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1.
Nat Commun ; 10(1): 2884, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253780

RESUMO

Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e., a 3.5-fold enrichment; p-value = 9.2 × 10-5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.


Assuntos
Ciliopatias/genética , Proteínas do Olho/genética , Predisposição Genética para Doença , Doenças Retinianas/genética , Elementos Alu/genética , Grupo com Ancestrais do Continente Asiático/genética , Genômica , Humanos , Japão , Mutação , Linhagem
2.
J Hum Genet ; 64(7): 701-702, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31028281

RESUMO

Since the publication of this article, it has been brought to our attention, that the identified mutation (NM_015277: c.2617 G > A; p.Glu873Lys) is identical with the mutation (NM_001144967: c.2677 G > A; p.Glu893Lys) reported by Broix et al (Nature Genetics 48, 1349-1358, 2016 https://doi.org/10.1038/ng.3676 ). Therefore the mutation is not novel but recurrent. Accordingly, the word "novel" should be deleted throughout the article including the title. Thus, the title should read "A missense mutation in the HECT domain of NEDD4L identified in a girl with periventricular nodular heterotopia, polymicrogyria, and cleft palate."

3.
J Med Genet ; 56(6): 388-395, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30573562

RESUMO

BACKGROUND: In this study, we aimed to identify the gene abnormality responsible for pathogenicity in an individual with an undiagnosed neurodevelopmental disorder with megalencephaly, ventriculomegaly, hypoplastic corpus callosum, intellectual disability, polydactyly and neuroblastoma. We then explored the underlying molecular mechanism. METHODS: Trio-based, whole-exome sequencing was performed to identify disease-causing gene mutation. Biochemical and cell biological analyses were carried out to elucidate the pathophysiological significance of the identified gene mutation. RESULTS: We identified a heterozygous missense mutation (c.173C>T; p.Thr58Met) in the MYCN gene, at the Thr58 phosphorylation site essential for ubiquitination and subsequent MYCN degradation. The mutant MYCN (MYCN-T58M) was non-phosphorylatable at Thr58 and subsequently accumulated in cells and appeared to induce CCND1 and CCND2 expression in neuronal progenitor and stem cells in vitro. Overexpression of Mycn mimicking the p.Thr58Met mutation also promoted neuronal cell proliferation, and affected neuronal cell migration during corticogenesis in mouse embryos. CONCLUSIONS: We identified a de novo c.173C>T mutation in MYCN which leads to stabilisation and accumulation of the MYCN protein, leading to prolonged CCND1 and CCND2 expression. This may promote neurogenesis in the developing cerebral cortex, leading to megalencephaly. While loss-of-function mutations in MYCN are known to cause Feingold syndrome, this is the first report of a germline gain-of-function mutation in MYCN identified in a patient with a novel megalencephaly syndrome similar to, but distinct from, CCND2-related megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. The data obtained here provide new insight into the critical role of MYCN in brain development, as well as the consequences of MYCN defects.

4.
Sci Rep ; 8(1): 15554, 2018 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-30349143

RESUMO

Macaca fascicularis is a highly advantageous model in which to study human cochlea with regard to both evolutionary proximity and physiological similarity of the auditory system. To better understand the properties of primate cochlear function, we analyzed the genes predominantly expressed in M. fascicularis cochlea. We compared the cochlear transcripts obtained from an adult male M. fascicularis by macaque and human GeneChip microarrays with those in multiple macaque and human tissues or cells and identified 344 genes with expression levels more than 2-fold greater than in the other tissues. These "cochlear signature genes" included 35 genes responsible for syndromic or nonsyndromic hereditary hearing loss. Gene set enrichment analysis revealed groups of genes categorized as "ear development" and "ear morphogenesis" in the top 20 gene ontology categories in the macaque and human arrays, respectively. This dataset will facilitate both the study of genes that contribute to primate cochlear function and provide insight to discover novel genes associated with hereditary hearing loss that have yet to be established using animal models.

5.
J Hum Genet ; 63(10): 1083-1091, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30054556

RESUMO

To identify factors associated with ranibizumab responses in patients with exudative age-related macular degeneration (AMD), we performed a genome-wide association study (GWAS) and a replication study using a total of 919 exudative AMD patients treated with intravitreal ranibizumab in a Japanese population. In the combined analysis of GWAS and the replication study, no loci reached genome-wide significant level; however, we found four variants showed suggestive level of associations with visual loss at month three (rs17822656, rs76150532, rs17296444, and rs75165563: Pcombined < 1.0 × 10-5). Of the candidate genes within these loci, three were relevant to VEGF-related pathway (KCNMA1, SOCS2, and OTX2). The proportions of patients who worsened visual acuity were 13.7%, 38.8%, 58.0%, and 80.0% in patients with 0, 1, 2, and 3 or more identified risk variants, respectively. Changes in visual acuity decreased linearly as the number of risk variants increased (P = 1.67 × 10-12). The area under the curve using age, baseline visual acuity, and history of previous treatment was 0.607, and improved significantly to 0.713 in combination with identified variants (P < 0.0001). Although further study is needed to confirm their associations, our results offer candidate variants influencing response to ranibizumab therapy.

7.
J Hum Genet ; 63(9): 957-963, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29907875

RESUMO

Microcephaly-capillary malformation syndrome is a congenital and neurodevelopmental disorder caused by biallelic mutations in the STAMBP gene. Here we identify the novel homozygous mutation located in the SH3 binding motif of STAMBP (NM_006463.4) (c.707C>T: p.Ser236Phe) through whole-exome sequencing. The case patient was a 2-year-old boy showing severe global developmental delay, progressive microcephaly, refractory seizures, dysmorphic facial features, and multiple capillary malformations. Immunoblot analysis of patient-derived lymphoblastoid cell lines (LCLs) revealed a severe reduction in STAMBP expression, indicating that Ser236Phe induces protein instability. STAMBP interacts with the SH3 domain of STAM and transduces downstream signals from the Jaks-STAM complex. The substitution of Ser236Phe found in the case patient was located in the SH3-binding motif, and we propose the mutation may block STAM binding and subsequently induce STAMBP degradation. Contrary to previously reported STAMBP mutations, the Ser236Phe mutation did not lead to constitutive activation of the PI3K-AKT-mTOR pathway in patient-derived LCLs, as indicated by the expression of phosphorylated S6 ribosomal protein, suggesting that it is not the major pathomechanism underlying the disorder in this patient.

8.
BMC Pediatr ; 18(1): 171, 2018 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-29792164

RESUMO

BACKGROUND: Waardenburg syndrome type 1 (WS1) can be distinguished from Waardenburg syndrome type 2 (WS2) by the presence of dystopia canthorum. About 96% of WS1 are due to PAX3 mutations, and SOX10 mutations have been reported in 15% of WS2. CASE PRESENTATION: This report describes a patient with WS1 who harbored a novel SOX10 nonsense mutation (c.652G > T, p.G218*) in exon 3 which is the penultimate exon. The patient had mild prodromal neurological symptoms that were followed by severe attacks of generalized seizures associated with delayed myelination of the brain. The immature myelination recovered later and the neurological symptoms could be improved. This is the first truncating mutation in exon 3 of SOX10 that is associated with neurological symptoms in Waardenburg syndrome. Previous studies reported that the neurological symptoms that associate with WS are congenital and irreversible. These findings suggest that the reversible neurological phenotype may be associated with the nonsense mutation in exon 3 of SOX10. CONCLUSIONS: When patients of WS show mild prodromal neurological symptoms, the clinician should be aware of the possibility that severe attacks of generalized seizures may follow, which may be associated with the truncating mutation in exon 3 of SOX10.

9.
Sci Rep ; 8(1): 5608, 2018 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-29618752

RESUMO

Insertions and deletions (indels) have been implicated in dozens of human diseases through the radical alteration of gene function by short frameshift indels as well as long indels. However, the accurate detection of these indels from next-generation sequencing data is still challenging. This is particularly true for intermediate-size indels (≥50 bp), due to the short DNA sequencing reads. Here, we developed a new method that predicts intermediate-size indels using BWA soft-clipped fragments (unmatched fragments in partially mapped reads) and unmapped reads. We report the performance comparison of our method, GATK, PINDEL and ScanIndel, using whole exome sequencing data from the same samples. False positive and false negative counts were determined through Sanger sequencing of all predicted indels across these four methods. The harmonic mean of the recall and precision, F-measure, was used to measure the performance of each method. Our method achieved the highest F-measure of 0.84 in one sample, compared to 0.56 for GATK, 0.52 for PINDEL and 0.46 for ScanIndel. Similar results were obtained in additional samples, demonstrating that our method was superior to the other methods for detecting intermediate-size indels. We believe that this methodology will contribute to the discovery of intermediate-size indels associated with human disease.

10.
Am J Med Genet A ; 176(3): i, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29446569

RESUMO

The cover image, by Kei Tamai et al., is based on the Clinical Report Fetal ultrasonographic findings including cerebral hyperechogenicity in a patient with non-lethal form of Raine syndrome, DOI: 10.1002/ajmg.a.38598.

11.
Invest Ophthalmol Vis Sci ; 59(2): 826-830, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29411010

RESUMO

Purpose: To accelerate the development of new therapies, an inherited retinal degeneration model in a nonhuman primate would be useful to confirm the efficacy in preclinical studies. In this study, we describe the discovery of retinitis pigmentosa in a cynomolgus monkey (Macaca fascicularis) pedigree. Methods: First, screening with fundus photography was performed on 1443 monkeys at the Tsukuba Primate Research Center. Ophthalmic examinations, such as indirect ophthalmoscopy, ERGs using RETeval, and optic coherent tomography (OCT) measurement, were then performed to confirm diagnosis. Results: Retinal degeneration with cystoid macular edema was observed in both eyes of one 14-year-old female monkey. In her examinations, the full-field ERGs were nonrecordable and the outer layer of the retina in the parafoveal area was not visible on OCT imaging. Moreover, less frequent pigmentary retinal anomalies also were observed in her 3-year-old nephew. His full-field ERGs were almost nonrecordable and the outer layer was not visible in the peripheral retina. His father was her cousin (the son of her mother's older brother) and his mother was her younger half-sibling sister with a different father. Conclusions: The hereditary nature is highly probable (autosomal recessive inheritance suspected). However, whole-exome analysis performed identified no pathogenic mutations in these monkeys.


Assuntos
Modelos Animais de Doenças , Macaca fascicularis/genética , Retinite Pigmentosa/genética , Animais , Eletrorretinografia , Feminino , Angiofluoresceinografia , Edema Macular/diagnóstico , Edema Macular/genética , Masculino , Oftalmoscopia , Linhagem , Reação em Cadeia da Polimerase , Retina/fisiopatologia , Retinite Pigmentosa/diagnóstico , Retinite Pigmentosa/fisiopatologia , Tomografia de Coerência Óptica , Sequenciamento Completo do Exoma
12.
Am J Med Genet A ; 176(3): 682-686, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29341424

RESUMO

Raine syndrome is a rare osteosclerotic bone dysplasia characterized by craniofacial anomalies and intracranial calcification. Most patients with Raine syndrome are of Arab ancestry and die during the neonatal period. We herein report a Japanese patient with non-lethal Raine syndrome who presented with characteristic cerebral hyperechogenicity and a hypoplastic nose by fetal ultrasonography. She was admitted to the NICU due to pyriform aperture stenosis. Craniofacial abnormalities, intracranial calcification, osteosclerosis, chondrodysplasia punctata, and a mutation of FAM20C was identified. She was subsequently discharged without surgical intervention and is now 2 years old with mild neurodevelopmental delays. Images of cerebral hyperechogenicity by fetal ultrasonography in a non-lethal case were described herein for the first time. This patient represents a rare occurrence of a child with Raine syndrome born to Japanese parents and confirms that this syndrome is not always lethal. Even if Raine syndrome is suspected in a fetus due to cerebral hyperechogenicity and a hypoplastic nose, cerebral hyperechogenicity without pulmonary hypoplasia does not always predict lethality or severe neurodevelopmental delays. The information provided herein will be useful for prenatal counseling.

13.
Am J Med Genet A ; 173(10): 2690-2696, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28777490

RESUMO

Intellectual disability (ID) is one of neurodevelopmental disorders characterized by serious defects in both intelligence and adaptive behavior. Although it has been suggested that genetic aberrations associated with the process of cell division underlie ID, the cytological evidence for mitotic defects in actual patient's cells is rarely reported. Here, we report a novel mutation in the STARD9 (also known as KIF16A) gene found in a patient with severe ID, characteristic features, epilepsy, acquired microcephaly, and blindness. Using whole-exome sequence analysis, we sequenced potential candidate genes in the patient. We identified a homozygous single-nucleotide deletion creating a premature stop codon in the STARD9 gene. STARD9 encodes a 4,700 amino acid protein belonging to the kinesin superfamily. Depletion of STARD9 or overexpression of C-terminally truncated STARD9 mutants were known to induce spindle assembly defects in human culture cells. To determine cytological features in the patient cells, we isolated lymphoblast cells from the patient, and performed immunofluorescence analysis. Remarkably, mitotic defects, including multipolar spindle formation, fragmentation of pericentriolar materials and centrosome amplification, were observed in the cells. Taken together, our findings raise the possibility that controlled expression of full-length STARD9 is necessary for proper spindle assembly in cell division during human development. We propose that mutations in STARD9 result in abnormal spindle morphology and cause a novel genetic syndrome with ID.


Assuntos
Proteínas de Transporte/genética , Mutação da Fase de Leitura , Deficiência Intelectual/patologia , Mitose/genética , Fuso Acromático/patologia , Centrossomo , Criança , Feminino , Humanos , Deficiência Intelectual/genética , Fuso Acromático/genética , Síndrome
14.
Diabetes ; 66(10): 2713-2723, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28765322

RESUMO

The insulin receptor (INSR) gene was analyzed in four patients with severe insulin resistance, revealing five novel mutations and a deletion that removed exon 2. A patient with Donohue syndrome (DS) had a novel p.V657F mutation in the second fibronectin type III domain (FnIII-2), which contains the α-ß cleavage site and part of the insulin-binding site. The mutant INSR was expressed in Chinese hamster ovary cells, revealing that it reduced insulin proreceptor processing and impaired activation of downstream signaling cascades. Using online databases, we analyzed 82 INSR missense mutations and demonstrated that mutations causing DS were more frequently located in the FnIII domains than those causing the milder type A insulin resistance (P = 0.016). In silico structural analysis revealed that missense mutations predicted to severely impair hydrophobic core formation and stability of the FnIII domains all caused DS, whereas those predicted to produce localized destabilization and to not affect folding of the FnIII domains all caused the less severe Rabson-Mendenhall syndrome. These results suggest the importance of the FnIII domains, provide insight into the molecular mechanism of severe insulin resistance, will aid early diagnosis, and will provide potential novel targets for treating extreme insulin resistance.


Assuntos
Resistência à Insulina/fisiologia , Receptor de Insulina/genética , Adolescente , Pré-Escolar , Síndrome de Donohue/genética , Feminino , Genótipo , Humanos , Lactente , Resistência à Insulina/genética , Masculino , Mutação/genética , Mutação de Sentido Incorreto/genética , Fenótipo
15.
Sci Rep ; 7(1): 3552, 2017 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-28615637

RESUMO

Vici syndrome (VICIS) is a rare, autosomal recessive neurodevelopmental disorder with multisystem involvement characterized by agenesis of the corpus callosum, cataracts, cardiomyopathy, combined immunodeficiency, developmental delay, and hypopigmentation. Mutations in EPG5, a gene that encodes a key autophagy regulator, have been shown to cause VICIS, however, the precise pathomechanism underlying VICIS is yet to be clarified. Here, we describe detailed clinical (including brain MRI and muscle biopsy) and genetic features of nine Japanese patients with VICIS. Genetic dissection of these nine patients from seven families identified 14 causative mutations in EPG5. These included five nonsense, two frameshift, three splicing, one missense, and one multi-exon deletion mutations, and two initiation codon variants. Furthermore, cultured skin fibroblasts (SFs) from two affected patients demonstrated partial autophagic dysfunction. To investigate the function of EPG5, siRNA based EPG5 knock-down, and CRISPR/Cas9 mediated EPG5 knock-out HeLa cells were generated. EPG5-depleted cells exhibited a complete block of autophagic flux caused by defective autophagosome-lysosome fusion. Unexpectedly, endocytic degradation was normal in both VICIS SFs and EPG5 depleted cells, suggesting that EPG5 function is limited to the regulation of autophagosome-lysosome fusion.

16.
J Hum Genet ; 62(10): 927-929, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28638143

RESUMO

Inherited optic neuropathies (IONs) are neurodegenerative disorders affecting the optic nerve and the nervous system. Dominant and recessive IONs are known. Many of the dominant IONs are caused by mutations of OPA1. Autosomal-recessive IONs are rare. OPA10 is an autosomal-recessive ION due to mutations in RTN4IP1. Patients with RTN4IP1 mutations show extraocular manifestations. We report brothers with optic neuropathy who had novel mutations in the RTN4IP1 gene. This is the first report of Japanese patients with OPA10. They showed extraocular manifestations resembling mitochondrial encephalopathy.


Assuntos
Proteínas de Transporte/genética , Proteínas Mitocondriais/genética , Mutação , Doenças do Nervo Óptico/diagnóstico , Doenças do Nervo Óptico/genética , Irmãos , Adolescente , Análise Mutacional de DNA , DNA Mitocondrial/genética , Heterozigoto , Humanos , Masculino , Oftalmoscópios , Atrofia Óptica/genética , Atrofia Óptica/patologia , Linhagem , Fenótipo
17.
J Hum Genet ; 62(9): 861-863, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28515470

RESUMO

We identified a novel de novo heterozygous missense mutation in the NEDD4L gene (NM_015277: c.2617G>A; p.Glu873Lys) through whole-exome sequencing in a 3-year-old girl showing severe global developmental delay, infantile spasms, cleft palate, periventricular nodular heterotopia and polymicrogyria. Mutations in the HECT domain of NEDD4L have been reported in patients with a neurodevelopmental disorder along with similar brain malformations. All patients reported with NEDD4L HECT domain mutations showed periventricular nodular heterotopia, and most had seizures, cortex anomalies, cleft palate and syndactyly. The unique constellation of clinical features in patients with NEDD4L mutations might help clinically distinguish them from patients with other genetic mutations including FLNA, which is a well-known causative gene of periventricular nodular heterotopia. Although mutations in the HECT domain of NEDD4L that lead to AKT-mTOR pathway deregulation in forced expression system were reported, our western blot analysis did not show an increased level of AKT-mTOR activity in lymphoblastoid cell lines (LCLs) derived from the patient. In contrast to the forced overexpression system, AKT-mTOR pathway deregulation in LCLs derived from our patient seems to be subtle.


Assuntos
Fissura Palatina/diagnóstico , Fissura Palatina/genética , Mutação de Sentido Incorreto , Ubiquitina-Proteína Ligases Nedd4/genética , Heterotopia Nodular Periventricular/diagnóstico , Heterotopia Nodular Periventricular/genética , Polimicrogiria/diagnóstico , Polimicrogiria/genética , Encéfalo/anormalidades , Pré-Escolar , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Humanos , Imagem por Ressonância Magnética , Domínios Proteicos/genética
18.
Nat Genet ; 49(7): 1120-1125, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28553958

RESUMO

Recent evidence suggests that a substantial portion of complex disease risk alleles modify gene expression in a cell-specific manner. To identify candidate causal genes and biological pathways of immune-related complex diseases, we conducted expression quantitative trait loci (eQTL) analysis on five subsets of immune cells (CD4+ T cells, CD8+ T cells, B cells, natural killer (NK) cells and monocytes) and unfractionated peripheral blood from 105 healthy Japanese volunteers. We developed a three-step analytical pipeline comprising (i) prediction of individual gene expression using our eQTL database and public epigenomic data, (ii) gene-level association analysis and (iii) prediction of cell-specific pathway activity by integrating the direction of eQTL effects. By applying this pipeline to rheumatoid arthritis data sets, we identified candidate causal genes and a cytokine pathway (upregulation of tumor necrosis factor (TNF) in CD4+ T cells). Our approach is an efficient way to characterize the polygenic contributions and potential biological mechanisms of complex diseases.


Assuntos
Artrite Reumatoide/genética , Herança Multifatorial , Adulto , Alelos , Artrite Reumatoide/etnologia , Artrite Reumatoide/imunologia , Grupo com Ancestrais do Continente Asiático/genética , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Citocinas/genética , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Sistema Imunitário , Inflamação/genética , Masculino , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Risco
19.
Immunity ; 46(5): 835-848.e4, 2017 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-28514689

RESUMO

Monocytes give rise to macrophages and dendritic cells (DCs) under steady-state and inflammatory conditions, thereby contributing to host defense and tissue pathology. A common monocyte progenitor (cMoP) that is strictly committed to the monocyte lineage has been recently identified in mice. Here, we identified human cMoPs as a CLEC12AhiCD64hi subpopulation of conventional granulocyte-monocyte progenitors (cGMPs) in umbilical cord blood and in bone marrow. Human cMoPs gave rise to monocyte subsets without showing any potential for differentiating into myeloid or lymphoid cells. Within the cGMP population, we also identified revised GMPs that completely lacked DC and lymphoid potential. Collectively, our findings expand and revise the current understanding of human myeloid cell differentiation pathways.


Assuntos
Diferenciação Celular , Evolução Clonal , Células Precursoras de Monócitos e Macrófagos/citologia , Células Precursoras de Monócitos e Macrófagos/metabolismo , Monócitos/citologia , Monócitos/metabolismo , Animais , Antígenos CD/metabolismo , Biomarcadores , Ciclo Celular , Linhagem da Célula , Proliferação de Células , Células Cultivadas , Análise por Conglomerados , Citocinas/metabolismo , Sangue Fetal/citologia , Perfilação da Expressão Gênica , Humanos , Imunofenotipagem , Camundongos
20.
Cancer Med ; 6(7): 1627-1638, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28544536

RESUMO

The goal of this study is to establish a method for predicting overall survival (OS) and disease-free survival (DFS) in breast cancer patients after surgical operation. The gene expression profiles of cancer tissues from the patients, who underwent complete surgical resection of breast cancer and were subsequently monitored for postoperative survival, were analyzed using cDNA microarrays. We detected seven and three probes/genes associated with the postoperative OS and DFS, respectively, from our discovery cohort data. By incorporating these genes associated with the postoperative survival into MammaPrint genes, often used to predict prognosis of patients with early-stage breast cancer, we constructed postoperative OS and DFS prediction models from the discovery cohort data using a Cox proportional hazard model. The predictive ability of the models was evaluated in another independent cohort using Kaplan-Meier (KM) curves and the area under the receiver operating characteristic curve (AUC). The KM curves showed a statistically significant difference between the predicted high- and low-risk groups in both OS (log-rank trend test P = 0.0033) and DFS (log-rank trend test P = 0.00030). The models also achieved high AUC scores of 0.71 in OS and of 0.60 in DFS. Furthermore, our models had improved KM curves when compared to the models using MammaPrint genes (OS: P = 0.0058, DFS: P = 0.00054). Similar results were observed when our model was tested in publicly available datasets. These observations indicate that there is still room for improvement in the current methods of predicting postoperative OS and DFS in breast cancer.


Assuntos
Neoplasias da Mama/mortalidade , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Modelos Estatísticos , Período Pós-Operatório , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Reprodutibilidade dos Testes
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