adult patients prospectively treated in the ALFA-0702 trial. RUNX1 or TP53 mutations were associated with higher LSC1 scores while CEBPA and NPM1 mutations were associated with lower scores. Patients with high LSC17 scores had a lower rate of complete response (CR) in a multivariable analysis (odds ratio, 0.41; P = .0007), accounting for European LeukemiaNet 2022 (ELN22), age, and white blood cell count (WBC). LSC17-high status was associated with shorter overall survival (OS) (3-year OS: 70.0% vs 52.7% in patients with LSC17-low status; P < .0001). In a multivariable analysis considering ELN22, age, and WBC, patients with LSC17-high status had shorter disease-free survival (DFS) (hazard ratio [HR], 1.36; P = .048) than those with LSC17-low status. In 123 patients with NPM1-mutated AML in CR, LSC17-high status predicted poorer DFS (HR, 2.34; P = .01), independent of age, WBC, ELN22 risk, and NPM1-MRD. LSC-low status and negative NPM1-MRD identified a subset comprising 48% of patients with mutated NPM1 with a 3-year OS from CR of 93.1% compared with 60.7% in those with LSC17-high status and/or positive NPM1-MRD (P = .0001). Overall, LSC17 assessment refines genetic risk stratification in adult patients with AML treated intensively. Combined with MRD, LSC17 identifies a subset of patients with NPM1-mutated AML with excellent clinical outcome.

Comparison of the 2022 and 2017 European LeukemiaNet risk classifications in a real-life cohort of the PETHEMA group

Next-Generation Sequencing is needed for the accurate genetic risk stratification of acute myeloid leukemia according to European LeukemiaNet (ELN) guidelines. We validated and compared the 2022 ELN risk classification in a real-life cohort of 546 intensively and 379 non-intensively treated patients. Among fit patients, those aged ≥65 years old showed worse OS than younger regardless risk classification. Compared with the 2017 classification, 14.5% of fit patients changed the risk with the 2022 classification, increasing the high-risk group from 44.3% to 51.8%. 3.7% and 0.9% FLT3-ITD mutated patients were removed from the favorable and adverse 2017 categories respectively to 2022 intermediate risk group. We suggest that midostaurin therapy could be a predictor for 3 years OS (85.2% with vs. 54.8% without midostaurin, P = 0.04). Forty-seven (8.6%) patients from the 2017 intermediate group were assigned to the 2022 adverse-risk group as they harbored myelodysplasia (MDS)-related mutations. Patients with one MDS-related mutation did not reach median OS, while patients with ≥2 mutations had 13.6 months median OS (P = 0.002). Patients with TP53 ± complex karyotype or inv(3) had a dismal prognosis (7.1 months median OS). We validate the prognostic utility of the 2022 ELN classification in a real-life setting providing supportive evidences to improve risk stratification guidelines.

Validation and refinement of the 2022 European LeukemiaNet genetic risk stratification of acute myeloid leukemia

The revised 2022 European LeukemiaNet (ELN) AML risk stratification system requires validation in large, homogeneously treated cohorts. We studied 1118 newly diagnosed AML patients (median age, 58 years; range, 18–86 years) who received cytarabine-based induction chemotherapy between 1999 and 2012 and compared ELN-2022 to the previous ELN-2017 risk classification. Key findings were validated in a cohort of 1160 mostly younger patients. ELN-2022 reclassified 15% of patients, 3% into more favorable, and 12% into more adverse risk groups. This was mainly driven by patients reclassified from intermediate- to adverse-risk based on additional myelodysplasia-related mutations being included as adverse-risk markers. These patients (n = 79) had significantly better outcomes than patients with other adverse-risk genotypes (5-year OS, 26% vs. 12%) and resembled the remaining intermediate-risk group. Overall, time-dependent ROC curves and Harrel’s C-index controlling for age, sex, and AML type (de novo vs. sAML/tAML) show slightly worse prognostic discrimination of ELN-2022 compared to ELN-2017 for OS. Further refinement of ELN-2022 without including additional genetic markers is possible, in particular by recognizing TP53-mutated patients with complex karyotypes as “very adverse”. In summary, the ELN-2022 risk classification identifies a larger group of adverse-risk patients at the cost of slightly reduced prognostic accuracy compared to ELN-2017.

High Polygenic Risk Is Associated with Earlier Initiation and Escalation of Treatment in Early Primary Open-Angle Glaucoma

To assess the association between a glaucoma polygenic risk score (PRS) and treatment outcomes in primary open-angle glaucoma. Prospective, observational cohort study. Participants from the Progression Risk of Glaucoma: Relevant SNPs with Significant Association Study were divided into a cohort with suspect glaucoma who were treatment naive at enrollment and one with early manifest and suspect glaucoma receiving treatment at enrollment. A per-allele weighted glaucoma PRS was calculated for 1107 participants. Multivariable mixed-effects Cox proportional regression analysis assessed the association between PRS and time to commencement of intraocular pressure (IOP)-lowering therapy in 416 patients with suspect glaucoma who were treatment naive at study enrollment. Secondary analysis evaluated the association between PRS and escalation of IOP-lowering therapy among 691 patients with suspect and early manifest glaucoma who were receiving IOP-lowering therapy at enrollment. Commencement or escalation of IOP-lowering therapy. A higher PRS was associated with a greater risk of commencing IOP-lowering therapy within 5 years (hazard ratio [HR], 1.45per 1 standard deviation [/SD]; 95% confidence interval [CI], 1.27-1.62; P < 0.001). Participants in the upper population-based quintile showed a 3.3 times greater risk of commencing therapy by 5 years than those in the lowest quintile (HR, 3.30; 95% CI, 1.63-6,70; P < 0.001) and a 5.4 times greater risk of commencing IOP-lowering therapy by 2 years than the those in the lowest quintile (HR, 5.45; 95% CI, 2.08-14.25; P < 0.001). A higher PRS was associated with a greater risk of treatment escalation among patients receiving treatment at enrollment (HR, 1.19/SD; 95% CI, 1.09-1.31; P < 0.001). In combined analysis of all participants, participants in the top population-based quintile were at 2.3 times greater risk of requiring initiation or escalation of IOP-lowering therapy than those in the lowest quintile (HR, 2.33; 95% CI, 1.75-3.01; P < 0.001). This study demonstrated novel associations between glaucoma polygenic risk and risk of commencement or escalation of IOP-lowering therapy, building on previous work highlighting the potential clinical usefulness of genetic risk stratification in glaucoma. Proprietary or commercial disclosure may be found after the references.

Focal Cryoablation of the Prostate: Primary Treatment in 163 Patients With Localized Prostate Cancer.

Objective Whole gland treatment of the prostate has known efficacy in treating many grades of prostate cancer. However, it is often associated with increased morbidity, including erectile dysfunction and urinary incontinence. Focal ablative therapies, including focal cryoablation (FC), are utilized to minimize the risk of tumor progression and preserve erectile and urinary function. There is little to no consensus on whether intermediate or high-risk prostate cancer should be treated with focal therapy. However, there is a growing body of literature on the effectiveness of FC as an effective means of prostate cancer control. We characterize our experience with 163 patients who underwent FC with a median follow-up of 39 months (IQR: 24-60). Methods A 163-patient retrospective cohort underwent FC of the prostate at a single clinic by a physician from November 2008 to December 2020. Each of these T1c patients in this single-tail study was monitored for biochemical recurrence (BCR) and oncologic outcomes. American Society for Radiation Oncology (ASTRO) definition of BCR is three consecutive prostate-specific antigens (PSA) increases of more than 0.5 ng/mL or, along with the utilization of the Phoenix definition, a PSA greater than nadir by 2 ng/mL was used to define BCR. This study's primary endpoint includes BCR or biochemical disease-free survival rates. Secondary endpoints include patient side effects, such as measuring for urinary incontinence and outcomes of salvage treatments. Cox proportional hazard analyses defined univariate HRs and 95% CIs for pre-operative PSA (POPSA), Decipher, and Gleason Grade Groups (GGGs) to determine the prognostic impact of pathologic factors. Statistical analysis and BCR timeline analysis also included logistic regression and the Kaplan-Meier method, with significance considered at p < 0.05. Select focal cryotherapy patients were monitored utilizing genomic sequencing tests. Results Our cohort included 27 patients (16.5%) with D'Amico low, 115 patients (70.5%) with intermediate, and 23 patients (14.1%) with high-risk prostate cancers. One month after FC, a 73% reduction in PSA resulted in a median post-operative PSA of 1.39 ng/mL (IQR: 0.46-2.80 ng/mL). At five years, our cohort yielded biochemical disease-free recurrence rates of 78%, 74%, and 55% for low, intermediate, and high-grade cancers, respectively. Genetic risk stratification results showed very similar BCR rates to patients whose tissues did not undergo genomic testing, at 27%, 26%, and 46% for low, intermediate, and high-grade cancers, respectively. Log-rank tests to map for BCR and HRs for pathologic factors did not yield any statistically significant predictive results. Urinary incontinence and erectile dysfunction were reported in 1.8% and 3.1% of patients in the focal cohort. Conclusions Our results add to the expanding body of literature around the efficacy of focal ablative therapies in contrast to whole gland treatment. The definitive extent of FC's efficacy still remains to be explored, but our conclusions demonstrate favorable PSA kinetics at five years follow-up.

RNA sequencing of myeloid sarcoma, shed light on myeloid sarcoma stratification.

Myeloid sarcoma (MS) is a rare, extramedullary tumor consisting of myeloid blasts. Little is known about the genetic background of MS and the prognostic value of genetic abnormalities in MS. In particular, the broad variety of gene fusions that occur in MS is marginally covered by traditional testing methods due to lack of fresh tumor specimens. Here, we analyzed the clinical and genetic features of 61 MS cases. We performed RNA sequencing (RNA-seq) on formalin-fixed paraffin-embedded (FFPE) or fresh samples to analyze fusion genes in 26 cases. In addition, we performed genetic abnormalities-based risk stratification using fusion genes and gene mutations. A total of 305 fusion genes were identified in 22 cases, including the following five recurrent fusion genes: RUNX1-RUNX1T1, CBFβ-MYH11, ETV6-MECOM, FUS-ERG, and PICALM-MLLT10. The prognosis in the adverse-risk group was significantly worse than that in the favorable/intermediate-risk group (median survival: 12 months vs. not reached; p = 0.0004). These results indicated the efficacy of RNA-seq using FFPE-derived RNA as a clinical routine for detecting fusion genes, which can be used as markers for risk stratification in MS.

Genetic stratification reveals COL4A variants and spontaneous remission in Egyptian children with proteinuria in the first 2 years of life.

The earlier the onset of proteinuria, the higher the incidence of genetic forms. Therefore, we aimed to analyse the spectrum of monogenic proteinuria in Egyptian children presenting at age <2 years. The results of 27-gene panel or whole-exome sequencing were correlated with phenotype and treatment outcomes in 54 patients from 45 families. Disease-causing variants were identified in 29/45 (64.4%) families. Mutations often occurred in three podocytopathy genes: NPHS1, NPHS2 and PLCE1 (19 families). Some showed extrarenal manifestations. Additionally, mutations were detected in 10 other genes, including novel variants of OSGEP, SGPL1 and SYNPO2. COL4A variants phenocopied isolated steroid-resistant nephrotic syndrome (2/29 families, 6.9%). NPHS2 M1L was the single most common genetic finding beyond the age of 3 months (4/18 families, 22.2%). Biopsy results did not correlate with genotypes (n=30). On renin-angiotensin-aldosterone system antagonists alone, partial and complete remission occurred in 3/24 (12.5%) patients with monogenic proteinuria each, whereas 6.3% (1/16) achieved complete remission on immunosuppression. Genotyping is mandatory to avoid biopsies and immunosuppression when proteinuria presents at age <2 years. Even with such a presentation, COL4A genes should be included. NPHS2 M1L was prevalent in Egyptian children (4 months-2 years) with proteinuria, demonstrating precision diagnostic utility.

From Genetics to Clinical Implications: A Study of 675 Dutch Osteogenesis Imperfecta Patients.

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder that causes bone fragility due to pathogenic variants in genes responsible for the synthesis of type I collagen. Efforts to classify the high clinical variability in OI led to the Sillence classification. However, this classification only partially takes into account extraskeletal manifestations and the high genetic variability. Little is known about the relation between genetic variants and phenotype as of yet. The aim of the study was to create a clinically relevant genetic stratification of a cohort of 675 Dutch OI patients based on their pathogenic variant types and to provide an overview of their respective medical care demands. The clinical records of 675 OI patients were extracted from the Amsterdam UMC Genome Database and matched with the records from Statistics Netherlands (CBS). The patients were categorized based on their harbored pathogenic variant. The information on hospital admissions, outpatient clinic visits, medication, and diagnosis-treatment combinations (DTCs) was compared between the variant groups. OI patients in the Netherlands appear to have a higher number of DTCs, outpatient clinic visits, and hospital admissions when compared to the general Dutch population. Furthermore, medication usage seems higher in the OI cohort in comparison to the general population. The patients with a COL1A1 or COL1A2 dominant negative missense non-glycine substitution appear to have a lower health care need compared to the other groups, and even lower than patients with COL1A1 or COL1A2 haploinsufficiency. It would be useful to include the variant type in addition to the Sillence classification when categorizing a patient's phenotype.

Genetic Risk for Alzheimer Disease and Plasma Tau Are Associated With Accelerated Parietal Cortex Thickness Change in Middle-Aged Adults.

Neuroimaging and biomarker studies in Alzheimer disease (AD) have shown well-characterized patterns of cortical thinning and altered biomarker concentrations of tau and β-amyloid (Aβ). However, earlier identification of AD has great potential to advance clinical care and determine candidates for drug trials. The extent to which AD risk markers relate to cortical thinning patterns in midlife is unknown. The first objective of this study was to examine cortical thickness change associated with genetic risk for AD among middle-aged military veterans. The second objective was to determine the relationship between plasma tau and Aβ and change in brain cortical thickness among veterans stratified by genetic risk for AD. Participants consisted of post-9/11 veterans (N = 155) who were consecutively enrolled in the Translational Research Center for TBI and Stress Disorders prospective longitudinal cohort and were assessed for mild traumatic brain injury (TBI) and posttraumatic disorder (PTSD). Genome-wide polygenic risk scores (PRSs) for AD were calculated using summary results from the International Genomics of Alzheimer's Disease Project. T-tau and Aβ40 and Aβ42 plasma assays were run using Simoa technology. Whole-brain MRI cortical thickness change estimates were obtained using the longitudinal stream of FreeSurfer. Follow-up moderation analyses examined the AD PRS × plasma interaction on change in cortical thickness in AD-vulnerable regions. Higher AD PRS, signifying greater genetic risk for AD, was associated with accelerated cortical thickness change in a right hemisphere inferior parietal cortex cluster that included the supramarginal gyrus, angular gyrus, and intraparietal sulcus. Higher tau, but not Aβ42/40 ratio, was associated with greater cortical thickness change among those with higher AD PRS. Mild TBI and PTSD were not associated with cortical thickness change. Plasma tau, particularly when combined with genetic stratification for AD risk, can be a useful indicator of brain change in midlife. Accelerated inferior parietal cortex changes in midlife may be an important factor to consider as a marker of AD-related brain alterations.

Подход к кластеризации пациентов по микрочиповым данным внутри отдельных локусов с использованием комбинаций вариантов

Fuchs' endothelial corneal dystrophy is a socially significant hereditary disease. More than a half of cases in the European population are caused by the increased number of trinucleotude repeats in the TCF4 gene. The study was aimed to develop and test the approach of dividing patients into groups based on the chip-based genotyping and genome-wide association study (GWAS) results. The analysis was conducted using FECD Genetics Multi-center Study and AREDs project datasets containing the data of 1721 clinical cases and 2408 control patients. When analyzing the GWAS results, the patients and the control group were divided into two groups by means of hierarchical clustering suggesting that patients with the increased number of repeats in the TCF4 gene are carriers of specific combinations of genomic variants (haplotypes). It was shown that individual variants cannot be used for the molecular genetic stratification of patients with the increased number of repeats in TCF4 due to inconsistent results obtained for the variants. Furthermore, the haplotype-based approach outperformed the SNPs in terms of odds ratio. The paper proposes a method that enables further search for the biologically relevant combinations of genomic variants.

A simple genetic stratification method for lower cost, more expedient clinical trials in early Alzheimer's disease: A preliminary study of tau PET and cognitive outcomes.

Identifying individuals who are most likely to accumulate tau and exhibit cognitive decline is critical for Alzheimer's disease (AD) clinical trials. Participants (N=235) who were cognitively normal or with mild cognitive impairment from the Alzheimer's Disease Neuroimaging Initiative were stratified by a cutoff on the polygenic hazard score (PHS) at 65th percentile (above as high-risk group and below as low-risk group). We evaluated the associations between the PHS risk groups and tau positron emission tomography and cognitive decline, respectively. Power analyses estimated the sample size needed for clinical trials to detect differences in tau accumulation or cognitive change. The high-risk group showed faster tau accumulation and cognitive decline. Clinical trials using the high-risk group would require a fraction of the sample size as trials without this inclusion criterion. Incorporating a PHS inclusion criterion represents a low-cost and accessible way to identify potential participants for AD clinical trials.