Purpose
BRCA1/2
mutations represent a high risk of breast cancer and are related to early-onset breast cancer. However, few studies have reported the relationship between
BRCA1/2
mutations and their ...clinical characteristics in early-onset breast cancers. This study is the first article that characterizes the risk factor profiles in Chinese patients selected by the age of onset (≤ 40 years old). We found some differences in the prevalence of germline
BRCA1/2
mutations between Asian and Western countries.
Methods
A total of 1371 consecutive unselected Chinese early-onset breast cancer patients were enrolled from the Fujian Medical University Union Hospital, China, and screened for germline
BRCA1/2
mutations. Full-exome sequencing in next-generation sequencing technology was performed in all patients to examine
BRCA1/2
mutations.
Results
In our study, 25 (1.8%) and 61 (4.4%) patients were identified with
BRCA1
and
BRCA2
mutations, respectively, among the unselected early-onset breast cancer patients.
BRCA1
mutations were associated with pregnancies (
p
= 0.026), and
BRCA1
carriers had a higher likelihood of being HR positive (
p
< 0.001), HER2 negative (
p
< 0.001), or high grade (
p
= 0.002) than noncarriers. Among
BRCA2
mutations, the age of onset was younger in carriers than in noncarriers (
p
= 0.017), and
BRCA2
carriers were more likely to have lymph node metastasis (
p
= 0.004). HR-positive or HER2-negative patients were likely to be positive for
BRCA2
mutations (
p
< 0.001). Overall, 14
BRCA1
mutations and 8
BRCA2
mutations were first reported in our study
Conclusion
This study provided some information about the spectrum of
BRCA1/2
mutations and characterized the risk factors for early-onset breast cancer in China.
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•Laboratory testing and quantification of soil erosion.•Effects of topography on runoff, sediment yield and water and soil loss regulations.•For sediment yield and water and soil ...loss, topography has the greatest influence.•Anti-S-shaped slopes exhibit favorable erosion resistance.
Due to frequent severe mining activities and globally destructive extreme storms, soil and water loss in open-pit coal mine dumps is extremely serious. To investigate the effect of topography on soil erosion, rainfall with a constant intensity of 1.50 mm·min−1 was conducted on topography models for 60 min. We investigated the effects of 4 topographies (straight slope, concave slope, S-shaped slope and anti-S-shaped slope) and 4 slope gradients (20°, 25°, 30° and 35°) on runoff, sediment yield, and soil and water loss. The results show that the 25° slope gradient was not conducive to infiltration, but the S-shaped slope was favorable. The runoff and sediment yield increased rapidly, then fluctuated upward in a certain range and eventually stabilized with increasing rainfall duration. With increasing slope gradient, the total runoff decreased exponentially, the total sediment yield decreased linearly, and the total amount of water and soil loss declined continuously. The initial runoff time results exhibited the order of anti-S-shaped slope > straight slope > concave slope > S-shaped slope, but the stable runoff size satisfied the S-shaped slope > straight slope > concave slope > anti-S-shaped slope. The results of the significant degree of influence of topography on sediment yield and water and soil loss exhibited the order of anti-S-shaped slope > S-shaped slope > straight slope > concave slope and S-shaped slope > straight slope > concave slope and anti-S-shaped slope. The effect of slope gradient on soil humidity and runoff was more significant than that on topography and their interaction (p < 0.001). Nevertheless, for sediment yield and water and soil loss, topography had the greatest influence (p < 0.001). Notably, the total amount of water and soil loss on the anti-S-shaped slope was relatively minimal.
Background
Breakthrough progress has been made in Cyclin-Dependent kinase 4 and 6 (CDK4/6) inhibitors when combined with endocrine therapy (ET) for hormone receptor-positive (HR+), HER2-negative ...(HER2−) advanced breast cancer (ABC). Though significant improvements of progression-free survival (PFS) for CDK4/6 inhibitors were demonstrated, however, the results of overall survival (OS) profile were not consistent. This study is conducted to further evaluate the efficacy and safety of CDK4/6 inhibitors for HR+ /HER2− ABC, and explore the prefer population through subgroup analysis.
Method
We identified relevant randomized controlled trials that compared CDK4/6 inhibitors plus ET to ET alone in HR+ /HER2− ABC. We calculated the hazard ratios (HRs) for PFS and OS, and risk ratios (RRs) for objective response rate (ORR), clinical benefit rate (CBR), adverse events (AEs). Statistical analysis was performed with the random-effects model.
Result
Eight trials and 4580 patients were included in this meta-analysis. Compared to ET alone, CDK4/6 inhibitors plus ET not only produced a significantly longer PFS (HR = 0.55, 95% confidence interval CI 0.50–0.59,
p
< 0.00001), but also manifested an extension of OS (HR = 0.79, 95% CI 0.67–0.93,
p
= 0.004) for HR+ /HER2− ABC. Similarly, the benefit was also manifested in ORR (RR = 1.47, 95% CI 1.30–1.67,
p
< 0.00001) and CBR (RR = 1.20, 95% CI 1.12–1.30,
p
< 0.00001). The improvements of PFS were observed in the combined treatment group as both the first-line (HR = 0.56) and the second-line therapy (HR = 0.53), and irrespective of menopausal status, the presence of visceral metastasis, previous treatment with chemotherapy, their race or age. Nevertheless, more hematologic and gastrointestinal adverse events were observed with CDK4/6 inhibitors. The most common Grade 3–4 AEs is neutropenia (RR 31.95).
Conclusion
Significant advantages of PFS and OS were observed for CDK4/6 inhibitors in HR+/HER2− ABC. Furthermore, the benefit of PFS was across all subgroups. Though associated with an increased occurrence of AEs, most of which are reversible, manageable, and acceptable. Therefore, CDK4/6 inhibitors could be recommended as a preferred options for patients with HR+ /HER2− ABC.
Background:
The incidence of clear cell renal cell carcinoma (ccRCC) is high and has increased gradually in recent years. At present, due to the lack of effective prognostic indicators, the prognosis ...of ccRCC patients is greatly affected.Necroptosis is a type of cell death, and along with cell necrosis is considered a new cancer treatment strategy. The aim of this study was to construct a new marker for predicting the prognosis of ccRCC patients based on long non-coding RNA (nrlncRNAs) associated with necroptosis.
Methods:
RNA sequence data and clinical information of ccRCC patients from the Cancer Genome Atlas database (TCGA) were downloaded. NrlncRNA was identified by Pearson correlation study. The differentially expressed nrlncRNA and nrlncRNA pairs were identified by univariate Cox regression and Lasso-Cox regression. Finally, a Kaplan-Meier survival study, Cox regression, clinicopathological features correlation study, and receiver operating characteristic (ROC) spectrum were used to evaluate the prediction ability of 25-nrlncrnas for markers. In addition, correlations between the risk values and sensitivity to tumor-infiltrating immune cells, immune checkpoint inhibitors, and targeted drugs were also investigated.
Results:
In the current research, a novel marker of 25-nrlncRNAs pairs was developed to improve prognostic prediction in patients with ccRCC. Compared with clinicopathological features, nrlncRNAs had a higher diagnostic validity for markers, with the 1-year, 3-years, and 5-years operating characteristic regions being 0.902, 0.835, and 0.856, respectively, and compared with the stage of 0.868, an increase of 0.034. Cox regression and stratified survival studies showed that this marker could be an independent predictor of ccRCC patients. In addition, patients with different risk scores had significant differences in tumor-infiltrating immune cells, immune checkpoint, and semi-inhibitory concentration of targeted drugs. The feature could be used to evaluate the clinical efficacy of immunotherapy and targeted drug therapy.
Conclusion:
25-nrlncRNAs pair markers may help to evaluate the prognosis and molecular characteristics of ccRCC patients, which improve treatment methods and can be more used in clinical practice.
Thousands of genes are expressed in the testis of mice. However, the details about their roles during spermatogenesis have not been well-clarified for most genes. The purpose of this study was to ...examine the effect of
deficiency on mouse spermatogenesis and male fertility.
-knockout (KO) mice were generated using CRISPR/Cas9 technology on C57BL/6J background. We found no obvious differences between
-KO and
-WT mice in fertility tests, testicular weight, sperm concentrations, or morphology. Histological analysis found that
-KO mouse testes had normal germ cell types and mature sperm. These findings indicated that
was dispensable for male fertility in mice. Our results may save time and resources by allowing other researchers to focus on genes that are more meaningful for fertility studies. We also found that mRNAs of two
family members (
and
) were expressed on higher mean levels in
-KO total mouse testes, compared to
-WT mice. This effect was not found in mouse GC-1 and GC-2 germ cell lines with the
gene transiently knocked down. This result may indicate that a gene compensation phenomenon was present in the testes of
-KO mice.
Asthenozoospermia (AZS) is a leading cause of male infertility, affecting an estimated 18% of infertile patients. Kinesin proteins function as molecular motors capable of moving along microtubules. ...The highly conserved kinesin family member 9 (
) localizes to the central microtubule pair in the flagella of
cells. The loss of KIF9 expression in mice has been linked to AZS phenotypes.
Variant screening was performed by whole exome sequencing from 92 Chinese infertile patients with AZS. Western blot was used to was used for analyzing of candidate proteins expression. Patients' sperm samples were stained with immunofluorescent to visualise proteins localization and were visualised by transmission electron microscopy (TEM) to determine axoneme structures. Co-immunoprecipitation assay was used to verify the binding proteins of KIF9. In vitro fertilization (IVF) was used to evaluate the efficiency of clinical treatment.
Bi-allelic
loss-of-function variants were identified in two unrelated Chinese males exhibiting atypical sperm motility phenotypes. Both of these men exhibited typical AZS and suffered from infertility together with the complete absence of
expression. In contrast to these KIF9-deficient patients, positive
staining was evident throughout the flagella of sperm from normal control individuals.
was able to interact with the microtubule central pair (CP) component hydrocephalus-inducing protein homolog (HYDIN) in human samples. And
was undetectable in spermatozoa harboring CP deletions. The morphologicy of
-deficient spermatozoa appeared normal under gross examination and TEM. Like in mice,
fertilization was sufficient to overcome the fertility issues for these two patients.
These findings indicate that KIF9 associates with the central microtubules in human sperm and that it functions to specifically regulate flagellar swinging. Overall, these results offer greater insight into the biological functions of KIF9 in the assembly of the human flagella and its role in male fertility.
Background Bilateral breast cancer (BBC), as well as ovarian cancer, are significantly associated with germline deleterious variants in BRCA1/2, while BRCA1/2 germline deleterious variants carriers ...can exquisitely benefit from poly (ADP-ribose) polymerase (PARP) inhibitors. However, formal genetic testing could not be carried out for all patients due to extensive use of healthcare resources, which in turn results in high medical costs. To date, existing BRCA1/2 deleterious variants prediction models have been developed in women of European or other descent who are quite genetically different from Asian population. Therefore, there is an urgent clinical need for tools to predict the frequency of BRCA1/2 deleterious variants in Asian BBC patients balancing the increased demand for and cost of cancer genetics services. Methods The entire coding region of BRCA1/2 was screened for the presence of germline deleterious variants by the next generation sequencing in 123 Chinese BBC patients. Chi-square test, univariate and multivariate logistic regression were used to assess the relationship between BRCA1/2 germline deleterious variants and clinicopathological characteristics. The R software was utilized to develop artificial neural network (ANN) and nomogram modeling for BRCA1/2 germline deleterious variants prediction. Results Among 123 BBC patients, we identified a total of 20 deleterious variants in BRCA1 (8; 6.5%) and BRCA2 (12; 9.8%). c.5485del in BRCA1 is novel frameshift deleterious variant. Deleterious variants carriers were younger at first diagnosis (P = 0.0003), with longer interval between two tumors (P = 0.015), at least one medullary carcinoma (P = 0.001), and more likely to be hormone receptor negative (P = 0.006) and HER2 negative (P = 0.001). Area under the receiver operating characteristic curve was 0.903 in ANN and 0.828 in nomogram modeling individually (P = 0.02). Conclusion This study shows the spectrum of the BRCA1/2 germline deleterious variants in Chinese BBC patients and indicates that the ANN can accurately predict BRCA deleterious variants than conventional statistical linear approach, which confirms the BRCA1/2 deleterious variants carriers at the lowest costs without adding any additional examinations. Keywords: Bilateral breast cancer, BRCA1, BRCA2, Germline deleterious variant, Artificial neural network
Abstract
Background: For now, Seldom studies have reported that relationship between BRCA1/2 mutation and their clinical characteristics in young-onset breast cancers. This study is the first article ...which characterizes the risk factor profiles in Chinese patients selected by the age of onset (<40 years old).Patient and method:A total of 1371 consecutive unselected Chinese young-onset breast cancer patients were collected form Fujian Union hospital, China, screened for germline BRCA1/2 mutation. The full-exome sequencing in the next generation sequencing technology was performed in all patients to examine the BRCA1/2 mutation.Result: In our study, 25 (1.8%) and 61 (4.4%) patients were identified with BRCA1 and BRCA2 mutation among the unselected early-onset breast cancer patients, respectively. BRCA1 mutations were associated with pregnancies (p=0.026), BRCA1-carriers had a higher likelihood of HR positive(p<0.001), or HER-2 negative(p<0.001), or high grade(p=0.002) than non-carriers. Among BRCA2 mutations, the age of onset was younger than non-carriers(P=0.017), BRCA2-carriers were more likely to have lymph node metastasis(P=0.004). with HR positive or HER-2 negative were likely to detected positive for BRCA2(p<0.001).
Citation Format: Lili Chen, Fangmeng Fu, Jinxing Lv, Chuan Wang. The spectrum of BRCA1 and BRCA2 mutations and clinicopathologic characteristics of young-onset breast cancer in BRCA-carriers and non-carriers abstract. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-03-10.
HER-2 positive breast cancer is a subtype of breast cancer with poor clinical outcome. The aim of this study was to identify differentially expressed genes (DEGs) for HER-2 positive breast cancer and ...elucidate the potential interactions among them.
Three gene expression profiles (GSE29431, GSE45827, and GSE65194) were derived from the Gene Expression Omnibus (GEO) database. GEO2R tool was applied to obtain DEGs between HER-2 positive breast cancer and normal breast tissues. Gene ontology (GO) annotation analysis and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analysis was performed by the Database for Annotation, Visualization and Integrated Discovery (David) online tool. Protein-protein interaction (PPI) network, hub gene identification and module analysis was conducted by Cytoscape software. Online Kaplan-Meier plotter survival analysis tool was also used to investigate the prognostic values of hub genes in HER-2 positive breast cancer patients.
A total of 54 upregulated DEGs and 269 downregulated DEGs were identified. Among them, 10 hub genes including CCNB1, RAC1, TOP2A, KIF20A, RRM2, ASPM, NUSAP1, BIRC5, BUB1B, and CEP55 demonstrated by connectivity degree in the PPI network were screened out. In Kaplan-Meier plotter survival analysis, the overexpression of RAC1 and RRM2 were shown to be associated with an unfavorable prognosis in HER-2 positive breast cancer patients.
This present study identified a number of potential target genes and pathways which might impact the oncogenesis and progression of HER-2 positive breast cancer. These findings could provide new insights into the detection of novel diagnostic and therapeutic biomarkers for this disease.
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