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1.
Nat Commun ; 12(1): 1098, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33597505

RESUMO

Many diseases exhibit population-specific causal effect sizes with trans-ethnic genetic correlations significantly less than 1, limiting trans-ethnic polygenic risk prediction. We develop a new method, S-LDXR, for stratifying squared trans-ethnic genetic correlation across genomic annotations, and apply S-LDXR to genome-wide summary statistics for 31 diseases and complex traits in East Asians (average N = 90K) and Europeans (average N = 267K) with an average trans-ethnic genetic correlation of 0.85. We determine that squared trans-ethnic genetic correlation is 0.82× (s.e. 0.01) depleted in the top quintile of background selection statistic, implying more population-specific causal effect sizes. Accordingly, causal effect sizes are more population-specific in functionally important regions, including conserved and regulatory regions. In regions surrounding specifically expressed genes, causal effect sizes are most population-specific for skin and immune genes, and least population-specific for brain genes. Our results could potentially be explained by stronger gene-environment interaction at loci impacted by selection, particularly positive selection.

2.
Nucl Med Commun ; 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33596032

RESUMO

OBJECTIVES: This study assessed the factors related to the intake rate of adrenocortical scintigraphy in Cushing's and subclinical Cushing's syndromes, in addition to the methods for differentiating between the two. METHODS: Clinical findings, blood sampling, and adrenocortical scintigraphy collected at St. Marianna University School of Medicine from 1 January 2010 to 31 December 2019 were used to diagnose initial-onset Cushing's syndrome and subclinical Cushing's syndrome, and patients who underwent 131I-NP-59 adrenocortical scintigraphy were used as study subjects. RESULTS: A total of 24 (8 male and 16 female) patients were selected. Of them, 7 had Cushing's syndrome and 17 had subclinical Cushing's syndrome. A correlation coefficient of -0.432 (P = 0.04) was determined between the intake rate after 7 days and adrenocorticotropic hormone levels. Intake rates after 5 days were 0.51% and 0.31% for Cushing's and subclinical Cushing's syndromes, respectively, and were statistically significant (P = 0.03). Intake rates after 7 days were 0.47% and 0.30% for Cushing's and subclinical Cushing's syndromes, respectively, and were statistically significant (P = 0.04). Receiver operating characteristic analysis results of Cushing's and subclinical Cushing's syndromes for intake rates after 7 days were as follows: cutoff value, 0.248; area under curve, 0.769; and 95% confidence interval, 0.561-0.987. CONCLUSION: There were differences in the intake rates of adrenocortical scintigraphy between the Cushing's syndrome group and subclinical Cushing's syndrome group, making it possible to differentiate between the two using the intake rate.

3.
Hum Mol Genet ; 2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33577681

RESUMO

Approaches toward new therapeutics using disease genomics such as genome-wide association study (GWAS) are anticipated. Here we developed Trans-Phar (integration of Transcriptome-wide association study [TWAS] and pharmacological database), achieving in silico screening of compounds from a large-scale pharmacological database (L1000 Connectivity Map) that have inverse expression profiles compared to tissue-specific genetically regulated gene expression. After confirmation of the statistical robustness by the application of the null GWAS data and of enrichment in true-positive drug-disease relationships by the application of UK-Biobank GWAS summary statistics in broad disease categories, we applied GWAS summary statistics of large-scale European meta-analysis (17 traits; naverage = 201 849) and the hospitalized COVID-19 (n = 900 687), which has urgent need for drug development. We detected potential therapeutic compounds, as well as anisomycin in schizophrenia (FDR-q = 0.056) and verapamil in hospitalized COVID-19 (FDR-q = 0.068) as top-associated compounds. This approach could be effective in disease genomics-driven drug development.

4.
Nat Genet ; 53(2): 195-204, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33462486

RESUMO

Admixed populations are routinely excluded from genomic studies due to concerns over population structure. Here, we present a statistical framework and software package, Tractor, to facilitate the inclusion of admixed individuals in association studies by leveraging local ancestry. We test Tractor with simulated and empirical two-way admixed African-European cohorts. Tractor generates accurate ancestry-specific effect-size estimates and P values, can boost genome-wide association study (GWAS) power and improves the resolution of association signals. Using a local ancestry-aware regression model, we replicate known hits for blood lipids, discover novel hits missed by standard GWAS and localize signals closer to putative causal variants.

5.
Genomics ; 113(2): 564-575, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33482326

RESUMO

The recent outbreak of coronavirus disease 2019 (COVID-19) by SARS-CoV-2 has led to uptodate 24.3 M cases and 0.8 M deaths. It is thus in urgent need to rationalize potential therapeutic targets against the progression of diseases. An effective, feasible way is to use the pre-existing ΔORF6 mutant of SARS-CoV as a surrogate for SARS-CoV-2, since both lack the moiety responsible for interferon antagonistic effects. By analyzing temporal profiles of upregulated genes in ΔORF6-infected Calu-3 cells, we prioritized 55 genes and 238 ligands to reposition currently available medications for COVID-19 therapy. Eight of them are already in clinical trials, including dexamethasone, ritonavir, baricitinib, tofacitinib, naproxen, budesonide, ciclesonide and formoterol. We also pinpointed 16 drug groups from the Anatomical Therapeutic Chemical classification system, with the potential to mitigate symptoms of SARS-CoV-2 infection and thus to be repositioned for COVID-19 therapy.

6.
EBioMedicine ; 63: 103157, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33418499

RESUMO

BACKGROUND: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants. METHODS: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity. FINDINGS: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10-11; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10-9; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10-9). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10-9, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10-9, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants. INTERPRETATION: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.

9.
Front Cell Infect Microbiol ; 10: 585973, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33363050

RESUMO

While microbiome plays key roles in the etiology of multiple sclerosis (MS), its mechanism remains elusive. Here, we conducted a comprehensive metagenome-wide association study (MWAS) of the relapsing-remitting MS gut microbiome (n case = 26, n control = 77) in the Japanese population, by using whole-genome shotgun sequencing. Our MWAS consisted of three major bioinformatic analytic pipelines (phylogenetic analysis, functional gene analysis, and pathway analysis). Phylogenetic case-control association tests showed discrepancies of eight clades, most of which were related to the immune system (false discovery rate [FDR] < 0.10; e.g., Erysipelatoclostridium_sp. and Gemella morbillorum). Gene association tests found an increased abundance of one putative dehydrogenase gene (Clo1100_2356) and one ABC transporter related gene (Mahau_1952) in the MS metagenome compared with controls (FDR < 0.1). Molecular pathway analysis of the microbiome gene case-control comparisons identified enrichment of multiple Gene Ontology terms, with the most significant enrichment on cell outer membrane (P = 1.5 × 10-7). Interaction between the metagenome and host genome was identified by comparing biological pathway enrichment between the MS MWAS and the MS genome-wide association study (GWAS) results (i.e., MWAS-GWAS interaction). No apparent discrepancies in alpha or beta diversities of metagenome were found between MS cases and controls. Our shotgun sequencing-based MWAS highlights novel characteristics of the MS gut microbiome and its interaction with host genome, which contributes to our understanding of the microbiome's role in MS pathophysiology.

11.
Bioinformatics ; 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33135050

RESUMO

MOTIVATION: Genetic linkage analysis has made a huge contribution to the genetic mapping of Mendelian diseases. However, most previously available linkage analysis methods have limited applicability. Since parametric linkage analysis requires predefined model of inheritance with a fixed set of parameters, it is inapplicable without fully structured pedigree information. Furthermore, the analytical results are dependent on the specification of model parameters. While nonparametric linkage analysis can avoid these problems, the runs of homozygosity (ROH) mapping, a widely used nonparametric linkage analysis method, can only deal with recessive inheritance. The implementation of nonparametric linkage analyses capable of dealing with both dominant and recessive inheritance has been required. RESULTS: We have developed the Obelisc (Observational linkage scan), a flexibly applicable user-friendly nonparametric linkage analysis tool, which also provides an intuitive visualization of the analytical results. Obelisc is based on the SNP streak approach, which does not require any predefined inheritance model with parameters. In contrast to the ROH mapping, the SNP streak approach is applicable to both dominant and recessive traits. To illustrate the performance of Obelisc, we generated a pseudo-pedigree from the publicly available BioBank Japan Project genome-wide genotype dataset (n > 180,000). By applying Obelisc to this pseudo-pedigree, we successfully identified the regions with inherited identical-by-descent haplotypes shared among the members of the pseudo-pedigree, which was validated by the population-based haplotype phasing approach. AVAILABILITY AND IMPLEMENTATION: Obelisc is feely available at https://github.com/qsonehara/Obelisc as a python package with example datasets. CONTACT: yokada@sg.med.osaka-u.ac.jp. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

12.
JAMA Netw Open ; 3(10): e2023248, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33119109

RESUMO

Importance: Understanding the genetic contribution of the major histocompatibility complex (MHC) region to the risk of cervical cancer (CC) will help understand how immune responses to infection with human papillomaviruses are associated with CC. Objective: To determine whether the HLA-B*52:01 allele is associated with CC in Japanese women. Design, Setting, and Participants: This was a multicenter genetic association study. Genotype and phenotype data were obtained from BioBank Japan Project. Additional patients with CC were enrolled from the Aichi Cancer Center Research Institute. An MHC fine-mapping study was conducted on CC risk in the Japanese population by applying a human leukocyte antigen (HLA) imputation method to the large-scale CC genome-wide association study data of using the Japanese population-specific HLA reference panel. Participants included 540 women in BioBank Japan Project with CC or 39 829 women without gynecologic diseases, malignant neoplasms, and MHC-related diseases as controls. An additional 168 patients with CC were recruited from Aichi Cancer Center Research Institute. Histopathological subtypes and clinical stages were not considered. Participants with low genotype call rate, closely related participants, and outliers in the principal component analysis were excluded. Data analysis was performed from August 2018 to January 2020. Main Outcomes and Measures: Loci within the MHC region associated with CC risk, and the direction and size of association. Results: A total of 704 CC cases and 39 556 controls were analyzed. All participants were Japanese women with a median (range) age of 67 (18 to 100) years. One of the class I HLA alleles of HLA-B*52:01 was significantly associated with CC risk (odds ratio, 1.60; 95% CI, 1.38-1.86; P = 7.4 × 10-10). Allele frequency spectra of HLA-B*52:01 are heterogeneous among worldwide populations with high frequency in Japanese populations (0.109 in controls), suggesting its population-specific risk associated with CC. The conditional analysis suggested that HLA-B*52:01 could explain most of the MHC risk associated with CC because no other HLA alleles remained significant after conditioning on the HLA-B*52:01. The HLA amino acid residue-based analysis suggested that HLA-B p.Tyr171His located in the peptide-binding groove was associated with the most significant CC risk (odds ratio, 1.47; 95% CI, 1.30-1.66; P = 1.2 × 10-9). Conclusions and Relevance: The results of this study contribute to understanding of the genetic background of CC. The results suggest that immune responses mediated by class I HLA molecules are associated with susceptibility to CC.

13.
J Cell Mol Med ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33002292

RESUMO

Identification of genetic variants associated with glucocorticoids (GC) sensitivity of leukaemia cells may provide insight into potential drug targets and tailored therapy. In the present study, within 72 leukaemic cell lines derived from Japanese patients with B-cell precursor acute lymphoblastic leukaemia (ALL), we conducted genome-wide genotyping of single nucleotide polymorphisms (SNP) and attempted to identify genetic variants associated with GC sensitivity and NR3C1 (GC receptor) gene expression. IC50 measures for prednisolone (Pred) and dexamethasone (Dex) were available using an alamarBlue cell viability assay. IC50 values of Pred showed the strongest association with rs904419 (P = 4.34 × 10-8 ), located between the FRMD4B and MITF genes. The median IC50 values of prednisolone for cell lines with rs904419 AA (n = 13), AG (n = 31) and GG (n = 28) genotypes were 0.089, 0.139 and 297 µmol/L, respectively. For dexamethasone sensitivity, suggestive association was observed for SNP rs2306888 (P = 1.43 × 10-6 ), a synonymous SNP of the TGFBR3 gene. For NR3C1 gene expression, suggestive association was observed for SNP rs11982167 (P = 6.44 × 10-8 ), located in the PLEKHA8 gene. These genetic variants may affect GC sensitivity of ALL cells and may give rise to opportunities in personalized medicine for effective and safe chemotherapy in ALL patients.

14.
Int Immunol ; 2020 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-32866240

RESUMO

Novel biomarkers of rheumatoid arthritis (RA), in addition to antibodies against cyclic citrullinated peptides, are required. Metabolome analysis is a promising approach to identify metabolite biomarkers for clinical diagnosis. We adopted a comprehensive nontargeted metabolomics approach combining capillary electrophoresis time-of-flight mass-spectrometry (TOFMS) and liquid chromatography TOFMS. We constructed metabolomics profiling of 286 plasma samples of the Japanese population. (92 RA patients, 13 systemic lupus erythematosus (SLE) patients, and 181 healthy controls). RA case-control association tests showed that seven metabolites exhibited significantly increased levels in RA samples than in controls [P & 1.0×10 -4; UTP, ethanolamine phosphate, ATP, GDP, ADP, 6-aminohexanoic acid, and taurine], whereas one exhibited a decreased level (xanthine). The plasma levels of these eight metabolites were not significantly different between seropositive and seronegative RA patients (P > 0.05; n = 68 and 24, respectively). The four nucleotide levels (UTP, ATP, GDP, and ADP) were significantly higher in the non-treatment patients in comparison between patients with and without treatment (P & 0.014; n = 57 and 35, respectively). Furthermore, we found that none of the four nucleotides levels showed significant differences in SLE case-control association tests (P > 0.2; 13 patients with SLE and the 181 shared controls) and psoriatic arthritis (PsA) case-control association tests (P > 0.11; 42 patients with PsA and 38 healthy controls), indicating disease specificity in RA. In conclusion, our large-scale metabolome analysis demonstrated the increased plasma nucleotides levels in RA patients, which could be used as potential clinical biomarkers of RA, especially for seronegative RA.

15.
Cancer Sci ; 2020 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-32981178

RESUMO

Causal inference is one of the challenges in epidemiologic studies. Gynecologic diseases have been reported to have association with obesity, however the causality remained controversial except for uterine endometrial cancer. We conducted two-sample Mendelian randomization (MR) analysis using the large-scale genome-wide association study (GWAS) results of gynecologic diseases and body mass index (BMI) in the Japanese population to assess causal effect of BMI on gynecologic diseases. We first conducted GWAS of ovarian cancer, uterine endometrial cancer, uterine cervical cancer, endometriosis, and uterine fibroid (n = 647, 909, 538, 5236, and 645 cases, respectively, and 39 556 shared female controls), and BMI (81 610 males and non-overlapping 23 924 females). We then applied two-sample MR using 74 BMI-associated variants as instrumental variables. We observed significant causal effect of increased BMI on uterine endometrial cancer (ß = 0.735, P = .0010 in inverse variance-weighted analysis), which is concordant with results of European studies. Causal effect of obesity was not apparent in the other gynecologic diseases tested. Our MR analyses provided strong evidence of the causal role of obesity in gynecologic diseases etiology, and suggested a possible preventive effect of intervention for obesity.

16.
Diabetes Res Clin Pract ; 169: 108461, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32971154

RESUMO

AIMS: Monogenic diabetes is clinically heterogeneous and differs from common forms of diabetes (type 1 and 2). We aimed to investigate the clinical usefulness of a comprehensive genetic testing system, comprised of targeted next-generation sequencing (NGS) with phenotype-driven bioinformatics analysis in patients with monogenic diabetes, which uses patient genotypic and phenotypic data to prioritize potentially causal variants. METHODS: We performed targeted NGS of 383 genes associated with monogenic diabetes or common forms of diabetes in 13 Japanese patients with suspected (n = 10) or previously diagnosed (n = 3) monogenic diabetes or severe insulin resistance. We performed in silico structural analysis and phenotype-driven bioinformatics analysis of candidate variants from NGS data. RESULTS: Among the patients suspected having monogenic diabetes or insulin resistance, we diagnosed 3 patients as subtypes of monogenic diabetes due to disease-associated variants of INSR, LMNA, and HNF1B. Additionally, in 3 other patients, we detected rare variants with potential phenotypic effects. Notably, we identified a novel missense variant in TBC1D4 and an MC4R variant, which together may cause a mixed phenotype of severe insulin resistance. CONCLUSIONS: This comprehensive approach could assist in the early diagnosis of patients with monogenic diabetes and facilitate the provision of tailored therapy.

17.
Nat Cell Biol ; 22(10): 1252-1263, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32989250

RESUMO

Sensing and clearance of dysfunctional lysosomes is critical for cellular homeostasis. Here we show that transcription factor EB (TFEB)-a master transcriptional regulator of lysosomal biogenesis and autophagy-is activated during the lysosomal damage response, and its activation is dependent on the function of the ATG conjugation system, which mediates LC3 lipidation. In addition, lysosomal damage triggers LC3 recruitment on lysosomes, where lipidated LC3 interacts with the lysosomal calcium channel TRPML1, facilitating calcium efflux essential for TFEB activation. Furthermore, we demonstrate the presence and importance of this TFEB activation mechanism in kidneys in a mouse model of oxalate nephropathy accompanying lysosomal damage. A proximal tubule-specific TFEB-knockout mouse exhibited progression of kidney injury induced by oxalate crystals. Together, our results reveal unexpected mechanisms of TFEB activation by LC3 lipidation and their physiological relevance during the lysosomal damage response.

18.
Ann Rheum Dis ; 79(10): 1305-1309, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32737115

RESUMO

OBJECTIVES: The genetic background of rheumatoid arthritis-interstitial lung disease (RA-ILD) has been evaluated in Europeans, but little knowledge has been obtained in non-Europeans. This study aimed to elucidate genome-wide risk of RA-ILD in non-Europeans. METHODS: We performed an initial genome-wide association study (GWAS) of RA-ILD in the Japanese population. By conducting the meta-analysis of the three GWAS datasets of the RA cohorts and biobank of Japanese, our study included 358 RA-ILD cases and 4550 RA subjects without ILD. We then conducted the stratified analysis of the effect of the GWAS risk allele in each CT image pattern. RESULTS: We identified one novel RA-ILD risk locus at 7p21 that satisfied the genome-wide significance threshold (rs12702634 at RPA3-UMAD1, OR=2.04, 95% CI 1.59 to 2.60, p=1.5×10-8). Subsequent stratified analysis based on the CT image patterns demonstrated that the effect size of the RA-ILD risk allele (rs12702634-C) was large with the UIP pattern (OR=1.86, 95% CI 0.97 to 3.58, p=0.062) and the probable UIP pattern (OR=2.26, 95% CI 1.36 to 3.73, p=0.0015). CONCLUSION: We revealed one novel genetic association with RA-ILD in Japanese. The RA-ILD risk of the identified variant at RPA3-UMAD1 was relatively high in the CT image patterns related to fibrosis. Our study should contribute to elucidation of the complicated aetiology of RA-ILD.


Assuntos
Artrite Reumatoide/genética , Proteínas de Ligação a DNA/genética , Doenças Pulmonares Intersticiais/genética , Artrite Reumatoide/complicações , Grupo com Ancestrais do Continente Asiático/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Doenças Pulmonares Intersticiais/complicações , RNA Antissenso/genética
19.
Medicine (Baltimore) ; 99(31): e21333, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756119

RESUMO

This study aimed to evaluate the imaging findings and prognostic factors after whole-brain radiotherapy in patients with carcinomatous meningitis from breast cancer.A retrospective analysis of imaging data and prognostic factors was performed in patients treated with whole-brain radiotherapy or whole-brain/spine radiotherapy immediately after the first diagnosis of carcinomatous meningitis from breast cancer at our hospital from January 1, 2010 to December 31, 2018. Statistical significance was set at P < .05 (two-tailed).All patients (n = 31) were females with the mean age of 58.0 ±â€Š11.0 years. The breast cancer subtypes were luminal (n = 14, 45.1%), human epidermal growth factor receptor 2 (HER2)-positive (n = 9, 29.0%), and triple-negative (n = 8, 26.0%) breast cancer. Brain metastasis and abnormal contrast enhancement in the sulci were observed in 21 (67.7%) and 24 (80.6%) patients, respectively. The median survival time after cancerous meningitis diagnosis was 62 (range, 6-657) days. Log-rank test showed significant differences in median survival time after cancerous meningitis diagnosis: 18.0 days for subjects treated with 30 Gy in < 10 fractions (n = 7) vs 78.5 days for subjects treated with 30 Gy in ≥10 fractions (n = 24) (P < .01) and 23.0 days for the triple-negative subtype vs 78.5 days for the other subtype (P < .01) groups. Univariate analysis using the Cox regression model showed significant differences in median survival time after cancerous meningitis diagnosis between the group treated with 30 Gy in <10 fractions and the group treated in ≥10 fractions (hazard ratio [HR] 0.08, 95% confidence interval [CI], 0.03-0.26; P < .01), and between the triple-negative subtype and the other subtypes (HR = 5.48; 95% CI, 1.88-16.0; P < .01) groups.Discontinuation of whole-brain radiotherapy and the presence of triple-negative breast cancer were indicators of poor prognosis.


Assuntos
Neoplasias Encefálicas/secundário , Carcinomatose Meníngea/secundário , Neoplasias de Mama Triplo Negativas/mortalidade , Idoso , Biomarcadores Tumorais , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Relação Dose-Resposta à Radiação , Feminino , Humanos , Imagem por Ressonância Magnética , Carcinomatose Meníngea/diagnóstico por imagem , Carcinomatose Meníngea/radioterapia , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Neoplasias de Mama Triplo Negativas/patologia
20.
Acta Radiol Open ; 9(7): 2058460120938744, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32670619

RESUMO

Background: Breast cancer has a poor prognosis due to the high risk of distant metastasis. Purpose: To identify the prognosticators of brain metastasis from breast cancer treated by whole-brain radiotherapy. Material and Methods: We evaluated patients diagnosed with primary brain metastasis without carcinomatous meningitis from breast cancer and had undergone whole-brain radiotherapy as initial treatment between 1 January 2010 and 30 September 2019. We investigated associations between overall survival time from diagnosis using cranial contrast-enhanced magnetic resonance imaging (MRI)/computed tomography (CT) and the following parameters: (i) age; (ii) sex; (iii) time to appearance of brain metastasis; (iv) other metastasis at appearance of brain metastasis; (v) blood test; (vi) symptoms at time of brain metastasis; (vii) whole-brain radiotherapy dose; (viii) whether whole-brain radiotherapy was completed; (ix) course of chemo- or radiotherapy; (x) subtype; (xi) additional irradiation after whole-brain radiotherapy; (xii) pathology; and (xiii) imaging findings. Results: We evaluated 29 consecutive female patients (mean age 55.2 ± 12.1 years). Median overall survival time after diagnosis on cranial contrast-enhanced MRI/CT was 135 days (range 16-2112 days). Multivariate stepwise analysis of the three parameters of lactate dehydrogenase, dose, and subtype identified the following significant differences: Hazard Ratio (HR) for dose (discontinued, 30 Gy/10 fractions, 31.5 Gy/11 fractions, 32.5 Gy/11 fractions, 37.5 Gy/15 fractions) was 0.08 (95% confidence interval [CI] 0.02-0.30, P < 0.01), and HR for subtype (luminal, HER2, triple-negative) was 2.70 (95% CI 1.16-6.243, P < 0.01). Conclusion: HER2-type and 37.5 Gy/15 fractions are good prognostic factor after whole-brain radiotherapy in breast cancer with brain metastases.

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