Genetic Mutations In Patients Research Articles

Detection of genetic mutations in 855 cases of papillary thyroid carcinoma by next generation sequencing and its clinicopathological features.

To investigate the genetic mutations in patients with papillary thyroid carcinoma (PTC) and their clinicopathological features by next generation sequencing (NGS). NGS technology was used to detect genetic mutations in PTC patients, and clinicopathological features were collected. ①Among 855 PTC patients, 810 patients had genetic mutations, and 45 patients had no genetic mutation. ②BRAF mutation was associated with tumor diameter (P < 0.001) and histological subtypes (P = 0.002). The abundance of V600E mutation was associated with gender (P = 0.004), tumor diameter (P < 0.001), bilateral presentation (P = 0.001), extrathyroidal extension (P < 0.001), lymphatic metastasis (P < 0.001), histological subtypes (P = 0.002) and TNM staging (P = 0.000); The different mutation abundance of V600E was associated with tumor diameter (P < 0.001), multifocal presentation (P = 0.047), bilateral presentation (P = 0.001), extrathyroidal extension (P = 0.001), lymphatic metastasis (P < 0.001), histological subtypes (P = 0.022) and TNM staging (P = 0.000). ③RET fusion was associated with tumor diameter (P < 0.001) and lymphatic metastasis (P = 0.005). ④TERT mutation was associated with gender (P = 0.043), tumor diameter (P < 0.001), extrathyroidal extension (P = 0.028) and TNM staging (P = 0.017). ⑤RAS mutation was associated with histological subtypes (P < 0.001). ⑥NTRK and PIK3CA mutations were not associated with clinicopathological features. NGS technology can comprehensively analyze the genetic mutations in PTC patients, which provides important prompts for the occurrence, development, diagnosis and treatment of PTC. In addition, BRAF V600E mutation, RET fusion and TERT mutation are associated with a number of high-risk clinicopathological features. Detection of genetic mutations in PTC patients by NGS is of great significance.

CRISPR System and Its Applications in Medicine and Stem Cell Engineering

Context: The clustered regularly interspaced short palindromic repeat (CRISPR)/Cas system is a groundbreaking gene-editing tool that shows great promise for modifying genomes. Derived from prokaryotic adaptive immune defense mechanisms, this technique has been used in research on human diseases, demonstrating remarkable therapeutic potential. Through CRISPR, specific genetic mutations in patients can be corrected during gene therapy, offering a solution for treating diseases that were previously untreatable using conventional methods. This review explores the recent progress and future prospects of the CRISPR system, focusing on its applications in medicine and stem cell engineering. Special emphasis is placed on medical applications, the latest target design or analysis tools for genome editing, advancements in stem cell engineering, and associated innovations and challenges. Evidence Acquisition: This study reviewed articles indexed in ISI, SID, PubMed, and PubMed Central from 2007 to 2024. Results: Cas9, a key protein in CRISPR gene editing, is an endonuclease capable of targeting and cutting specific DNA sequences, guided by short RNA sequences. The gene editing process involves homology-directed repair (HDR), non-homologous end joining (NHEJ), and base editing pathways. Base editing, which modifies the epigenome without inducing DNA breaks, is gaining increasing attention. However, CRISPR still faces technical challenges, and the development of more efficient "super" CRISPR technology will likely require time. This article reviews the effectiveness, limitations, and applications of the CRISPR system. Conclusions: CRISPR/Cas9 tools allow for the creation of precise models, leading to more effective treatment options for patients.

Một số bất thường gen ở bệnh nhân ung thư phổi không tế bào nhỏ tại Bệnh viện Đại học Y Hà Nội phát hiện bằng phương pháp giải trình tự gen thế hệ mới

This study aimed to evaluate the rate of genetic mutations in patients with non- small-cell lung cancer by Next-Generation Sequencing at Hanoi Medical university hospital from 2022 to 2023 and to assess the relationship between genetic mutations and pathological characteristics in non-small-cell lung cancer. In 90 non-small-cell lung cancer patients in the study, we found EGFR gene mutations in 41.1% of cases; KRAS gene mutation in 11.1%; ALK gene fusion in 4.4%; PIK3CA gene mutation in 2.2%; BRAF gene mutation in 1.1%; MET gene mutation in 1.1% and ROS1 gene fusion in 1.1%. We found that EGFR mutations were more commonly detected in female, non-smokers and having adenocarcinoma while KRAS mutations were more commonly detected in male.

Frequency of Genetic Mutations in Patients With Chronic Lymphocytic Leukemia and Their Effects on Survival

Frequency of Genetic Mutations in Patients With Chronic Lymphocytic Leukemia and Their Effects on Survival

New Variants Identified by Next-Generation Sequencing in Polycystic Kidney Disease Patients.

Polycystic kidney disease (PKD) is a common inherited disease characterized by multiple cysts in kidneys and various extra renal manifestations. Molecular diagnosis plays a crucial role in confirming both the clinical diagnosis and preimplantation genetic diagnosis furthermore, selecting appropriate treatment options. This study aimed to expand the understanding of genetic mutations in patients with polycystic kidney disease and to improve the management of patients. The study included 92 patients with a clinical diagnosis of PKD based on renal ultrasound criteria. Targeted next-generation sequencing was performed using a custom panel kit. Of the 92 patients included in the study, pathogenic/likely pathogenic variants of the PKD1, PKD2 genes were detected in 37 patients (40.2%), while 8 patients (8.6%) had variants with uncertain clinical significance. After the additional assessment of pathogenic/likely pathogenic variants, it was found that 15 of the variants in PKD1 and 2 of the variants in PKD2 have not been reported in the literature previously. Additionally, pathogenic variants, 5 of which were novel, have been identified in different genes in 8 patients. This study presented the largest patient cohort conducted in Turkey. These findings were significant in expanding our understanding of the genetic variations associated with polycystic kidney disease. The study contrıbuted the literature data on polycystic kidney disease by reporting important findings that could pave the way for further investigations in the diagnosis, treatment, and management of the affected patients.

Unexpected Genetic Twists in Patients with Cardiac Devices.

Objective: To assess the frequency and types of genetic mutations in patients with arrhythmias who underwent cardiac device implantation. Methods: Retrospective observational study, including 38 patients with different arrhythmias and cardiac arrest as a first cardiac event. Treatment modalities encompass pacemakers, transvenous defibrillators, loop recorders, subcutaneous defibrillators, and cardiac resynchronization therapy. All patients underwent genetic testing, using commercially available panels (106-174 genes). Outcome measures include mortality, arrhythmia recurrence, and device-related complications. Results: Clinical parameters revealed a family history of sudden cardiac death in 19 patients (50%), who were predominantly male (58%) and had a mean age of 44.5 years and a mean left ventricle ejection fraction of 40.3%. Genetic testing identified mutations in various genes, predominantly TMEM43 (11%). In two patients (3%) with arrhythmogenic cardiomyopathy, complete subcutaneous defibrillator extraction with de novo transvenous implantable cardioverter-defibrillator implantation was needed. The absence of multiple associations among severe gene mutations was crucial for cardiac resynchronization therapy response. Mortality in this group was around 3% in titin dilated cardiomyopathy patients. Conclusions: Integration of genetic testing into the decision-making process for patients with electronic devices represents a paradigm shift in personalized medicine. By identifying genetic markers associated with arrhythmia susceptibility, heart failure etiology, and cardiac resynchronization therapy response, clinicians can tailor device choices to optimize patient outcomes.

Prevalence of Genetic Mutations in Patients with Metastatic Prostate Cancer in a Cohort of Mexican Patients

Background: Prostate cancer is a malignant neoplasm of the male genitourinary system with the highest incidence worldwide. Susceptibility genes related to aggressiveness and prognosis, such as BRCA1/2, ATM, PTEN, have been identified. Currently, reports related to germline mutations in patients with prostate cancer in Latin American populations are very limited or absent. In the Mexican population, reports are also limited, especially in the context of metastatic prostate cancer. Determining the prevalence of these mutations is relevant to predict the potential aggressiveness of tumors and allow the use of targeted therapies, such as PARPi inhibitors. Objective: Determine the prevalence of germline mutations in patients with metastatic prostate cancer and establish their clinical characteristics at diagnosis. Material and Methods: Sixty-nine patients with metastatic PCa underwent testing and genetic analysis using the Comprehensive Multi-Cancer Hereditary Cancer Panel. The prevalence of germline mutations was assessed, and the cohort was divided into two groups for the evaluation and analysis of clinical characteristics between the mutated and non-mutated populations. Results: We identified mutations in 15 out of 69 patients (21.73%), while 54 patients (78.26%) had no mutations. Pathogenic mutations were observed in 15.9% of patients, Variants of Uncertain Significance (VUS) in 34.78%, and 5.79% had both. The most frequent mutations included ATM (11.54%), BRCA1 (11.54%), BRCA2 (7.69%), FANCA (7.69%), and FANCM (7.69%). No statistically significant differences were found in PSA levels, age at diagnosis, and resistance to castration between the two groups. Conclusions: Our study unveiled a mutation rate of 21.73%, marked by a significant prevalence of ATM, FANCA, FANCM, and Variants of Uncertain Significance (VUS). This pattern deviates from findings in other series, underscoring the necessity for improved access to clinical genetic testing in our population.

Screening for Mutations in Hereditary Cancer Susceptibility Genes in a Region with High Endogamy in Brazil

Abstract Introduction Cancer is a multifactorial disease dependent on the influence of genetic and environmental factors. About 10% of cancers are associated with germline mutations, which predispose to a higher risk of developing cancer. Currently, the use of panels that identify susceptibility and/or association genes cancer has been increasingly used, both in clinical practice and in scientific research. Objective To investigate genetic mutations in patients with a profile for hereditary cancer in individuals from a region of northeast Brazil, where there is a high frequency of endogenous and consanguineous marriages. Methods A set of 17 genes (BRCA1, BRCA2, APC, TP53, PTEN, RET, VHL, RB1, CDKN2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, XPA, and XPC) associated with cancer and hereditary syndromes were analyzed. Fifteen patients with a hereditary cancer profile were evaluated. Results The pathogenic variant found was c.1187G &gt; A (p.Gly396Asp), rs36053993 in the MUTYH gene in a male patient diagnosed with melanoma at the age of 43 years and a family history for this tumor. This gene encodes an important enzyme related to DNA repair and has been associated with other types of cancer, this is the first report of an association with melanoma, the biological plausibility of this association is given once the MUTYH protein is expressed in the skin tissue and is responsible for repairing damage caused, for example, by sun exposure. Conclusion The results of this study suggest that this mutation may be important for the hereditary predisposition to melanoma, but a broader investigation of this mutation is needed.

Targeted next-generation sequencing of Japanese patients with sinonasal mucosal melanomas identifies frequent NRAS and CTNNB1 mutations

ObjectiveMucosal melanoma is a rare malignancy; however, the reported incidence rate of mucosal melanoma is higher in Asians than in Caucasians. Sinonasal mucosal melanoma (SNMM) is an aggressive malignancy with a poor prognosis due to distant metastasis. Systemic therapy with BRAF inhibitor and MEK inhibitor is one of the standards of care for cutaneous melanoma patients with BRAF V600 mutations. However, no molecular targeted therapy for patients with mucosal melanoma has been established. Relatively few studies have described the genetic mutations associated with mucosal melanoma because of its low frequency. Furthermore, to the best of our knowledge, the genetic mutations among Japanese patients have not been reported. Therefore, in the current study, we evaluated the genetic and clinicopathological characteristics of patients with SNMM. MethodsA total of 18 tissue samples obtained from patients with SNMM were analyzed for genetic mutations based on targeted next-generation sequencing to investigate the driver of tumorigenesis and/or candidate genes for predicting clinical outcomes in SNMM. We also performed immunohistochemistry for patients identified with CTNNB1 mutations. ResultsEight of the 18 (44 %) patients had genetic mutations. The most frequent mutation was NRAS (6/18, 33 %), followed by CTNNB1 (2/18, 11 %) and BRAF (1/18, 5.6 %). One patient had both NRAS and CTNNB1 mutations. Clinical outcomes did not differ significantly between those with and without genetic mutations. NRAS mutations were associated with relatively higher T classification and worse survival rates, although the differences were not significant. The nuclear translocation of β-catenin was detected in both tumors with CTNNB1 mutations. The amino acid change in the BRAF mutation was K601R in exon 15. In the current study, no BRAF V600 mutations were detected. ConclusionGenetic mutations were not significantly associated with clinical outcomes. However, NRAS mutations may be a prognostic predictor and CTNNB1 mutation may be a treatment effector for immune check inhibitors. A larger prospective study is required to clarify the clinical importance of genetic mutations in patients with SNMM.

Assessment of intestinal status in MPLW515L mutant myeloproliferative neoplasms mice model

The MPLW515L mutation is a prevalent genetic mutation in patients with myeloproliferative neoplasms (MPN), and utilizing this mutation in mice model can provide important insights into the disease. However, the relationship between intestinal homeostasis and MPN mice model remains elusive. In this study, we utilized a retroviral vector to transfect hematopoietic stem cells with the MPLW515L mutation, creating mutated MPN mice model to investigate their intestinal status. Our results revealed that the MPLW515L in MPN mice model aggravated inflammation in the intestines, decreased the levels of tight junction proteins and receptors for bacteria metabolites. Additionally, there was increased activation of the caspase1/IL-1β signaling pathway and a significant reduction in phos-p38 levels in the intestinal tissue in MPN mice. The MPLW515L mutation also led to up-expression of anti-microbial genes in the intestinal tract. Though the mutation had no impact on the alpha diversity and dominant bacterial taxa, it did influence the rare bacterial taxa/sub-communities and consequently impacted intestinal homeostasis. Our findings demonstrate the significance of MPLW515L mice model for studying MPN disease and highlight the mutation's influence on intestinal homeostasis, including inflammation, activation of the IL-1β signaling pathway, and the composition of gut microbial communities.

Clinical and genetic predictors of cardiac dysfunction assessed by echocardiography in patients with hereditary hemochromatosis.

Hereditary hemochromatosis (HH) may cause iron deposition in cardiac tissue. We aimed to describe the echocardiographic findings in patients with HH and identify risk factors for cardiac dysfunction. In this retrospective study, we included patients with HH who underwent transthoracic echocardiography at our tertiary care center between August 2000 and July 2022. We defined three primary outcomes for cardiac dysfunction: 1) left ventricular ejection fraction (LVEF) < 55%, 2) ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e') > 15, and 3) global longitudinal strain (GLS) < 18. Multivariable logistic regression was utilized to identify predictors of cardiac dysfunction. 582 patients (median age 57 years, 61.2% male) were included. The frequency of LVEF < 55%, E/e' > 15 and GLS < 18 was 9.0% (52/580), 9.6% (51/534) and 20.2% (25/124), respectively. In multivariable analysis, non-White race, age, and hypertension were associated with E/e' > 15. No specific HFE genetic mutation was associated with LVEF < 55%. A history of myocardial infarction was strongly associated with both LVEF < 55% and E/e' > 15. In patients with LVEF ≥ 55%, the C282Y/H63D genetic mutation was associated with reduced likelihood of E/e' > 15, p = 0.024. Patients with C282Y/H63D had a higher frequency of myocardial infarction. Smoking and alcohol use were significantly associated with GLS < 18 in unadjusted analysis. We found the traditional risk factors of male sex, and history of myocardial infarction or heart failure, were associated with a reduced LVEF, irrespective of the underlying HFE genetic mutation. Patients with a C282Y/H63D genetic mutation had a higher frequency of myocardial infarction, yet this mutation was associated with reduced odds of diastolic dysfunction compared to other genetic mutations in patients with a normal LVEF.

Investigating the Effects of Tumor Treating Fields and Genetic Mutations in Patients With Glioblastoma (P13-13.005)

<h3>Objective:</h3> Here, we evaluate the efficacy of Optune treatment on survival, as well as perform extensive genetic sequencing on a subset of these patients to examine genetic associations with survival. <h3>Background:</h3> Patients with glioblastomas (GBMs) typically expire within 12–18 months after diagnosis. Optune is a wearable device that has been emerging as a treatment modality. <h3>Design/Methods:</h3> Patient data was collected between 2011 to 2021 from electronic health records at a single tertiary care medical center, which included age at diagnosis, presenting concern, presence/absence of seizures, tumor location, extent of surgical resection, steroid use, Karnofsky performance scale (KPS), time to progression, survival, and treatment modalities. Optune efficacy was measured via survival comparisons between patients treated with or without Optune. Foundation One sequencing was performed on most patient’s tumor samples. Survival time and genetic mutations were analyzed using a univariate Cox regression model to determine hazard ratios (HRs). <h3>Results:</h3> All patients were treated with the Stupp protocol, and those treated with Optune (n=25) were diagnosed at an average age of 62.3 years with an average KPS of 73.33, while patients treated without Optune (n=32) were diagnosed at an average age of 64.5 years old with an average KPS of 72.16. Overall survival after diagnosis was 23.7 months with Optune, and 14.4 months without Optune, though the study is not sufficiently powered to establish statistical significance. A subset of 54 patients also underwent genetic sequencing of 324 oncogenic gene mutations. IDH1 and ATRX were associated with prolonged survival (HR&lt;1), whereas PDGFRA, CDKN2A/B, NF1, PTEN, KDR, and TERT mutations were associated with worse overall survival (HR&gt;1). <h3>Conclusions:</h3> We assess the efficacy of Optune treatment and establish genetic markers of long-term survival in glioblastoma patients. Patients treated with Optune survive for an additional 9.3 months, and key genes were identified to have differential effects on survival. <b>Disclosure:</b> Mr. Wang has nothing to disclose. Knarik Arkun has nothing to disclose.

Genetic variations in the retrograde endocannabinoid signaling pathway in Chinese patients with major depressive disorder.

The retrograde endocannabinoid (eCB) pathway is closely associated with the etiology of major depressive disorder (MDD) at both pathophysiological and genetic levels. This study aimed to investigate the potential role of genetic mutations in the eCB pathway and underlying mechanisms in Han Chinese patients with MDD. A total of 96 drug-naïve patients with first-episode MDD and 62 healthy controls (HCs) were recruited. Whole-exome sequencing was performed to identify the gene mutation profiles in patients with MDD. Results were filtered to focus on low-frequency variants and rare mutations (minor allele frequencies <0.05) related to depressive phenotypes. Enrichment analyses were performed for 146 selected genes to examine the pathways in which the most significant enrichment occurred. A protein-protein interaction (PPI) network analysis was performed to explore the biological functions of the eCB pathway. Finally, based on current literature, a preliminary analysis was conducted to explore the effect of genetic mutations on the function of this pathway. Our analysis identified 146 (15.02%) depression-related genetic mutations in patients with MDD when compared with HCs, and 37 of the mutations were enriched in the retrograde eCB signaling pathway. Seven hub genes in the eCB pathway were closely related to mitochondrial function, including Complex I genes (NDUFS4, NDUFV2, NDUFA2, NDUFA12, NDUFB11) and genes associated with protein (PARK7) and enzyme (DLD) function in the regulation of mitochondrial oxidative stress. These results indicate that genetic mutations in the retrograde eCB pathway represent potential etiological factors associated with the pathogenesis of MDD.

PD04-03 GENETIC AND PATHWAY ALTERATIONS OF PROSTATE CANCER: FROM LOCALIZED TO METASTATIC PROSTATE CANCER

You have accessJournal of UrologyCME1 Apr 2023PD04-03 GENETIC AND PATHWAY ALTERATIONS OF PROSTATE CANCER: FROM LOCALIZED TO METASTATIC PROSTATE CANCER Chang Eil Yoon, Seung Ah Rhew, Hyeok Jae Kwon, Dongho Shin, and Ji Youl Lee Chang Eil YoonChang Eil Yoon More articles by this author , Seung Ah RhewSeung Ah Rhew More articles by this author , Hyeok Jae KwonHyeok Jae Kwon More articles by this author , Dongho ShinDongho Shin More articles by this author , and Ji Youl LeeJi Youl Lee More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003228.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Although prostate cancer is one of the most commonly diagnosed male cancer, because of it’s heterogeneity the treatment options are limited and the prognosis varies widely. Recently, interest in genetic analysis and targeted therapy has been increasing. In particular, Mutation in DNA repair pathways, such as BRCA1/2 genes, has been found to be associated with poor prognosis. Accordingly, the purpose of this study was to identify genetic mutations in patients with localized and metastatic prostate cancer, and to analyze the association between these genes and each patient's clinical course. METHODS: We analyzed 74 patients diagnosed with prostate cancer. Tissue specimens were obtained from prostate biopsy or surgical excision, and were analyzed through Next-generation sequencing at Seoul St. Mary's Hospital between July 1, 2021 and September 31, 2022. We retrospectively evaluated baseline characteristics including PSA score, TNM staging, Gleason’s score and the clinical course including additional treatment and biochemical recurrence. RESULTS: The patients are classified as follows: 49 localized prostate cancer and 25 metastatic prostate cancer. The average age of the patients and initial PSA values were 69.8±8.4 years and 155.6±588.1 ng/dL. 8p copy number alteration (24.3%), and SPOP(18.9%), IGF2R (17.6%), BRCA2(12.2%), NOTCH2(10.8%) gene mutations were most frequently detected gene mutations. BRCA2, NOTCH2 mutations showed a significant relationships with high M stage (p=0.041, 0.001 respectively) and high Gleason's score. (p= 0.01, 0.043 respectively. KMT2C (associated with histone methyltransferase) and TP53 (known as Tumor suppressor gene) mutations also showed high frequency (21.6%, 13.5% respectively), with KMT2C frequently found in local prostate cancer (p=0.011) and TP53 frequently found in metastatic prostate cancer (p=0.046). Although the incidence was low, PI3K pathway aberrations including PTEN (4.1%) and PIK3CA (5.4%) gene mutation was identified. Both were associated with high Gleason’s score (p=0.002, 0.048 respectively). CONCLUSIONS: Through genetic analysis of prostate cancer, it was possible to analyze numerous gene mutations, and to find clinically significant mutations. Several genes, such as BRCA2, NOTCH2 and TP53 gene mutations have been found to be associated with advanced prostate cancer. The prognosis of prostate cancer can be predicted by genetic analysis, and the better prognosis can be expected through the application of a proper targeted therapy for each pathway alterations. Source of Funding: NA © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e143 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Chang Eil Yoon More articles by this author Seung Ah Rhew More articles by this author Hyeok Jae Kwon More articles by this author Dongho Shin More articles by this author Ji Youl Lee More articles by this author Expand All Advertisement PDF downloadLoading ...

Research Progress of Next Generation Sequencing in Acute Leukemia --Review

With the advent of precision medicine, next-generation sequencing (NGS) is playing an increasingly important role in clinical oncology diagnosis and treatment with its advantages of high sensitivity, high accuracy, high efficiency and operability. NGS reveals the genetic characteristics of acute leukemia(AL) patients by screening for specific disease-causing genes to identify occult as well as complex genetic mutations in patients with AL, leading to early diagnosis and targeted drug therapy for AL patients, as well as to predict disease recurrence by detecting mnimal residual disease (MRD) and analyzing mutated genes to determine patient prognosis. NGS plays an increasingly important role in the diagnosis, treatment and prognosis assessment in AL, providing a direction for the pursuit of precision medicine. This paper reviews the research progress of NGS in AL.

Molecular genetics of early-onset colorectal cancer.

Early-onset colorectal cancer (EOCRC) has been rising in global prevalence and incidence over the past several decades. Environmental influences, including generational lifestyle changes and rising obesity, contribute to these increased rates. While the rise in EOCRC is best documented in western countries, it is seen throughout the world, although EOCRC may have distinct genetic mutations in patients of different ethnic backgrounds. Pathological and molecular characterizations show that EOCRC has a distinct presentation compared with later-onset colorectal cancer (LOCRC). Recent studies have identified DNA, RNA, and protein-level alterations unique to EOCRC, revealing much-needed biomarkers and potential novel therapeutic targets. Many molecular EOCRC studies have been performed with Caucasian and Asian EOCRC cohorts, however, studies of other ethnic backgrounds are limited. In addition, certain molecular characterizations that have been conducted for LOCRC have not yet been repeated in EOCRC, including high-throughput analyses of histone modifications, mRNA splicing, and proteomics on large cohorts. We propose that the complex relationship between cancer and aging should be considered when studying the molecular underpinnings of EOCRC. In this review, we summarize current EOCRC literature, focusing on sporadic molecular alterations in tumors, and their clinical implications. We conclude by discussing current challenges and future directions of EOCRC research efforts.

Multiple genetic mutations increase the risk of thrombosis associated with clopidogrel after percutaneous coronary intervention.

Background: The effect of multiple mutations in CYP2C19, PON1 and ABCB1 genes on the effectiveness and safety of dual antiplatelet therapy after percutaneous coronary interventionremains unclear. Methods: In total, 263 Chinese Han patients were enrolled in this study. Platelet aggregation rates and thrombosis risk were used to compare clopidogrel responses and outcomes in patients with different numbers of genetic mutations. Results: Our study demonstrated that 74% of the patients carried more than two genetic mutations. High platelet aggregation rates were associated with genetic mutations in patients receiving clopidogrel and aspirin after percutaneous coronary intervention. Genetic mutations were closely related to the recurrence of thrombotic events, but not bleeding. The number of genes that become dysfunctional in patients is directly correlated with the risk of recurrent thrombosis. Conclusion: Compared with CYP2C19 alone or the platelet aggregation rate, it is more helpful to predict clinical outcomes by considering the polymorphisms of all three genes.

Assessing the Immune Cell Subset and Genetic Mutations in Patients With Palindromic Rheumatism Seronegative for Rheumatoid Factor and Anti-Cyclic Citrullinated Peptide.

The etiology underlying cases of palindromic rheumatism (PR) not associated with other rheumatic diseases in patients who are seronegative for rheumatoid factor and anti-cyclic citrullinated peptide (seronegative PR) is unclear. We aimed to investigate the immune cells and genes involved. This was a single-center comparative study of 48 patients with seronegative PR and 48 healthy controls. Mass cytometry and RNA sequencing were used to identify distinct immune cell subsets in blood. Among the 48 seronegative PR patients, plasma samples from 40 patients were evaluated by enzyme-linked immunosorbent assay for cytokine levels, and peripheral blood samples from 25 patients were evaluated by flow cytometry for mononuclear cell subsets. Plasma samples from 21 patients were evaluated by real-time polymerase chain reaction for differential gene and protein expression, and samples from 3 patients were analyzed with whole-exome sequencing for gene mutations. Immunophenotyping revealed a markedly increased frequency of CD14+CD11b+CD36+ and CD4+CD25-CD69+ cells in seronegative PR patients with active flares compared with healthy controls (P < 0.0001 for both cell subset comparisons). Gene enrichment analyses of RNA-sequencing data from sorted CD14+CD11b+CD36+ and CD4+CD25-CD69+ cells showed involvement of the inflammatory/stress response, phagocytosis, and regulation of apoptosis functional pathways. Up-regulated expression of CXCL16 and IL10RA was observed in monocytes from PR patients. Up-regulation of PFKFB3, DDIT4, and TGFB1, and down-regulation of PDIA6 were found in monocytes and lymphocytes from PR patients with active flares and PR patients in intercritical periods. Plasma levels of S100A8/A9 and interleukin-1β were elevated in PR patients. Whole-exome sequencing revealed novel polygenic mutations in HACL1, KDM5A, RASAL1, HAVCR2, PRDM9, MBOAT4, and JRKL. In seronegative PR patients, we identified a distinct CD14+CD11b+CD36+ cell subset that can induce an inflammatory response under stress and exert antiinflammatory effects after phagocytosis of apoptotic cells, and a CD4+CD25-CD69+ T cell subset with pro- and antiinflammatory properties. Individuals with genetic mutations involving epigenetic modification, potentiation and resolution of stress-induced inflammation/apoptosis, and a dysregulated endoplasmic reticulum stress response could be predisposed to seronegative PR.

632 PREVALENCE OF VARIANT GENOTYPE IN PATIENTS WITH SUSPECTED CARDIAC ATTR AMYLOIDOSIS

Abstract Background Emerging therapeutic options and availability of non-invasive diagnostic tools are increasing recognition of cardiac ATTR (transthyretin) amyloidosis worldwide. However, the relative prevalence of hereditary ATTR amyloidosis may be underestimated, particularly in aged males in whom the disease may be assumed to be wild- type and TTR genetic test not performed. TTR gene variants associated with a predominant cardiac phenotype are known to result in worse prognosis. Identification of a pathogenic variant may not only guide treatment strategy but also allow for genetic counselling and cascade testing in at risk relatives. Purpose To identify the prevalence and type of genetic mutations in patients referred to our Centre for suspected cardiac ATTR amyloidosis. Methods We evaluated consecutive patients referred to our Centre from January 2017 to December 2021 for suspected cardiac ATTR amyloidosis based on signs of heart involvement on echocardiogram or magnetic resonance, a Perugini score 2 or 3 bone scintigraphy or a tissue biopsy proving TTR amyloid deposition, no family history, no signs of neurological or other organ involvement. All patients underwent clinical evaluation and laboratory analysis including serum and urine immunofixation, serum free light chains, and TTR genetic testing. As AAPOA-I amyloidosis is reported in Northern Italy we also routinely perform APOA1 genetic test in patients with suspected cardiac amyloidosis. Diagnosis was ultimately established on a tissue biopsy in patients in which a monoclonal component (CM) was identified. Results 481 patients were included, mean age at presentation was 76 years (min-max 50-93), 40 (8%) were women. In all patients with CM (29%), tissue biopsy confirmed TTR amyloid deposition by immunoelectron microscopy or proteomics. 439 patients (91%) did not carry TTR or APOA1 variants, while 42 (9%) had a heterozygous pathogenic mutation. 41 patients have a pathogenic TTR mutation the most frequent being Ile68Leu (n=28; 67%), followed by Tyr78Phe, Val122Ile and Val94Leu (n=3/2/2 respectively). One novel mutation, namely Pro43Thr, was identified. In one patient APOA1 Leu75Pro variant was identified and diagnosis of AApoA-I amyloidosis confirmed by typing on endomyocardial biopsy. No significant differences were found between ATTRwt and ATTRv patients apart from gender distribution. Although age did not differ among the two groups, the prevalence of a variant genotype raises when considering only patients younger than 70 years (14%). 20% of women carry a pathogenic variant, irrespective of age. Interestingly, among women with ATTRwt (n=32), almost one third (31%) was diagnosed with hip dysplasia in childhood, requiring multiple orthopaedic surgeries and prothesis implantation. Conclusions In our cohort, one out of ten patients referred for suspected cardiac ATTR amyloidosis was ultimately diagnosed with ATTRv. Our results emphasize the importance of performing genetic testing irrespective of age at presentation. Diagnosis of ATTRv is relevant for monitoring disease progression, for defining treatment strategy and for offering genetic counselling and presymptomatic test in at risk relatives. Finally, the high prevalence of hip dysplasia among women with ATTRwt deserves further investigation to define whether it may represent a novel, gender-related red flag for this disease.

Recurrent acute myocarditis: An under-recognized clinical entity associated with the later diagnosis of a genetic arrhythmogenic cardiomyopathy.

Myocardial inflammation has been consistently associated with genetic arrhythmogenic cardiomyopathy (ACM) and it has been hypothesized that episodes mimicking acute myocarditis (AM) could represent early inflammatory phases of the disease. We evaluated the temporal association between recurrent acute myocarditis (RAM) episodes and the later diagnosis of a genetic ACM. Between January 2012 and December 2021, patients with RAM and no previous cardiomyopathy were included (Recurrent Acute Myocarditis Registry, NCT04589156). A follow-up visit including clinical evaluation, resting and stress electrocardiogram, cardiac magnetic resonance imaging, and genetic testing was carried out. Endpoints of the study was the incidence of both ACM diagnosis criteria and ACM genetic mutation at the end of follow-up. Twenty-one patients with RAM were included and follow-up was completed in 19/21 patients (90%). At the end of follow-up, 3.3 ± 2.9 years after the last AM episode, 14/21 (67%) patients with an ACM phenotype (biventricular: 10/14, 71%; left ventricular: 4/14, 29%) underwent genetic testing. A pathogenic or likely pathogenic mutation was found in 8/14 patients (57%), 5/8 in the Desmoplakin gene, 2/8 in the Plakophillin-2 gene, and 1/8 in the Titin gene. Family history of cardiomyopathy or early sudden cardiac death had a positive predictive value of 88% for the presence of an underlying genetic mutation in patients with RAM. RAM is a rare entity associated with the latter diagnosis of an ACM genetic mutation in more than a third of the cases. In those patients, RAM episodes represent early inflammatory phases of the disease. Including RAM episodes in ACM diagnosis criteria might allow early diagnosis and potential therapeutic interventions.