Mutations In High-risk Genes Research Articles

Somatic Profiling Prospectively Guides Germline Genetic Testing in Patients with Mutations in High-Risk Cancer Predisposition Genes

Somatic Profiling Prospectively Guides Germline Genetic Testing in Patients with Mutations in High-Risk Cancer Predisposition Genes

The potential role of RNA sequencing in diagnosing unexplained insensitivity to conventional chemotherapy in pediatric patients with B-cell acute lymphoblastic leukemia

Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is a highly heterogeneous disease. According to large-scale RNA sequencing (RNA-seq) data, B-ALL patients can be divided into more than 10 subgroups. However, many genomic defects associated with resistance mechanisms have not yet been identified. As an individual clinical tool for molecular diagnostic risk classification, RNA-seq and gene expression pattern-based therapy could be potential upcoming strategies. In this study, we retrospectively analyzed the RNA-seq gene expression profiles of 45 children whose molecular diagnostic classifications were inconsistent with the response to chemotherapy. The relationship between the transcriptome and chemotherapy response was analyzed. Fusion gene identification was conducted for the included patients who did not have known high-risk associated fusion genes or gene mutations. The most frequently detected fusion gene pair in the high-risk group was the DHRSX duplication, which is a novel finding. Fusions involving ABL1, LMNB2, NFATC1, PAX5, and TTYH3 at onset were more frequently detected in the high-risk group, while fusions involving LFNG, TTYH3, and NFATC1 were frequently detected in the relapse group. According to the pathways involved, the underlying drug resistance mechanism is related to DNA methylation, autophagy, and protein metabolism. Overall, the implementation of an RNA-seq diagnostic system will identify activated markers associated with chemotherapy response, and guide future treatment adjustments.

ELF5: A Molecular Clock for Breast Aging and Cancer Susceptibility.

Breast cancer is predominantly an age-related disease, with aging serving as the most significant risk factor, compounded by germline mutations in high-risk genes like BRCA1/2. Aging induces architectural changes in breast tissue, particularly affecting luminal epithelial cells by diminishing lineage-specific molecular profiles and adopting myoepithelial-like characteristics. ELF5 is an important transcription factor for both normal breast and breast cancer development. This review focuses on the role of ELF5 in normal breast development, its altered expression throughout aging, and its implications in cancer. It discusses the lineage-specific expression of ELF5, its regulatory mechanisms, and its potential as a biomarker for breast-specific biological age and cancer risk.

Machine Learning for Identification of High-Risk Clonal Haematopoiesis Using Blood Count Data

Introduction: Clonal haematopoiesis (CH) is a common, age-related phenomenon associated with an increased risk of myeloid malignancies (MM), raising the prospect of screening to identify individuals at high risk of progression from CH to MM. The nature of the driver mutation(s) is the major determinant of the risk of progression to MM. Presently, the identification of these mutations relies on next generation sequencing (NGS) of blood DNA, making it impractical to identify those at risk at scale. We previously reported that the presence of CH is associated with changes in complete blood count (CBC) parameters such as the red cell distribution width (RDW), mean corpuscular volume (MCV) and others. However, individual parameters have limited discriminative power to distinguish those with CH versus those without. Here, we present a machine learning (ML) pipeline applied to a combined CBC dataset, which can be harnessed to improve our ability to identify individuals with high likelihood of carrying CH, who can subsequently be prioritised for genetic testing. Methods: Whole exome sequencing (WES) data from 454,052 UK Biobank (UKB) participants were analysed using Mutect2 to detect CH-driver mutations across the exons of 43 CH-associated genes. Germline variants were filtered using a panel of ormal and a one-sided exact binomial test. A final set of driver mutations was derived by filtering variants based on a pre-defined list of recurrent CH mutations or recurrence of >= 7 times in haematological cancers in the catalogue of somatic mutations in cancer. Fields pertaining to blood count variables were extracted and filtered to remove individuals with missing data, extreme outliers, highly correlated parameters and variables with near zero-variance resulting in 434,057 participants with complete datasets. Individuals were annotated as “CH” or “no-CH”; a Random Forest (RF) binary classifier was optimised on age, sex and 13 blood count variables as features. To quantify the robustness and stability of the model, the RF optimisation was iterated ten times, on a customised cross validation approach by using a different random sample from the majority (control) class each time. All ML models were constructed using the Caret package (R version 3.6.3). Results: We first found that RF classifiers to identify the presence of CH overall performed poorly (median AUC: 0.640/0.671 for any/large clone VAF >=10% CH respectively). However, gene-specific models showed that the presence of CH associated with mutations in certain high risk genes ( SF3B1, SRSF2, JAK2, CALR) could be predicted from blood counts more confidently (median AUC 0.776, 0.834, 0.933, 0.849 respectively). By contrast, mutations in the more common CH driver genes ( DNMT3A and TET2) could not be accurately predicted from blood count data (median AUC 0.618 and 0.666 respectively) (Figure 1). In light of these findings, we proceeded to build a single RF model to predict the presence of high-risk CH associated with mutations in any of SF3B1, SRSF2, JAK2 or CALR. This performed well, with median AUC of 0.816/0.888 for any/large clone high-risk CH respectively (Figure 2). Our RF models were also able to give insights into novel blood count association with specific types of CH; in particular we found that the basophil count was an important predictor of the presence of CH driven by mutation in codon K57 of the GNB1 gene. To investigate this further, we analysed basophil counts in the UKB and confirmed that basophilia (basophils >0.2 x 10 9/L) was more common amongst carriers of GNB1-K57 mutations (14/234 = 5.9%) than controls (2597/433,863 = 0.5%). Conclusions: Data-driven ML models applied to blood count data can identify individuals with high-risk CH driven by genes associated with progression to myelodysplastic syndrome and myeloproliferative neoplasms, who should be prioritised for genetic testing for somatic mutations. The future integration of raw blood analyser and longitudinal blood count data into predictive models would be an important next step towards improving our ability to identify individuals that may harbour CH and help facilitate the introduction of large-scale screening for the phenomenon.

Optimization of Idarubicin and Cytarabine Induction Regimen with Homoharringtonine for Newly Diagnosed AML Based on the Peripheral Blast Clearance Rate: First Result of the Multicenter, Randomized, Phase 3 Trial (RJ-AML 2016)

Background: Combination of idarubicin and cytarabine (IA) is still the basis of induction treatment for acute myeloid leukemia (AML). As previous reported in RJ-AML 2014 trial [1], day 5 peripheral blast clearance rate (D5-PBCR) can be used as an indicator of early treatment response, and for patients in the D5-PBCR (+) group, addition of homoharringtonine (HHT) to traditional IA induction showed good efficacy and safety. To further verify the efficacy in long-term outcome, we designed the RJ-AML 2016 trial. Here we report the latest response and survival results. Patients and Methods: The RJ-AML 2016 trial is a multicenter, randomized, phase 3 clinical trial, conducted to evaluate the efficacy of HHT in newly diagnosed young AML. Patients in D5-PBCR(+) group was eligible for addition of HHT, and were assigned in a 1:1 ratio, either to the intervention or control group. The primary end point was event-free survival (EFS). The secondary end points were composite complete remission (CR or CR with incomplete hematologic recovery), early death rate, measurable residual disease, drug toxicity, and safety. We hypothesized the 3-year EFS rate may increase from 30% to 50%, therefore the sample size of patients who enter randomization should be 250. Based on historical data, the rate of D5-PRCR(+) was 43%. Assume that 10% of patients may lost to follow-up, at least 638 eligible patients were needed. All patients enrolled in this study received induction regimen same as the RJ-AML 2014 trial. D5-PRCR(+) patients who assigned to the intervention group received additional chemotherapy (HHT 2 mg/m 2 on days 6-10). Favorable cytogenetic/molecular risks group received four courses of the HiDAC for consolidation. Patients with intermediate and unfavorable risks were recommended for allogeneic hematopoietic stem-cell transplantation. The trial is registered in the Chinese Clinical Trial Register, number ChiCTR-OIC-16007764. Results: From December 7, 2016, through April 29, 2023, a total of 747 patients underwent screening, 649 were included in the intention-to-treat (ITT) population and received IA induction from 6 sites in China. D5-PBCR were analyzed in 647 patients and 275 (42.5%) had D5-PBCR (+). Of the 275 D5-PBCR (+) patients, 145 were allocated to the intervention group, while 20 patients withdraw, of which 4 patients received additional FLT3 inhibitor and 16 cases continued IA induction; of the 130 patients allocated to the control group, 5 discontinued the IA regimen on day 6 or 7. Of the 372 D5-PBCR (-) patients, 2 patients discontinued IA. Baseline characteristics, including age, sex, blast counts in bone marrow, and cytogenetic parameters, were similar between two groups. While patients in D5-PBCR (-) group had higher white blood cell counts before treatment. Patients with CBFβ- MYH11 fusion, NPM1 and CEBPA bZIP mutations were more sensitive to IA induction. Meanwhile, high-risk gene mutations including ASXL1, RUNX1, TP53 and U2AF1 were more common in D5-PBCR (+) group. Details were showed in table. The overall composite CR rate after one course of induction was 73.2% in the ITT cohort. For patients in D5-PBCR (-) and D5-PBCR (+) groups, the CR rates were 82.8% and 60.4% , respectively (P<0.001). In the ITT cohort of D5-PBCR (+) group, CR rates were 51.1% and 68.3% for control and intervention arm, respectively (P=0.0046). In the Per-Protocol (PP) cohort, CR rates were 52.8% and 71.2% for IA and IA+HHT arm, respectively (P=0.0027). The overall early mortality rate was 4.9% in whole cohort, which were similar between two treatment arms. The last follow-up time was April 2023. Patients in the PP cohort who enrolled before April 2022 were included in this survival analysis (n=486), and the median duration of follow-up was 23.4 months. The median EFS was 40.6 months in the PP cohort, which showed significant difference between D5-PBCR (-) and D5-PBCR (+) groups [D5-PBCR (-): not reached, D5-PBCR (+): 16.0±1.9 months, P<0.001]. For patients in the D5-PBCR (+) group, no significant difference was found in 3-year EFS till the latest follow-up. While, the 3-year EFS was improved from 34.0±5.5% to 47.1±6.1% with the addition of HHT ( P=0.086). Conclusion: Current analysis indicated that addition of HHT can benefit young AML patients in the D5-PBCR (+) group. Complete follow-up combining with cytogenetic-molecular information can provide more reliable results. 1. Zhang Y, et al. Am J Hematol. 2022;97(1):43-51.

The NO Answer for Autism Spectrum Disorder.

Autism spectrum disorders (ASDs) include a wide range of neurodevelopmental disorders. Several reports showed that mutations in different high-risk ASD genes lead to ASD. However, the underlying molecular mechanisms have not been deciphered. Recently, they reported a dramatic increase in nitric oxide (NO) levels in ASD mouse models. Here, they conducted a multidisciplinary study to investigate the role of NO in ASD. High levels of nitrosative stress biomarkers are found in both the Shank3 and Cntnap2 ASD mouse models. Pharmacological intervention with a neuronal NO synthase (nNOS) inhibitor in both models led to a reversal of the molecular, synaptic, and behavioral ASD-associated phenotypes. Importantly, treating iPSC-derived cortical neurons from patients with SHANK3 mutation with the nNOS inhibitor showed similar therapeutic effects. Clinically, they found a significant increase in nitrosative stress biomarkers in the plasma of low-functioning ASD patients. Bioinformatics of the SNO-proteome revealed that the complement system is enriched in ASD. This novel work reveals, for the first time, that NO plays a significant role in ASD. Their important findings will open novel directions to examine NO in diverse mutations on the spectrum as well as in other neurodevelopmental disorders. Finally, it suggests a novel strategy for effectively treating ASD.

Quantifying the Impact of Genetics on Neurocognition in Non-Syndromic Sagittal Craniosynostosis.

Previous work has identified an association between de novo and transmitted loss of function mutations in genes under high evolutionary constraint (high pLI) with neurodevelopmental delays in non-syndromic craniosynostosis (NSC). We sought to quantify the neurocognitive effect of these genetic lesions. In a prospective, double-blinded cohort study, demographic surveys and neurocognitive tests were administered to patients recruited from a national sample of children with sagittal NSC. Scores for academic achievement, full-scale intelligence quotient (FSIQ), and visuomotor skills were directly compared between patients with and without damaging mutations in high pLI genes using two-tailed t tests. Analysis of covariance was also used to compare test scores while controlling for surgery type, age at surgery, and sociodemographic risk. 56 patients completed neurocognitive testing, 18 of whom had a mutation in a highly constrained gene. There was no significant difference between groups in any sociodemographic factors. After controlling for patient factors, patients with high-risk mutations had poorer performance compared to patients without high-risk mutations in every testing category, with significant differences in FSIQ (102.9 ± 11.4 vs. 110.1 ± 11.3, P=0.033) and visuomotor integration (100.0 ± 11.9 vs. 105.2 ± 9.5, P=0.003). There were no significant differences in neurocognitive outcome when stratifying groups based on type of surgery or age at time of surgery. Even after controlling for exogenous factors, the presence of mutations in high-risk genes led to poorer neurocognitive outcomes. High risk genotypes may predispose individuals with NSC to deficits, particularly in full-scale IQ and visuomotor integration.

NRXN1 depletion in the medial prefrontal cortex induces anxiety-like behaviors and abnormal social phenotypes along with impaired neurite outgrowth in rat

BackgroundNeurodevelopmental disorders (NDDs) are a group of disorders induced by abnormal brain developmental processes. The prefrontal cortex (PFC) plays an essential role in executive function, and its role in NDDs has been reported. NDDs are associated with high-risk gene mutations and share partially overlapping genetic abnormalities.MethodsNeurexins (NRXNs) are related to autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). NRXN1, an essential susceptibility gene for NDDs, has been reported to be associated with NDDs. However, little is known about its key role in NDDs.ResultsNRXN1 downregulation in the medial PFC induced anxiety-like behaviors and abnormal social phenotypes with impaired neurite outgrowth in Sh-NRXN1 in prefrontal neurons. Moreover, tandem mass tag (TMT)-based proteomic analysis of rat brain samples showed that NRXN1 downregulation led to significant proteome alterations, including pathways related to the extracellular matrix, cell membrane, and morphologic change. Furthermore, full-automatic immunoblotting analysis verified the differently expressed proteins related to cell morphology and membrane structure.ConclusionsOur results confirmed the association of NRXN1 with abnormal behaviors in NDDs and provided richer insights into specific prefrontal knockdown in adolescence, potentially expanding the NRXN1 interactome and contributing to human health.Graphical abstract

Real-Life Experience of Use of Venetoclax in Patients with Relapsed/Refractory Acute Myeloid Leukemia. a Single Center Experience

INTRODUCTION: Venetoclax (VEN), a BCL-2 specific inhibitor, used in combination with azacitidine (AZA) in patients with newly-diagnosed acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy treatment, has shown high response rate and overall survival compared with AZA monotherapy (Di Nardo et al. N Engl J Med 2020; 383:617-629). For patients failing frontline, VEN-based salvage therapy prognosis appears very poor, although a subgroup of patients might benefit. Moreover, recently, had been published the European LeukemiaNet 2022 recommendations and classification in AML (Döhner et al. Blood 2022). AIMS: We performed a retrospective study of patients with relapsed/refractory (R/R) AML receiving salvage treatment with VEN combinations in the Catalan Institute of Oncology (ICO) in order to determine the efficacy and safety of the combination. We also explored the probability of response according to the ELN 2022 risk classification by genetics. METHODS: We analyze 60 patients with R/R AML at 4 hospitals belonging to ICO in Spain, treated with VEN (400mg/24h or 600mg/24h; with recommended 3-day ramp-up to target dose) in combination with hypomethylating (HMA) agents (AZA 75mg/m2 7/28 days or Decitabine (DEC) 20mg/m2 5/28 days) or low-dose cytarabine (LDAC) (20mg/m2 10/28 days) from May 2019 until December 2021. Event was defined as death, refractoriness to treatment or progressive disease. RESULTS: Characteristics of our cohort are described in table 1. Thirty-seven (62%) patients had next-generation sequencing (NGS) panel study at diagnosis and/or at the time of R/R disease. 31 (52%) patients had high-risk AML according to ELN 2017 classification, and 38 of 46 (83%) patients had high-risk AML according to ELN 2022 classification. Six of 37 patients (15%) had TP53 mutation at a variant allele fraction (VAF) of at least 10%. Seven (19%) patients were reclassified as high-risk AML according to ELN 2022 classification. NGS panel study didn't show high risk mutations in 10 patients. According to ELN 2022 classification, 8, 11 and 8 patients, presented 1, 2 or ≥ 3 high risk gene mutations, respectively. Fourteen (23%) patients received VEN + DEC, 34 (57%) VEN + AZA, and 12 (20%) VEN + LDAC. The median number of cycles received was 3 (range 1-28), with a median of one cycle to achieve the best response (range: 1-4). Early mortality in the first 30 days was 15% (9 patients), 5 due to progression disease, 2 due to infection and 2 due to clinical worsening. Overall response rate after first cycle [Complete response (CR) + complete response without hematological recovery (CRi) and partial response (PR)] was 58%. Three patients were treated in a molecular relapse (MRD positive status), and all of them achieved molecular response. Six of 19 fit young patients (32%) achieved CR and received an allogeneic stem cell transplantation (alloSCT). The median event-free survival (EFS) and overall survival (OS) was 4.03 months and 7.63 months, respectively. No significant differences of EFS and OS were found according to ELN 2022 risk classification, mutational profile or TP53 status. Response to treatment after 3-4 cycles, discriminate two groups of patients with an OS of 17.26 months in those patients who achieved CR or PR vs 2.4 months in non-responders (p=0.000). Patients relapsed after alloSCT (7 patients) presented a poor outcome (median OS was 1.6 months). SUMMARY/CONCLUSIONS: Our study showed that real-world experience of treating patients with R/R AML with VEN + HMA or LDAC is feasible as salvage treatment in patients relapsed to HMA and as bridge therapy to alloSCT with a rapid response rate. No significant differences of response were found according to ELN 2022 risk classification. Rapid responses shown with the combination, allow us to identify those patients who may benefit from this approach. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Allogeneic Hematopoietic Cell Transplantation in Patients with Relapsed or Refractory Acute Leukemia

Introduction: Current guidelines support allogeneic hematopoietic cell transplantation (allo-HCT) in patients with acute leukemia who achieve complete remission (CR) and are at high risk for relapse. Patients with primary refractory disease or those refractory to re-induction therapy after relapse have a poor prognosis in the absence of allo-HCT. While several studies have addressed the role of allo-HCT in those settings, the measurable benefit of allo-HCT has not been defined in such patients. Most previous studies have included patients who received myeloablative conditioning and did not address the possible impact of molecular genetic risk factors. Objective: The present study assessed outcomes of allo-HCT in patients with refractory or relapsed (R/R) acute leukemia receiving myeloablative (MAC) or reduced intensity conditioning (RIC) regimens. Our goal was to identify novel risk factors associated with improved outcomes to aid patient selection in the setting of R/R acute leukemia. Methods: Patients with R/R acute leukemia undergoing allo-HCT at Memorial Sloan Kettering Cancer Center (MSK) between 2009 and 2020 were included. Patients had a marrow blast count of 5% or more at the time of allo-HCT and were classified into one of the following categories: primary induction failure (PIF), at least 2 lines of induction therapy; not in CR (NCR), no more than one line of induction therapy; untreated relapse (UR); and refractory relapse (RR), no remission after at least one line of re-induction therapy for relapse. Results: We identified 101 patients with acute myeloid leukemia (AML; n=94), acute lymphoblastic leukemia (ALL; n=3), biphenotypic acute leukemia (n=2), and plasmacytoid dendritic cell leukemia (n=2). Table 1 depicts patient and transplant characteristics. Median blast count at the time of allo-HCT was 8% (IQR, 5%,15%). 37 patients had at least one genomic alteration, and 30 patients had circulating blasts at the time of transplant. Grafts were from HLA-identical siblings in 30 patients, from HLA-matched unrelated donors in 51 patients and from HLA-mismatched or HLA-haploidentical donors in 20 patients. 61 and 40 patients received MAC and RIC, respectively. Graft source was unmodified bone marrow (n=8), unmodified peripheral blood stem cells (PBSC; n=80), or CD34+ cellselected peripheral blood stem cells (n=7). Overall survival (OS) at 4 years was 25% (95% CI: 18%, 35%). In univariate analysis, RIC (HR 1.71, p=0.035), presence of circulating blasts (HR 2.21, p=0.002), and high pre-transplant ferritin levels (HR 1.43, p=0.049) were associated with inferior OS. In multivariate analysis, RIC was associated with reduced OS. The 4-year cumulative incidence of relapse/disease progression and non-relapse mortality (NRM) was 54% (95% CI: 43%, 63%) and 24% (CI, 16%, 33%) respectively. In univariate analysis, RIC, presence of circulating blasts, and elevated pre-transplant ferritin levels were associated with increased NRM. In multivariate analysis, RIC and elevated pre-transplant ferritin levels were associated with high NRM. The cumulative incidence of acute graft-vs-host disease (aGVHD) was 45% (95% CI: 35%, 54%) at day 100. There was no statistically significant effect of genomic and molecular parameters on NRM and OS. However, high risk molecular mutations (TP53, RUNX1, ASXL1 or FLT3-ITD) had borderline association with relapse/disease progression (HR 1.7, p=0.073). Conclusion: Allo-HCT provides durable remission in a select group of patients with relapsed or refractory acute leukemia with an OS of 25% at 4 years. The presence of circulating blasts and elevated ferritin levels at the time of allo-HCT was associated with increased NRM and inferior OS in this retrospective analysis. Known high-risk gene mutations did not affect outcomes in this population. The impact of these parameters should be evaluated in a larger cohort of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

MECOM copy number alterations identify a new group of myeloid neoplasms with a poor prognosis

Abstract Objective Myeloid neoplasms (MNs) harboring inv(3)(q21q26)/t(3;3)(q21;q26) or MECOM gene rearrangements as identified by fluorescence in situ hybridization (FISH) are known to carry a poor prognosis. The objective of this study is to assess prognostic impact of MNs with copy number alterations (CNA) in MECOM as compared to MNs with inv(3)/t(3;3) or MECOM rearrangements. We present those initial comparative results and secondarily assess whether genetic mutations that confer a worse clinical outcome are also associated with MNs with MECOM CNA. Methods A retrospective review of electronic pathology records was performed at Beth Israel Deaconess Medical Center. All MNs from 2016 – current with MECOM FISH (Abbott Molecular, Abbott Park, IL) confirmed analyses were extracted. Other additional items extracted included karyotype and next-generation sequencing (NGS) results of a 65 gene myeloid panel (SmartGenomics Myeloid Profile, PathGroup, Nashville, TN). Kaplan-Meier and ANOVA were performed using GraphPad Prism (San Diego, CA). Results A total of 307 cases were identified in which MECOM FISH was performed. Exclusion of cases lacking inv(3)/t(3;3), MECOM rearrangement, or MECOM CNA provided an initial study cohort of 20 cases. 5 cases had MECOM rearrangement with inv(3)/t(3;3), 7 had MECOM rearrangement without inv(3)/t(3;3), and 8 had MECOM CNA. 13 of 20 cases had a complex karyotype, 13 of 20 cases had a monosomal karyotype, 10 of 20 cases had both a complex and monosomal karyotype. Of the 20 cases in which MECOM FISH demonstrated inv(3)/t(3;3), MECOM rearrangement, or CNA, NGS was performed on 16 cases. Genes known to be associated with a significant negative overall survival (OS) include ASXL1, EZH2, IDH2, KRAS, NRAS, RAD21, RUNX1, SRSF2, STAG2, TP53 with single and multiple mutations found in 9 of 20 cases. Kaplan-Meier analysis revealed no significant difference in OS among the three MECOM aberration groupings (Log-rank test; p=0.77). Single factor ANOVA analysis revealed enrichment for high risk gene mutations in MECOM CNA (p=0.04) and TP53 mutations (p=0.04) when compared to MNs with MECOM rearrangements. Summary Our analysis of MNs with MECOM aberrations by FISH reveal that MECOM with CNA display similarly poor overall survival as MNs with inv(3)/t(3;3) and MECOM rearrangements. Additionally, the MECOM CNA group was enriched for high risk gene mutations and TP53 as compared to inv(3)/t(3;3) and MECOM rearrangement groups. Overall, the initial results of this study reveal a new group of MNs harboring MECOM CNA that confer a poor prognosis and high risk mutational profile.

Advances in the Study of High-Risk Gene Mutations for Primary Myelofibrosis

Primary myelofibrosis is a kind of MPNs due to clonal appreciation of hematopoietic stem cells. With the development of second-generation sequencing, high-risk mutation (HMR) genes such as ASXL1, EZH2, SRSF2, and IDH1/2 have been shown to be associated with disease prognosis and progression, and although allo-HSCT remains the only possible treatment for PMF, with the development of JAK inhibitors, there is an increasing interest in the study of inhibitors of these mutant loci.

Mutational Landscape of MDS Patients with HMA Failure Revealed By the Correlative Analysis from Inspire Trial

Mutational Landscape of MDS Patients with HMA Failure Revealed By the Correlative Analysis from Inspire Trial

Abstract 2605: A natural history study of men with high-risk genetics for prostate cancer (PCa) using multiparametric MRI (mpMRI)

Abstract Introduction: The understanding of molecular genetics in PCa provides insight into disease progression and treatment. Less is known about PCa development in men with known high-risk germline pathogenic/likely pathogenic variants in PCa related genes, particularly DNA damage repair (DDR). mpMRI can localize and detect PCa lesions in this population. We are conducting a multicenter natural history study of male participants (prts) with documented germline variant(s) in BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, EPCAM, HOXB13, ATM, NBN, TP53, CHEK2, PALB2, RAD51D, BRIP1, or FANCA who do not have a PCa diagnosis using mpMRI (NCT03805919). Methods: Up to 500 men, 30-75 years old (y/o) will undergo mpMRI evaluation at baseline and every 2 years (yrs). Prts are followed at 12-mo intervals to determine PSA, PCa diagnosis, and/or disease/survival status until death. Indication for prostate biopsy includes PSA >2.0 for 30 - 49 y/o; >2.5 ng/mL for 50 - 75 y/o and/or PIRADS 3+ MRI lesion or clinical discretion. Tissue obtained will undergo full transcriptome analysis. Results: 100 prts have enrolled. Median age is 47 y/o. Median on-study PSA is 0.87 (0.16-10.05 ng/mL). Median PSA density is 0.029. Gene mutations are BRCA2 (40%), BRCA1 (33%), MSH2 (9%), and CHEK2 (4%). Mutations in ATM, HOXB13, MLH1, MSH6, PMS2, and EPCAM are ≤3%. No significant AEs have been observed. Of 96 prts, 25 (26%), had indication for biopsy [PIRADS 4 lesion: 16 (64%), PIRADS 3 lesion: 4 (16%), elevated PSA: 6 (24%), or clinical indication 1: (4%)]. 22 prostate biopsies were performed and 6 prts were diagnosed with PCa. One prt was upstaged on radical prostatectomy (RP). Conclusions: We found mpMRI-based PCa screening in men with high-risk gene mutations, especially DDR genes, is feasible and can be used to identify clinically significant PCa and monitor for disease progression. Future guidelines should consider age, mutation specificity and mpMRI. Accrual and correlative studies (biomarkers, PBMCs) are on-going. AgeMutationPSA (ng/mL)Biopsy Gleason ScoreTreatment65BRCA22.253+3RP52BRCA10.693+3Active Surveillance (AS)62CHEK22.493+3AS59PMS21.033+3AS59CHEK22.243+4Radiation55BRCA21.683+3RP: 4+4=8 Citation Format: Fatima Karzai, Anna Couvillon, Yolanda McKinney, Katherine Lee-Wisdom, Peter L. Choyke, Veda N. Giri, Todd M. Morgan, Heather H. Cheng, Maria J. Merino, Peter A. Pinto, Baris Turkbey, William L. Dahut. A natural history study of men with high-risk genetics for prostate cancer (PCa) using multiparametric MRI (mpMRI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2605.

Gender-related differences in the outcomes and genomic landscape of patients with myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes.

Myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes show a male predominance and men with MDS/MPN have worse outcomes, but it is unknown if the mutational burden differs between genders. We reviewed 167 patients with MDS/MPN and found that men had worse overall survival [hazard ratio (HR) 2·09, 95% confidence interval (CI) 1·16-3·75; P=0·013] independent of subtype, Revised International Prognostic Scoring System score and age at diagnosis. We analysed the genomic data of a subset of 100 patients. Men had 0·88 more somatic mutations on average (95% CI 0·20-1·56, P=0·011) independent of subtype, sample source and blast percentage. More somatic mutations was associated with a higher incidence of transformation to acute myeloid leukaemia (subdistribution HR 1·30, 95% CI 1·01-1·70; P=0·046). Men had 0·70 more mutations in high-risk genes [additional sex combs like-1 (ASXL1), enhancer of zeste homolog 2 (EZH2), Runt-related transcription factor 1 (RUNX1), SET binding protein 1 (SETBP1), NRAS proto-oncogene, GTPase (NRAS), stromal antigen 2 (STAG2)] on average (95% CI 0·11-1·29, P=0·021), and 13-times higher odds of harbouring an EZH2 mutation (95% CI 1·64-102·94, P=0·015). The presence of an EZH2 mutation was associated with worse survival among men (HR 2·98, 95% CI 1·1-8·0; P=0·031). Our present findings suggest that the worse outcomes in men with MDS/MPN are associated with a higher number of somatic mutations, especially in high-risk genes. These results warrant validation in larger cohorts and investigation of the underlying mechanisms.

FORECASTING OF BREAST CANCER USING VOTING CLASSIFIER

Breast cancer is the most diagnosed and the leading cause of death in women. among women is breast cancer. Between 1 in 8 and 1 in 12 women in the developed world will experience breast cancer throughout their lives. The risk of breast cancer is of two primary types. The first type is that a person is likely to develop breast cancer over a specified time period. The second type reflects the likelihood of a high-risk gene mutation. Earlier work has shown that it has been better to predict the risk of breast cancer by adding input into the wide-spread Gail model. The main objective is to predict analytics model to diagnose breast cancer stages of patients. The main objective of this work is to detect and analyze breast cancer. It predicts the stages of the cancer and gives as the accurate result. In this work, to investigate a dataset of medical patient records for hospital sector using machine learning technique and to identify patients having breast cancer stages from given dataset attributes. Then the accurate result is found by naive Bayesian algorithm with precision, recall, F1score.

Sex-Related Differences in Chronic Myeloid Neoplasms: From the Clinical Observation to the Underlying Biology.

Chronic myeloid neoplasms are clonal diseases with variable clinical course and outcomes and despite the introduction of novel therapies, patients with high-risk disease continue to have overall poor outcomes. Different groups have highlighted that men have overall worse survival and higher incidence of transformation to acute leukemia compared to women across neoplasms such as myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap neoplasms, and CML. More recent studies evaluating the genomic profile of patients with these neoplasms demonstrated a male predominance for mutations in high-risk genes including ASXL1, U2AF1, SRSF2 and ZRSR2. The understanding of the underlying biology is limited but a number of hypotheses have been developed and are currently being investigated. This review summarizes the current knowledge about sex-related differences in the clinical outcomes and genomic profile of patients with chronic myeloid neoplasms and discusses the hypothesized biologic mechanisms as an attempt to explain these observations.

Sum of High-Risk Gene Mutation (SHGM): A Novel Attempt to Assist Differential Diagnosis for Adrenocortical Carcinoma with Benign Adenoma, Based on Detection of Mutations of Nine Target Genes

There has been no research on applying gene detection to differential diagnosis of adrenocortical carcinoma (ACC). We attempted to explore a novel auxiliary method for differential diagnosis between ACC with benign adrenocortical adenoma (ACA), based on mutations of target genes in tissues. Nine genes were chosen as target genes, including TP53, CTNNB1, ARMC5, PRKAR1A, ZNRF3, RB1, APC, MEN1, and RPL22. Exons sequencing of target genes were performed in 98 cases of tissue samples by FastTarget technology, including 41 ACC tissues, 32 ACA tissues, and 25 normal adrenal gland tissues. Significant mutations were detected and identified, and the clinical information was collected, for further comparative analysis and application to assist differential diagnosis of ACC. We identified 132 significant gene mutations and 227 significant mutation sites in 37 ACC tissues, much more than ACA and normal adrenal gland tissues. Mutation rates of 6 genes in ACC tissues were obviously higher than ACA tissues, including ZNRF3, ARMC5, TP53, APC, RB1, and PRKAR1A, regarded as high-risk genes. The sum of mutated high-risk genes detected in each sample was denominated sum of high-risk gene mutation (SHGM), and the rates of SHGM > 0 and SHGM > 1 in ACC tissues were 73.0% and 62.2%, respectively, both obviously higher than those in ACA tissues, with significant statistic differences. Especially for 8 cases of ACC with diameter < 5 cm, SHGM > 0 and SHGM > 1 were found in 6 samples (75%) and 4 samples (50%), respectively. However, no relevance was found between SHGM and clinical characteristics of ACC. We identified 6 high-risk genes in ACC tissues, with significantly higher mutation rates than ACA or normal adrenal gland tissues. The sum of mutated high-risk genes detected in ACC tissues was denominated SHGM, which was potential to assist the differential diagnosis of ACC with ACA, especially for the small-size ACC.

Survey on Physicians’ Knowledge and Training Needs in Genetic Counseling in Germany

Background: In recent years, germline testing of women with a risk of developing breast and ovarian cancer has increased rapidly. This is due to lower costs for new high-throughput sequencing technologies and the manifold preventive and therapeutic options for germline mutation carriers. The growing demand for genetic counseling meets a shortfall of counselors and illustrates the need to involve the treating clinicians in the genetic testing process. This survey was undertaken to assess their state of knowledge and training needs in the field of genetic counseling and testing. Methods: A cross-sectional survey within the European Bridges Study (Breast Cancer Risk after Diagnostic Gene Sequencing) was conducted among physician members (n = 111) of the German Cancer Society who were primarily gynecologists. It was designed to examine their experience in genetic counseling and testing. Results: Overall, the study revealed a need for training in risk communication and clinical recommendations for persons at risk. One-third of respondents communicated only relative disease risks (31.5%) instead of absolute disease risks in manageable time spans. Moreover, almost one-third of the respondents (31.2%) communicated bilateral and contralateral risk-reducing mastectomy as an option for healthy women and unilateral-diseased breast cancer patients without mutations in high-risk genes (e.g. BRCA1 or BRCA2). Most respondents expressed training needs in the field of risk assessment models, the clinical interpretation of genetic test results, and the decision-making process. Conclusion: The survey demonstrates a gap of genetic and risk literacy in a relevant proportion of physicians and the need for appropriate training concepts.

The application of thromboelastography in risk stratification for selective thromboembolism prophylaxis after total joint arthroplasty in Chinese: a randomized controlled trial.

As Asian populations, Chinese have a lower rate of high-risk gene mutations in venous thrombosis. Therefore, individual patient risk assessment, rather than a "blanket policy", is considered the best thromboembolism prophylaxis for Chinese. The purpose of this study was to evaluate the effectiveness and safety of selective thromboembolism prophylaxis compared with conventional thromboembolism prophylaxis by risk stratification with thromboelastography (TEG) after joint arthroplasty in Chinese. Between August 2016 to August 2017, Chinese patients who underwent hip or knee arthroplasty were randomly divided into a selective anticoagulation group (SAG) and a conventional anticoagulation group (CAG). Participants and outcome assessors were blinded. In the SAG, an anticoagulant was used when TEG indicated hypercoagulability; while in the CAG, an anticoagulant was regularly used until one month after surgery. Outcome evaluation included effectiveness (defined as the incidence of VTE), and safety (defined as the incidence of bleeding events, poor wound healing, blood loss, and infection). A total of 197 patients (79 in the SAG and 118 in the CAG) were included in the study. There was 1 case of deep vein thrombosis (DVT) in the SAG and 2 cases of DVT in the CAG, but there was no significant difference between the two groups. Hidden blood loss in the SAG was 707.4±539.8 mL and hidden blood loss in the CAG was 617±565.0 mL, respectively (P>0.05). No significant difference was observed in perioperative blood loss between the SAG and the CAG (1,024.9±597.9 and 1,139.3±620.9 mL, respectively). Volume of blood transfusion was 92.4±270.2 mL in the SAG and 224.6±416.3 mL in the CAG, respectively, while rate of transfusion was 13.9% in the SAG and 33.9% in the CAG, respectively, which were significantly different between the two groups (P<0.05). In Chinese patients who underwent hip or knee arthroplasty, the efficacy of selective anticoagulation using TEG in risk stratification was comparable to that of conventional anticoagulation. Furthermore, the safety of selective anticoagulant prophylaxis was superior to that of conventional anticoagulant prophylaxis.