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Genes Jun 2024Breast cancer (BC) has the highest morbidity rate and the second-highest mortality rate of all cancers among women. Recently, multi-cancer genome profiling (multi-CGP)...
Breast cancer (BC) has the highest morbidity rate and the second-highest mortality rate of all cancers among women. Recently, multi-cancer genome profiling (multi-CGP) tests have become clinically available. In this study, we aimed to clarify the significance of multi-CGP testing of BC by using the large clinical dataset from The Center for Cancer Genomics and Advanced Therapeutics (C-CAT) profiling database in Japan. A total of 3744 BC cases were extracted from the C-CAT database, which enrolled 60,250 patients between June 2019 and October 2023. Of the 3744 BC cases, a total of 3326 cases for which the C-CAT included information on ER, PR, and HER2 status were classified into four subtypes, including TNBC, HR+/HER2-, HR+/HER2+, and HR-/HER2+. Comparisons between groups were performed by the χ test or Fisher's exact test using EZR. Kaplan-Meier curves were created using the log-rank test. : Of all 3326 cases analyzed, 1114 (33.5%) were TNBC cases, HR+/HER2- accounted for 1787 cases (53.7%), HR+/HER2+ for 260 cases (7.8%), and HR-/HER2+ for 165 cases (5.0%). Genetic abnormalities were most frequently detected in (58.0%), (35.5%), (18.7%), (15.5%), and (15.1%) across all BCs. The rate of TMB-High was 12.3%, and the rate of MSI-High was 0.3%, in all BC cases. Therapeutic drugs were proposed for patients with mutations in six genes: , , , , , and . The prognoses of HR+/HER2- cases were significantly ( = 0.044) better in the treated group than in the untreated group. : These findings suggest that cancer gene panel testing is useful for HR+/HER2- cases.
Topics: Humans; Female; Japan; Middle Aged; Breast Neoplasms; Receptor, ErbB-2; Aged; Adult; Retrospective Studies; Biomarkers, Tumor; Receptors, Estrogen; Receptors, Progesterone; Aged, 80 and over; Prognosis; Mutation; Gene Expression Profiling; Class I Phosphatidylinositol 3-Kinases
PubMed: 38927728
DOI: 10.3390/genes15060792 -
Biomedicines Jun 2024Arrhythmic risk stratification in patients with Lamin A/C gene (LMNA)-related cardiomyopathy influences clinical decisions. An implantable cardioverter defibrillator...
Arrhythmic risk stratification in patients with Lamin A/C gene (LMNA)-related cardiomyopathy influences clinical decisions. An implantable cardioverter defibrillator (ICD) should be considered in patients with an estimated 5-year risk of malignant ventricular arrhythmia (MVA) of ≥10%. The risk prediction score for MVA includes non-missense LMNA mutations, despite their role as an established risk factor for sudden cardiac death (SCD) has been questioned in several studies. The purpose of this study is to investigate cardiac features and find gene-phenotype correlations that would contribute to the evidence on the prognostic implications of non-missense vs. missense mutations in a cohort of LMNA mutant patients. An observational, prospective study was conducted in which 54 patients positive for a Lamin A/C mutation were enrolled, and 20 probands (37%) were included. The median age at first clinical manifestation was 41 (IQR 19) years. The median follow-up was 8 years (IQR 8). The type of gene mutation was distributed as follows: missense in 26 patients (48%), non-frameshift insertions in 16 (30%), frameshift deletions in 5 (9%), and nonsense in 7 (13%). Among the missense mutation carriers, two (8%) died and four (15%) were admitted onto the heart transplant list or underwent transplantation, with a major adverse cardiovascular event (MACE) rate of 35%. No statistically significant differences in MACE prevalence were identified according to the missense and non-missense mutation groups ( value = 0.847). Our data shift the spotlight on this considerable topic and could suggest that some missense mutations may deserve attention regarding SCD risk stratification in real-world clinical settings.
PubMed: 38927500
DOI: 10.3390/biomedicines12061293 -
Biomolecules Jun 2024Lung cancer is a major global health concern with a low survival rate, often due to late-stage diagnosis. Liquid biopsy offers a non-invasive approach to cancer...
Lung cancer is a major global health concern with a low survival rate, often due to late-stage diagnosis. Liquid biopsy offers a non-invasive approach to cancer detection and monitoring, utilizing various features of circulating cell-free DNA (cfDNA). In this study, we established two models based on cfDNA coverage patterns at the transcription start sites (TSSs) from 6X whole-genome sequencing: an Early Cancer Screening Model and an mutation status prediction model. The Early Cancer Screening Model showed encouraging prediction ability, especially for early-stage lung cancer. The mutation status prediction model exhibited high accuracy in distinguishing between -positive and wild-type cases. Additionally, cfDNA coverage patterns at TSSs also reflect gene expression patterns at the pathway level in lung cancer patients. These findings demonstrate the potential applications of cfDNA coverage patterns at TSSs in early cancer screening and in cancer subtyping.
Topics: Humans; ErbB Receptors; Lung Neoplasms; Early Detection of Cancer; Mutation; Cell-Free Nucleic Acids; Female; Male; Middle Aged; Aged; Proof of Concept Study; Biomarkers, Tumor; Liquid Biopsy; Whole Genome Sequencing; Transcription Initiation Site; Circulating Tumor DNA
PubMed: 38927119
DOI: 10.3390/biom14060716 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To analyze the gene mutation types and frequence of thalassemia patients in Jingzhou area.
OBJECTIVE
To analyze the gene mutation types and frequence of thalassemia patients in Jingzhou area.
METHODS
A total of 721 suspected thalassemia patients who were visited in Jingzhou Central Hospital from June 2019 to June 2022 were selected as the research objects. There were 204 males and 517 females. PCR-reverse dot hybridization method was used to analyze the types and frequencies of 23 common α or β thalassemia gene mutations.
RESULTS
Among the 721 patients with suspected thalassemia, 228 cases were positive for α or β thalassemia gene, with a total positive rate of 31.62%, including 87 cases of α-thalassemia, accounting for 38.16%, and 140 cases of β-thalassemia, accounting for 61.40%. There was 1 case of α β complex thalassemia, accounting for 0.44%. A total of 4 types of α-thalassemia gene mutations were detected, all of which were deletion types, including αα/-- (64/87, 73.56%), αα/-α (14/87, 16.09%), -- /-α (7/87, 8.05%), αα/-α (2/87, 2.30%). Among 140 patients with β-thalassemia, 138 were pure heterozygotes, and the genotypes of (63/140, 45.00%), (34/140, 24.29%), (18/140, 12.86%) and (10/140, 7.14%) accounted for 89.29% of all mutations (125/140), 2 cases of double heterozygosity (2/140, 1.43%) were found, no homozygous β-thalassemia were detected; 1 case of αβ complex thalassemia with genotype -α/ was found. The incidence of difference types of thalassemia was statistically significant (χ=194.250, < 0.001). The percentage of positive thalassemia genes was not significantly difference between male and female suspected patients (χ=0.199, =0.655).
CONCLUSION
The α-thalassemia gene mutation in Jingzhou area is dominated by αα/--, and the mutation is more common in β-thalassemia, and α β complex thalassemia is relatively rare, which can provide a reference for the formulation of prevention and treatment measures for thalassemia in Jingzhou area.
Topics: Humans; Male; Female; Mutation; alpha-Thalassemia; beta-Thalassemia; China; Heterozygote; alpha-Globins
PubMed: 38926976
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.028 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To analyze the DTA (, , ) mutations in patients with myeloproliferative neoplasms (MPN), and preliminarily explore their correlation with thromboembolism.
OBJECTIVE
To analyze the DTA (, , ) mutations in patients with myeloproliferative neoplasms (MPN), and preliminarily explore their correlation with thromboembolism.
METHODS
Clinical characteristics of 62 patients diagnosed de novo MPN at Central Hospital Affiliated to Shandong First Medical University from September 2016 to September 2022 were retrospectively analyzed. Next-generation sequencing was used to detect 35 MPN-related genes, and the DTA mutations in MPN patients and their relationship with thromboembolic events were analyzed.
RESULTS
75.8% (47/62) of the patients presented pathogenic non-driver mutations, and the mean number of pathogenic non-driver mutations per patient was 1.08. Among them, the most frequently mutated non-driver genes were (38.7%, 24/62), (9.7%, 6/62) and (6.5%, 4/62). The presence of DTA gene mutations was 50% (31/62) in the total MPN patients, and mainly accompanied by driver mutations. The mutation rate of DTA in patients aged ≥60 years was significantly higher than that in patients <60 years old ( =0.039). The incidence of thromboembolism in patients with DTA mutation was 58.1% (18/31), which was significantly higher than that in patients without DTA mutation (19.4%, 6/31) ( =0.002). The gene mutation rate in MPN patients with thromboembolism was 66.7% (16/24), which was significantly higher than that in patients without thromboembolism (21.1%, 8/38) ( =0.00).
CONCLUSION
Patients with MPN have a higher incidence of DTA mutations, which are mainly accompanied by driver gene mutations. The incidence of thromboembolism in MPN patients with DTA mutations is higher than that in patients without DTA mutations. Especially, the elderly (≥60 years) essential thrombocythemia(ET) and polycythemia vera(PV) patients with mutation should be vigilant for thromboembolic events.
Topics: Humans; Mutation; Dioxygenases; Middle Aged; Myeloproliferative Disorders; Thromboembolism; Retrospective Studies; Proto-Oncogene Proteins; DNA-Binding Proteins; Repressor Proteins; DNA Methyltransferase 3A; DNA (Cytosine-5-)-Methyltransferases; Male; Female; High-Throughput Nucleotide Sequencing
PubMed: 38926973
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.025 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the clinical significance of allelic state in patients with myelodysplastic syndromes (MDS).
OBJECTIVE
To investigate the clinical significance of allelic state in patients with myelodysplastic syndromes (MDS).
METHODS
The clinical data of 858 MDS patients who underwent second-generation sequencing (NGS) testing in the First Affiliated Hospital of Soochow University from January 2019 to December 2021 were retrospectively analyzed.
RESULTS
The median age of the patients was 52 years old, and median follow-up time was 23.8 (0.4-109.6) months. Four hundred and one patients (46.7%) had at least one chromosomal abnormality, including 106 complex karyotypes and 78 monosomal karyotypes. A total of 103 cases of mutations were identified, with a mutation rate of 12%. Compared with wild-type, various types of chromosomal abnormalities were significantly more common in patients with mutations (all < 0.001). Patients with mutations had lower hemoglobin levels, lower platelet counts and higher percentage of bone marrow primitive cell compared with wild type (all < 0.05), and significantly shorter overall survival (OS). Among 97 evaluable patients, 33 cases (34%) were mono-allelic mutation, while 64 cases were bi-allelic mutation. Patients in bi-allelic mutation subgroup had a higher proportion of chromosomal abnormalities and a lower number of co-mutations compared with mono-allelic mutation. The median OS was 33.6 months in patients with mono-allelic state and only 11.4 months in patients with bi-allelic state (=2.138, 95% : 1.053-4.343, >0.05). Median OS was not reached in wild-type patients, and there was a significant difference in OS among wild-type, mono-allelic and bi-allelic mutation patients ( < 0.001). Multivariable Cox regression analysis showed that bi-allelic was an independent predictor of poor outcomes (=2.808, 95% : 1.487-5.003, =0.001), while mono-allelic mutation and wild-type were not.
CONCLUSION
Patients with mutations have a poor prognosis, and bi-allelic mutations have a worse prognosis compared with mono-allelic mutations and independently affect the prognosis of MDS patients.
Topics: Humans; Myelodysplastic Syndromes; Middle Aged; Prognosis; Retrospective Studies; Tumor Suppressor Protein p53; Mutation; Alleles; Chromosome Aberrations; Male; Female
PubMed: 38926972
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.024 -
Hamostaseologie Jun 2024Atypical sites for thrombosis include deep vein thrombosis (DVT) of the upper extremity (UE-DVT), splanchnic vein thrombosis (SVT), and cerebral venous sinus...
High Prevalence of F2 20210G > A in Splanchnic Vein Thrombosis and Cerebral Venous Sinus Thrombosis: A Retrospective Cohort Study of Patients with Thrombosis in Atypical Sites.
INTRODUCTION
Atypical sites for thrombosis include deep vein thrombosis (DVT) of the upper extremity (UE-DVT), splanchnic vein thrombosis (SVT), and cerebral venous sinus thrombosis (CVST). In addition to specific pathogenic factors, their underlying mechanisms share similarities with typical venous thromboembolism (VTE), namely, DVT of the lower extremity and/or pulmonary embolism, but are less understood.
METHODS
Records of unselected patients with a history of typical VTE ( = 2,011), UE-DVT ( = 117), SVT ( = 83), and CVST ( = 82), who were referred to the Institute in Bonn for ambulatory thrombophilia testing, were retrospectively analyzed. Acquired and hereditary thrombosis risk factors were comparatively assessed.
RESULTS
UE-DVT was characterized by a high rate (50.4%) of site-specific acquired risk factors. Compared with typical VTE, SVT was more frequently associated with systemic inflammation, infection, or malignancy (2.2 vs. 12.0%, = 3·10) and the V617F mutation was present in 16.9%. In CVST compared with typical VTE, demographics and higher rates of oral contraception (43.2 vs. 57.6%, = 0.011) and pregnancy (4.2 vs. 10.9%, = 0.012) suggest a significant hormonal influence on etiology. While the prevalence of inhibitor deficiencies and factor V Leiden mutation did not differ between cohorts, the prevalence of 20210G > A was higher in SVT (15.7%, = 0.003) and CVST (15.9%, = 0.003) than in typical VTE (7.0%).
CONCLUSION
The cohorts with thrombosis in atypical sites showed distinctive patterns of acquired risk factors. Further studies are warranted to provide additional mechanistic insight into the role of hormonal influence in CVST and the contribution of 20210G > A to the development of SVT and CVST.
PubMed: 38925156
DOI: 10.1055/a-2329-1798 -
Protein Science : a Publication of the... Jul 2024Variation in mutation rates at sites in proteins can largely be understood by the constraint that proteins must fold into stable structures. Models that calculate...
Variation in mutation rates at sites in proteins can largely be understood by the constraint that proteins must fold into stable structures. Models that calculate site-specific rates based on protein structure and a thermodynamic stability model have shown a significant but modest ability to predict empirical site-specific rates calculated from sequence. Models that use detailed atomistic models of protein energetics do not outperform simpler approaches using packing density. We demonstrate that a fundamental reason for this is that empirical site-specific rates are the result of the average effect of many different microenvironments in a phylogeny. By analyzing the results of evolutionary dynamics simulations, we show how averaging site-specific rates across many extant protein structures can lead to correct recovery of site-rate prediction. This result is also demonstrated in natural protein sequences and experimental structures. Using predicted structures, we demonstrate that atomistic models can improve upon contact density metrics in predicting site-specific rates from a structure. The results give fundamental insights into the factors governing the distribution of site-specific rates in protein families.
Topics: Proteins; Protein Conformation; Thermodynamics; Evolution, Molecular; Mutation; Models, Molecular; Molecular Dynamics Simulation
PubMed: 38923241
DOI: 10.1002/pro.5086 -
Animal Genetics Jun 2024We recently discovered that the Manech Tête Rousse (MTR) deficient homozygous haplotype 2 (MTRDHH2) probably carries a recessive lethal mutation in sheep. In this...
We recently discovered that the Manech Tête Rousse (MTR) deficient homozygous haplotype 2 (MTRDHH2) probably carries a recessive lethal mutation in sheep. In this study, we fine-mapped this region through whole-genome sequencing of five MTRDHH2 heterozygous carriers and 95 non-carriers from various ovine breeds. We identified a single base pair duplication within the SLC33A1 gene, leading to a frameshift mutation and a premature stop codon (p.Arg246Alafs*3). SLC33A1 encodes a transmembrane transporter of acetyl-coenzyme A that is crucial for cellular metabolism. To investigate the lethality of this mutation in homozygous MTR sheep, we performed at-risk matings using artificial insemination (AI) between heterozygous SLC33A1 variant carriers (SLC33A1_dupG). Pregnancy was confirmed 15 days post-AI using a blood test measuring interferon Tau-stimulated MX1 gene expression. Ultrasonography between 45 and 60 days post-AI revealed a 12% reduction in AI success compared with safe matings, indicating embryonic/fetal loss. This was supported by the MX1 differential expression test suggesting fetal losses between 15 and 60 days of gestation. We also observed a 34.7% pre-weaning mortality rate in 49 lambs born from at-risk matings. Homozygous SLC33A1_dupG lambs accounted for 47% of this mortality, with deaths occurring mostly within the first 5 days without visible clinical signs. Therefore, appropriate management of SLC33A1_dupG with an allele frequency of 0.04 in the MTR selection scheme would help increase overall fertility and lamb survival.
PubMed: 38922751
DOI: 10.1111/age.13459 -
Cancer Research Communications Jun 2024Evaluate the efficacy of WEE1 inhibitor adavosertib in patients (pts) with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B).
PURPOSE
Evaluate the efficacy of WEE1 inhibitor adavosertib in patients (pts) with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B).
PATIENTS AND METHODS
NCT03284385 was a parallel cohort, Simon two-stage, phase II study of adavosertib (300 mg QDAY by mouth on days 1-5 and 8-12 of each 21-day cycle) in pts with solid tumor malignancies harboring a pathogenic SETD2 mutation. The primary endpoint was objective response rate (ORR). Correlative assays evaluated loss of H3K36me3 by immunohistochemistry (IHC), a downstream consequence of SETD2 loss, in archival tumor tissue.
RESULTS
Eighteen pts were enrolled (9/cohort). Median age was 60 years (range 45 - 74). The median duration of treatment was 1.28 months (range 0 - 24+). No objective responses were observed in either cohort; accrual was halted following stage 1. Minor tumor regressions were observed in 4/18 (22%) evaluable pts. Stable disease (SD) was the best overall response in 10/18 (56%) pts, including three pts with SD >4 months. One pt with ccRCC remains on treatment for >24 months. The most common adverse events (AE) of any grade were nausea (59%), anemia (41%), diarrhea (41%), and neutropenia (41%). Nine pts (50%) experienced a Grade ≥ 3 AE. Of 8 evaluable archival tissue samples, 6 (75%) had loss of H3K36me3 by IHC.
CONCLUSIONS
Adavosertib failed to exhibit objective responses in SETD2-altered ccRCC and other solid tumor malignancies though prolonged stable disease was observed in a subset of pts. Combination approaches may yield greater depth of tumor response.
PubMed: 38920407
DOI: 10.1158/2767-9764.CRC-24-0213