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1.
N Engl J Med ; 388(13): 1181-1190, 2023 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-36988593

RESUMEN

BACKGROUND: Helicobacter pylori infection is a well-known risk factor for gastric cancer. However, the contribution of germline pathogenic variants in cancer-predisposing genes and their effect, when combined with H. pylori infection, on the risk of gastric cancer has not been widely evaluated. METHODS: We evaluated the association between germline pathogenic variants in 27 cancer-predisposing genes and the risk of gastric cancer in a sample of 10,426 patients with gastric cancer and 38,153 controls from BioBank Japan. We also assessed the combined effect of pathogenic variants and H. pylori infection status on the risk of gastric cancer and calculated the cumulative risk in 1433 patients with gastric cancer and 5997 controls from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC). RESULTS: Germline pathogenic variants in nine genes (APC, ATM, BRCA1, BRCA2, CDH1, MLH1, MSH2, MSH6, and PALB2) were associated with the risk of gastric cancer. We found an interaction between H. pylori infection and pathogenic variants in homologous-recombination genes with respect to the risk of gastric cancer in the sample from HERPACC (relative excess risk due to the interaction, 16.01; 95% confidence interval [CI], 2.22 to 29.81; P = 0.02). At 85 years of age, persons with H. pylori infection and a pathogenic variant had a higher cumulative risk of gastric cancer than noncarriers infected with H. pylori (45.5% [95% CI, 20.7 to 62.6] vs. 14.4% [95% CI, 12.2 to 16.6]). CONCLUSIONS: H. pylori infection modified the risk of gastric cancer associated with germline pathogenic variants in homologous-recombination genes. (Funded by the Japan Agency for Medical Research and Development and others.).


Asunto(s)
Infecciones por Helicobacter , Helicobacter pylori , Recombinación Homóloga , Neoplasias Gástricas , Humanos , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/microbiología , Helicobacter pylori/genética , Factores de Riesgo , Neoplasias Gástricas/etiología , Neoplasias Gástricas/genética , Mutación de Línea Germinal/genética , Predisposición Genética a la Enfermedad/genética , Recombinación Homóloga/genética
2.
J Med Genet ; 61(7): 613-620, 2024 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-38499336

RESUMEN

BACKGROUND: As gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa (RP)-related genes in a large number of Japanese patients with RP by applying the standardised variant interpretation guidelines for Japanese patients with IRD (J-IRD-VI guidelines) built upon the American College of Medical Genetics and Genomics and the Association for Molecular Pathology rules, and assess the contribution of these genes in RP-allied diseases. METHODS: We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, newly analysed), including Usher syndrome, Leber congenital amaurosis and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines. RESULTS: A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 patients with RP. This led to a genetic diagnostic rate in 38.6% of patients with RP, with EYS accounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for patients with CRD was 28.2%, with RP-related genes significantly contributing over other allied diseases. CONCLUSION: A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the population-specific genetic findings for Japanese patients with IRD; these findings serve as a foundation for the clinical application of gene-specific therapies.


Asunto(s)
Retinitis Pigmentosa , Femenino , Humanos , Masculino , Distrofias de Conos y Bastones/genética , Distrofias de Conos y Bastones/patología , Pueblos del Este de Asia/genética , Predisposición Genética a la Enfermedad , Variación Genética , Japón , Amaurosis Congénita de Leber/genética , Amaurosis Congénita de Leber/patología , Mutación , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/patología , Síndromes de Usher/genética
3.
Hum Mol Genet ; 31(12): 1962-1969, 2022 06 22.
Artículo en Inglés | MEDLINE | ID: mdl-35764097

RESUMEN

Identifying causative genes via genetic testing is useful for screening, preventing and treating cancer. Several hereditary syndromes occur in patients with renal cell carcinoma (RCC). However, the evidence is from the European population; it remains unclear how the RCC-related genes and other cancer-predisposing genes contribute to RCC development in the Japanese population. A case-control study of 14 RCC-related genes and 26 cancer-predisposing genes was performed in 1563 Japanese patients with RCC and 6016 controls. The patients were stratified into clear cell RCC (ccRCC) or non-ccRCC (nccRCC). Gene-based analysis of germline pathogenic variants in patients with each subtype and cancer-free subjects was performed. Following quality control, 1532 patients with RCC and 5996 controls were analyzed. For ccRCC, 52 of 1283 (4.05%) patients carried pathogenic variants mainly in the cancer-predisposing genes such as TP53 (P = 1.73 × 10-4; OR, 5.8; 95% CI, 2.2-15.7). Approximately 80% of patients with pathogenic variants in TP53 had p.Ala189Val that was specific in East Asian population. For nccRCC, 14 of 249 (5.62%) patients carried pathogenic variants mainly in the RCC-related genes such as BAP1 and FH (P = 6.27 × 10-5; OR, Inf; 95% CI, 10.0-Inf). The patients with the pathogenic variants in the associated genes were diagnosed 15.8 years earlier and had a higher proportion of patients with a family history of RCC (OR, 20.0; 95% CI, 1.3-237.4) than the non-carriers. We showed different and population-specific contributions of risk genes between ccRCC and nccRCC in Japanese for improved personalized medicine.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Carcinoma de Células Renales/genética , Estudios de Casos y Controles , Pruebas Genéticas , Humanos , Japón , Neoplasias Renales/genética
4.
J Hepatol ; 78(2): 333-342, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36243179

RESUMEN

BACKGROUND & AIMS: The heritability and actionability of variants in homologous recombination-related genes in biliary tract cancers (BTCs) are uncertain. Although associations between BTC and BRCA germline variants have been reported, homologous recombination deficiency has not been investigated in BTCs. METHODS: We sequenced germline variants in 27 cancer-predisposing genes in 1,292 BTC cases and 37,583 controls without a personal nor family history of cancer. We compared pathogenic germline variant frequencies between cases and controls and documented the demographic and clinical characteristics of carriers. In addition, whole-genome sequencing of 45 BTC tissues was performed to evaluate homologous recombination deficiency status. RESULTS: Targeted sequencing identified 5,018 germline variants, which were classified into 317 pathogenic, 3,611 variants of uncertain significance, and 1,090 benign variants. Seventy-one BTC cases (5.5%) had at least one pathogenic variant among 27 cancer-predisposing genes. Pathogenic germline variants enriched in BTCs were present in BRCA1, BRCA2, APC, and MSH6 (p <0.00185). PALB2 variants were marginally associated with BTC (p = 0.01). APC variants were predominantly found in ampulla of Vater carcinomas. Whole-genome sequencing demonstrated that three BTCs with pathogenic germline variants in BRCA2 and PALB2, accompanied by loss of heterozygosity, displayed homologous recombination deficiency. Conversely, pathogenic germline variants without a second hit or variants of other homologous recombination-related genes such as ATM and BRIP1 showed homologous recombination-proficient phenotypes. CONCLUSIONS: In this study, we describe the heritability and actionability of variants in homologous recombination-related genes, which could be used to guide screening and therapeutic strategies for BTCs. IMPACT AND IMPLICATIONS: We found that 5.5% of biliary tract cancers (BTCs) in a Japanese population possessed hereditary cancer-predisposing gene alterations, including in BRCA and genes associated with colorectal cancer. Two hits in homologous recombination-related genes were required to confer a homologous recombination-deficient phenotype. PARP inhibitors and DNA-damaging regimens may be effective strategies against BTCs exhibiting homologous recombination deficiency. Hence, in this study, genome-wide sequencing has revealed a potential new therapeutic strategy that could be applied to a subset of BTCs.


Asunto(s)
Neoplasias del Sistema Biliar , Predisposición Genética a la Enfermedad , Humanos , Mutación de Línea Germinal , Neoplasias del Sistema Biliar/genética , Secuenciación Completa del Genoma , Recombinación Homóloga
5.
Ophthalmology ; 130(4): 361-372, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36423732

RESUMEN

PURPOSE: To investigate the genetic architecture of age-related macular degeneration (AMD) in a Japanese population. DESIGN: Genome-wide association study (GWAS). PARTICIPANTS: Three thousand seven hundred seventy-two patients with AMD and 16 770 control participants from the Japanese population were enrolled in the association analyses. METHODS: We conducted a meta-analysis of 2 independent GWASs that included a total of 2663 patients with AMD and 9471 control participants using the imputation reference panel for genotype imputation specified for the Japanese population (n = 3541). A replication study was performed using an independent set of 1109 patients with AMD and 7299 control participants. MAIN OUTCOME MEASURES: Associations of genetic variants with AMD. RESULTS: A meta-analysis of the 2 GWASs identified 6 loci significantly associated with AMD (P < 5.0 × 10-8). Of these loci, 4 were known to be associated with AMD (CFH, C2/FB, TNFRSF10A, and ARMS2), and 2 were novel (rs4147157 near WBP1L and rs76228488 near GATA5). The newly identified associations were confirmed in a replication study (P < 0.01). After the meta-analysis of all datasets, we observed strong associations in these loci (P = 1.88 × 10-12 and P = 1.35 × 10-9 for meta-analysis for rs4147157 and rs76228488, respectively). When we looked up the associations in the reported central serous chorioretinopathy (CSC) GWAS conducted in the Japanese population, both loci were associated significantly with CSC (P = 4.86 × 10-3 and P = 4.28 × 10-3 for rs4147157 and rs76228488, respectively). We performed a genetic colocalization analysis for these loci and estimated that the posterior probabilities of shared causal variants between AMD and CSC were 0.39 and 0.60 for WBP1L and GATA5, respectively. Genetic correlation analysis focusing on the epidemiologically suggested clinical risk factors implicated shared polygenic architecture between AMD and smoking cessation (rg [the measure of genetic correlation] = -0.33; P = 0.01; false discovery rate, 0.099). CONCLUSIONS: Our findings imply shared genetic components conferring the risk of both AMD and CSC. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.


Asunto(s)
Coriorretinopatía Serosa Central , Degeneración Macular , Humanos , Estudio de Asociación del Genoma Completo , Predisposición Genética a la Enfermedad , Coriorretinopatía Serosa Central/diagnóstico , Coriorretinopatía Serosa Central/genética , Degeneración Macular/genética , Genotipo , Polimorfismo de Nucleótido Simple , Sitios Genéticos
6.
J Med Genet ; 59(11): 1133-1138, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35710107

RESUMEN

Despite the successful identification of causative genes and genetic variants of retinitis pigmentosa (RP), many patients have not been molecularly diagnosed. Our recent study using targeted short-read sequencing showed that the proportion of carriers of pathogenic variants in EYS, the cause of autosomal recessive RP, was unexpectedly high in Japanese patients with unsolved RP. This result suggested that causative genetic variants, which are difficult to detect by short-read sequencing, exist in such patients. Using long-read sequencing technology (Oxford Nanopore), we analysed the whole genomes of 15 patients with RP with one heterozygous pathogenic variant in EYS detected in our previous study along with structural variants (SVs) in EYS and another 88 RP-associated genes. Two large exon-overlapping deletions involving six exons were identified in EYS in two patients with unsolved RP. An analysis of an independent patient set (n=1189) suggested that these two deletions are not founder mutations. Our results suggest that searching for SVs by long-read sequencing in genetically unsolved cases benefits the molecular diagnosis of RP.


Asunto(s)
Proteínas del Ojo , Retinitis Pigmentosa , Humanos , Genes Recesivos , Linaje , Proteínas del Ojo/genética , Mutación/genética , Retinitis Pigmentosa/diagnóstico , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/patología , Análisis Mutacional de ADN
7.
Cancer Sci ; 113(11): 3972-3979, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36065483

RESUMEN

The application of advanced molecular technology has significantly expanded lymphoma classification, allowing risk stratification and treatment optimization. Limited evidence suggests the presence of a genetic predisposition in lymphoma, indicating the potential for better individualized clinical management based on a novel lymphoma classification. Herein, we examined the impact of germline pathogenic variants in 27 cancer-predisposing genes with lymphoma risk and explored the clinical characteristics of pathogenic variant carriers. This study included 2,066 lymphoma patients and 38,153 cancer-free controls from the Japanese population. Following quality control of sequencing data, samples from 1,982 lymphoma patients and 37,592 controls were further analyzed. We identified 309 pathogenic variants among 4,850 variants in the 27 cancer-predisposing genes. Pathogenic variants in the following four cancer-predisposing genes were associated with a high risk of lymphoma: ATM (odds ratio [OR], 2.63; 95% confidence interval [CI], 1.25-5.51; p = 1.06 × 10-2 ), BRCA1 (OR, 5.88; 95% CI, 2.65-13.02; p = 1.27 × 10-5 ), BRCA2 (OR, 2.94; 95% CI, 1.60-5.42; p = 5.25 × 10-4 ), and TP53 (OR, 5.22; 95% CI, 1.43-19.02; p = 1.23 × 10-2 ). The proportion of carriers of these genes was 1.6% of lymphoma patients. Furthermore, pathogenic variants in these genes were especially associated with a higher risk of mantle cell lymphoma (OR, 21.57; 95% CI, 7.59-61.26; p = 8.07 × 10-9 ). These results provide novel insights concerning monogenic form into lymphoma classification. Some lymphoma patients may benefit from surveillance and targeted treatment, such as other neoplasms.


Asunto(s)
Neoplasias de la Mama , Linfoma , Adulto , Humanos , Femenino , Mutación de Línea Germinal , Predisposición Genética a la Enfermedad , Heterocigoto , Linfoma/genética , Células Germinativas
8.
Jpn J Clin Oncol ; 52(12): 1441-1445, 2022 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-36093724

RESUMEN

Upper urinary tract urothelial carcinoma is a rare cancer that has been associated with mismatch repair genes such as MLH1, MSH2, MSH6 and PMS2. In addition, patients with pathogenic variants of cancer-predisposing genes such as BRCA1 and BRCA2 have been reported. However, how cancer-predisposing genes affect the risk of upper urinary tract urothelial carcinoma in the Japanese population remains unclear. Thus, we performed a case-control sequencing study of 27 cancer-predisposing genes in 208 upper urinary tract urothelial carcinoma patients and 37 727 controls. Only MSH6 and MSH2 were observed with a value of P < 0.05. However, there was no difference in the prevalence of pathogenic variants of BRCA1/2, which does not support the use of a poly adenosine diphosphate-ribose polymerase inhibitor in patients with upper urinary tract urothelial carcinoma. Only mismatch repair genes were associated with patients with upper urinary tract urothelial carcinoma, but the prevalence of pathogenic variants in mismatch repair genes was lower than that reported in previous studies from other populations.


Asunto(s)
Carcinoma de Células Transicionales , Neoplasias Renales , Neoplasias Ureterales , Neoplasias de la Vejiga Urinaria , Sistema Urinario , Humanos , Carcinoma de Células Transicionales/epidemiología , Carcinoma de Células Transicionales/genética , Proteína 2 Homóloga a MutS/genética , Homólogo 1 de la Proteína MutL/genética , Prevalencia , Japón/epidemiología , Neoplasias de la Vejiga Urinaria/genética , Neoplasias Ureterales/epidemiología , Neoplasias Ureterales/genética , Reparación de la Incompatibilidad de ADN , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética
10.
JCO Precis Oncol ; 8: e2400094, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39088769

RESUMEN

PURPOSE: Genetic susceptibility to nonsyndromic renal cell carcinoma (RCC) remains poorly understood, especially for different histological subtypes, as does variations in genetic predisposition in different populations. The objectives of this study were to identify risk genes for RCC in the Canadian population, investigate their clinical significance, and evaluate variations in germline pathogenic variants (PVs) among patients with RCC across the globe. MATERIALS AND METHODS: We conducted targeted sequencing of 19 RCC-related and 27 cancer predisposition genes for 960 patients with RCC from Canada and identified genes enriched in rare germline PVs in RCC compared with cancer-free controls. We combined our results with those reported for patients from Japan, the United Kingdom, and the United States to investigate PV variations in different populations. Furthermore, we evaluated the performance of referral criteria for genetic screening for including patients with rare PVs. RESULTS: We identified 39 germline PVs in 56 patients (5.8%) from the Canadian cohort. Compared with cancer-free controls, PVs in CHEK2 (odds ratio [OR], 4.8 [95% CI, 2.7 to 7.9], P = 3.94 × 10-5) and ATM (OR, 4.5 [95% CI, 2.0 to 8.7], P = .016) were significantly enriched in patients with clear cell, whereas PVs in FH (OR, 215.1 [95% CI, 64.4 to 597.8], P = 6.14 × 10-9) were enriched in patients with non-clear cell RCCs. PVs in BRCA1, BRCA2, and ATM were associated with metastasis (P = .003). Comparative analyses showed an enrichment of TP53 PVs in patients from Japan, of CHEK2 and ATM in patients from Canada, the United States and the United Kingdom, and of FH and BAP1 in the United States. CONCLUSION: CHEK2, ATM, and FH are risk genes for RCC in the Canadian population, whereas PVs in BRCA1/2 and ATM are associated with risk of metastasis. Globally, clinical guidelines for genetic screening in RCC fail to include more than 70% of patients with rare germline PVs.


Asunto(s)
Carcinoma de Células Renales , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Mutación de Línea Germinal , Neoplasias Renales , Humanos , Carcinoma de Células Renales/genética , Pruebas Genéticas/métodos , Neoplasias Renales/genética , Neoplasias Renales/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Canadá
11.
Nat Genet ; 55(6): 939-951, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37169872

RESUMEN

Mobile genetic elements (MEs) are heritable mutagens that recursively generate structural variants (SVs). ME variants (MEVs) are difficult to genotype and integrate in statistical genetics, obscuring their impact on genome diversification and traits. We developed a tool that accurately genotypes MEVs using short-read whole-genome sequencing (WGS) and applied it to global human populations. We find unexpected population-specific MEV differences, including an Alu insertion distribution distinguishing Japanese from other populations. Integrating MEVs with expression quantitative trait loci (eQTL) maps shows that MEV classes regulate tissue-specific gene expression by shared mechanisms, including creating or attenuating enhancers and recruiting post-transcriptional regulators, supporting class-wide interpretability. MEVs more often associate with gene expression changes than SNVs, thus plausibly impacting traits. Performing genome-wide association study (GWAS) with MEVs pinpoints potential causes of disease risk, including a LINE-1 insertion associated with keloid and fasciitis. This work implicates MEVs as drivers of human divergence and disease risk.


Asunto(s)
Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Humanos , Regulación de la Expresión Génica , Sitios de Carácter Cuantitativo , Fenotipo
12.
Diabetol Int ; 13(3): 580-583, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35693998

RESUMEN

An 85-year-old man was being treated with anti-cancer drugs for adenocarcinoma of the lung and was on a tapering dose of prednisolone for interstitial pneumonia. He attended our hospital complaining of fatigue, thirst, and polyuria in September 2020. His postprandial plasma glucose concentration was 976 mg/dL, his glycated hemoglobin was 8.0%, his plasma osmolality was 342 mOsm/kg H2O, his urine ketone body content was 1 +, and his blood pH was 7.356. Therefore, we diagnosed a hyperosmolar-hyperglycemic state and he was admitted to the hospital for treatment. He had had no previous upper respiratory symptoms, and his postprandial plasma glucose and glycated hemoglobin were normal 13 days before he was first assessed (90 mg/dL and 5.9%, respectively). On admission, his serum pancreatic exocrine enzyme activities were high and he was negative for islet-specific autoantibodies. His serum C-peptide concentration was 0.60 ng/mL, suggesting that his endogenous insulin secretion was partially intact at that time. Although he did not meet the diagnostic criteria, we suspected him of having fulminant type 1 diabetes mellitus, because of the abrupt onset of hyperosmolar-hyperglycemic state. His general condition was improved by fluid and insulin administration. His human leukocyte antigen genotype was DRB1*04:05 DQB1*04:01:01, which is a disease susceptibility haplotype for fulminant type 1 diabetes mellitus. In addition, his prednisolone treatment may have caused an autoimmune abnormality, further predisposing toward the development of fulminant type 1 diabetes mellitus.

13.
JAMA Oncol ; 8(6): 871-878, 2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35420638

RESUMEN

Importance: The clinical importance of genetic testing of BRCA1 and BRCA2 in breast, ovarian, prostate, and pancreatic cancers is widely recognized. However, there is insufficient evidence to include other cancer types that are potentially associated with BRCA1 and BRCA2 in clinical management guidelines. Objective: To evaluate the association of BRCA1 and BRCA2 pathogenic variants with additional cancer types and their clinical characteristics in 100 914 individuals across 14 cancer types. Design, Setting, and Participants: This case-control analysis to identify cancer types and clinical characteristics associated with pathogenic variants in BRCA1 and BRCA2 included DNA samples and clinical information from 63 828 patients with 14 common cancer types and 37 086 controls that were sourced from a multi-institutional hospital-based registry, BioBank Japan, between April 2003 and March 2018. The data were analyzed between August 2019 and October 2021. Main Outcomes and Measures: Germline pathogenic variants in coding regions and 2 bp flanking intronic sequences in BRCA1 and BRCA2 were identified by a multiplex polymerase chain reaction-based target sequence method. Associations of (likely) pathogenic variants with each cancer type were assessed by comparing pathogenic variant carrier frequency between patients in each cancer type and controls. Results: A total of 65 108 patients (mean [SD] age at diagnosis, 64.1 [11.6] years; 27 531 [42.3%] female) and 38 153 controls (mean [SD] age at registration, 61.8 [14.6] years; 17 911 [46.9%] female) were included in this study. A total of 315 unique pathogenic variants were identified. Pathogenic variants were associated with P < 1 × 10-4 with an odds ratio (OR) of greater than 4.0 in biliary tract cancer (OR, 17.4; 95% CI, 5.8-51.9) in BRCA1, esophageal cancer (OR, 5.6; 95% CI, 2.9-11.0) in BRCA2, and gastric cancer (OR, 5.2; 95% CI, 2.6-10.5) in BRCA1, and (OR, 4.7; 95% CI, 3.1-7.1) in BRCA2 in addition to the 4 established cancer types. We also observed an association with 2 and 4 other cancer types in BRCA1 and BRCA2, respectively. Biliary tract, female breast, ovarian, and prostate cancers showed enrichment of carrier patients according to the increased number of reported cancer types in relatives. Conclusions and Relevance: The results of this large-scale registry-based case-control study suggest that pathogenic variants in BRCA1 and BRCA2 were associated with the risk of 7 cancer types. These results indicate broader clinical relevance of BRCA1 and BRCA2 genetic testing.


Asunto(s)
Variación Genética , Neoplasias , Proteína BRCA1/genética , Proteína BRCA2/genética , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Mutación de Línea Germinal , Humanos , Japón , Masculino , Neoplasias/genética
14.
Nat Cancer ; 2(3): 340-356, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-35121960

RESUMEN

Aggressive therapy-resistant and refractory acute myeloid leukemia (AML) has an extremely poor outcome. By analyzing a large number of genetically complex and diverse, primary high-risk poor-outcome human AML samples, we identified specific pathways of therapeutic vulnerability. Through drug screens followed by extensive in vivo validation and genomic analyses, we found inhibition of cytosolic and mitochondrial anti-apoptotic proteins XIAP, BCL2 and MCL1, and a key regulator of mitosis, AURKB, as a vulnerability hub based on patient-specific genetic aberrations and transcriptional signatures. Combinatorial therapeutic inhibition of XIAP with an additional patient-specific vulnerability eliminated established AML in vivo in patient-derived xenografts (PDXs) bearing diverse genetic aberrations, with no signs of recurrence during off-treatment follow-up. By integrating genomic profiling and drug-sensitivity testing, this work provides a platform for a precision-medicine approach for treating aggressive AML with high unmet need.


Asunto(s)
Leucemia Mieloide Aguda , Proteínas Proto-Oncogénicas c-bcl-2 , Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/uso terapéutico , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteína Inhibidora de la Apoptosis Ligada a X/genética
15.
J Lipid Res ; 51(5): 975-82, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-19797618

RESUMEN

Perilipin A is the most abundant phosphoprotein on adipocyte lipid droplets and is essential for lipid storage and lipolysis. Perilipin null mice exhibit diminished adipose tissue, elevated basal lipolysis, reduced catecholamine-stimulated lipolysis, and increased insulin resistance. To understand the physiological consequences of increased perilipin expression in vivo, we generated transgenic mice that overexpressed either human or mouse perilipin using the adipocyte-specific aP2 promoter/enhancer. Phenotypes of female transgenic and wild-type mice were characterized on chow and high-fat diets (HFDs). When challenged with an HFD, transgenic mice exhibited lower body weight, fat mass, and adipocyte size than wild-type mice. Expression of oxidative genes was increased and lipogenic genes decreased in brown adipose tissue of transgenic mice. Basal and catecholamine-stimulated lipolysis was decreased and glucose tolerance significantly improved in transgenic mice fed a HFD. Perilipin overexpression in adipose tissue protects against HFD-induced adipocyte hypertrophy, obesity, and glucose intolerance. Alterations in brown adipose tissue metabolism may mediate the effects of perilipin overexpression on body fat, although the mechanisms by which perilipin overexpression alters brown adipose tissue metabolism remain to be determined. Our findings demonstrate a novel role for perilipin expression in adipose tissue metabolism and regulation of obesity and its metabolic complications.


Asunto(s)
Dieta/efectos adversos , Obesidad/genética , Obesidad/prevención & control , Fosfoproteínas/genética , Adipocitos/metabolismo , Adipocitos/patología , Animales , Proteínas Portadoras , Catecolaminas/farmacología , Tamaño de la Célula , Grasas de la Dieta/efectos adversos , Femenino , Expresión Génica , Glucosa/metabolismo , Homeostasis/genética , Humanos , Insulina/metabolismo , Lipólisis/efectos de los fármacos , Lipólisis/genética , Masculino , Ratones , Ratones Transgénicos , Obesidad/etiología , Obesidad/metabolismo , Especificidad de Órganos , Oxidación-Reducción , Perilipina-1 , Aumento de Peso/efectos de los fármacos , Aumento de Peso/genética
16.
EBioMedicine ; 60: 103033, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32980694

RESUMEN

BACKGROUND: National Comprehensive Cancer Network (NCCN) recently recommended germline genetic testing for all pancreatic cancer patients. However, the genes targeted by genetic testing and the feasibility of selecting patients likely to carry pathogenic variants have not been sufficiently verified. The purpose of this study was to genetically characterize Japanese patients and examine whether the current guideline is applicable in this population. METHODS: Using targeted sequencing, we analyzed the coding regions of 27 cancer-predisposing genes in 1,005 pancreatic cancer patients and 23,705 controls in Japan. We compared the pathogenic variant frequency between cases and controls and documented the demographic and clinical characteristics of carrier patients. We then examined if it was possible to use machine learning to predict carrier status based on those characteristics. FINDINGS: We identified 205 pathogenic variants across the 27 genes. Pathogenic variants in BRCA2, ATM, and BRCA1 were significantly associated with pancreatic cancer. Characteristics associated with carrier status were inconsistent with previous investigations. Machine learning classifiers had a low performance in determining the carrier status of pancreatic cancer patients, while the same classifiers, when applied to breast cancer data as a positive control, had a higher performance that was comparable to that of the NCCN guideline. INTERPRETATION: Our findings support the clinical significance of multigene panel testing for pancreatic cancer and indicate that at least 3.4% of Japanese patients may respond to poly (ADP ribose) polymerase inhibitor treatments. The difficulty in predicting carrier status suggests that offering germline genetic testing for all pancreatic cancer patients is reasonable. FUNDING: AMED under Grant Number JP19kk0305010 and Australian National Health and Medical Research funding (ID177524).


Asunto(s)
Alelos , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Neoplasias Pancreáticas/genética , Adulto , Anciano , Anciano de 80 o más Años , Proteína BRCA1/genética , Proteína BRCA2/genética , Biología Computacional/métodos , Femenino , Estudios de Asociación Genética , Pruebas Genéticas , Humanos , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Anotación de Secuencia Molecular , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidad , Curva ROC , Adulto Joven
17.
Appl Environ Microbiol ; 75(5): 1324-30, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19114506

RESUMEN

Gassericin A, produced by Lactobacillus gasseri LA39, is a hydrophobic circular bacteriocin. The DNA region surrounding the gassericin A structural gene, gaaA, was sequenced, and seven open reading frames (ORFs) of 3.5 kbp (gaaBCADITE) were found with possible functions in gassericin A production, secretion, and immunity. The deduced products of the five consecutive ORFs gaaADITE have homology to those of genes involved in butyrivibriocin AR10 production, although the genetic arrangements are different in the two circular bacteriocin genes. GaaI is a small, positively charged hydrophobic peptide of 53 amino acids containing a putative transmembrane segment. Heterologous expression and homologous expression of GaaI in Lactococcus lactis subsp. cremoris MG1363 and L. gasseri JCM1131(T), respectively, were studied. GaaI-expressing strains exhibited at least sevenfold-higher resistance to gassericin A than corresponding control strains, indicating that gaaI encodes an immunity peptide for gassericin A. Comparison of GaaI to peptides with similar characteristics found in the circular bacteriocin gene loci is discussed.


Asunto(s)
Antibacterianos/antagonistas & inhibidores , Proteínas Bacterianas/genética , Bacteriocinas/antagonistas & inhibidores , Farmacorresistencia Bacteriana , Lactobacillus/efectos de los fármacos , Secuencia de Aminoácidos , Antibacterianos/farmacología , Proteínas Bacterianas/metabolismo , Bacteriocinas/farmacología , Clonación Molecular , ADN Bacteriano/química , ADN Bacteriano/genética , Orden Génico , Lactobacillus/genética , Redes y Vías Metabólicas , Datos de Secuencia Molecular , Sistemas de Lectura Abierta , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido
18.
Endocrinology ; 145(5): 2346-56, 2004 May.
Artículo en Inglés | MEDLINE | ID: mdl-14726448

RESUMEN

Perilipin, a family of phosphoproteins located around lipid droplets in adipocytes, is essential for enlargement of lipid droplets and lipolytic reaction by hormone-sensitive lipase. Thiazolidinediones, peroxisome proliferator-activated receptor (PPAR) gamma agonists, have been shown to increase perilipin expression in fully differentiated adipocytes. However, the precise mechanism of transcriptional regulation of murine perilipin gene heretofore remains unclear. We determined the transcription start site of murine perilipin gene by RNA ligase-mediated rapid amplification of the cDNA ends method. We generated luciferase reporter gene constructs containing various lengths of the 5'-flanking region of the murine perilipin gene and assayed promoter/enhancer activities using differentiated 3T3-L1 adipocytes. We identified a functional PPAR-responsive element (PPRE) in the murine perilipin promoter, and this was confirmed by gel EMSAs using nuclear extracts from differentiated 3T3-L1 adipocytes. Furthermore, point mutations of the identified functional PPRE markedly reduced both the reporter gene activity in differentiated 3T3-L1 adipocytes and PPARgamma/thiazolidinedione-induced transactivation in NIH-3T3 fibroblasts. Real-time RT-PCR revealed that thiazolidinedione up-regulates endogenous perilipin mRNA levels. We propose that PPARgamma plays a significant role in the transcriptional regulation of murine perilipin gene via the PPRE in its promoter.


Asunto(s)
Fosfoproteínas/genética , Elementos de Respuesta/genética , Factores de Transcripción/farmacología , Adipocitos/química , Animales , Secuencia de Bases , Proteínas Portadoras , Diferenciación Celular , Análisis Mutacional de ADN , ADN Complementario/química , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Luciferasas/genética , Ratones , Datos de Secuencia Molecular , Células 3T3 NIH , Perilipina-1 , Regiones Promotoras Genéticas/genética , ARN Mensajero , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Secuencias Reguladoras de Ácidos Nucleicos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ADN , Factores de Transcripción/agonistas , Factores de Transcripción/antagonistas & inhibidores , Sitio de Iniciación de la Transcripción , Transfección
19.
Intern Med ; 43(7): 571-4, 2004 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15335182

RESUMEN

A 25-year-old Japanese man with adult-onset idiopathic hypogonadotropic hypogonadism is reported. He had been delivered normally, had normal puberty, and experienced erectile dysfunction at age 24 years. Brain MRI revealed no abnormal findings and endocrinological data supported the diagnosis of isolated gonadotropin deficiency. Although most patients with idiopathic hypogonadotropic hypogonadism have a hypothalamic dysfunction, the lesion in this case may be considered to be in the pituitary since repetitive GnRH loading failed to increase serum LH and FSH.


Asunto(s)
Gonadotropinas Hipofisarias/deficiencia , Hipogonadismo/diagnóstico , Hipogonadismo/etiología , Hipófisis/fisiopatología , Adulto , Gonadotropina Coriónica , Disfunción Eréctil/diagnóstico , Disfunción Eréctil/etiología , Estudios de Seguimiento , Hormona Liberadora de Gonadotropina , Humanos , Imagen por Resonancia Magnética , Masculino , Medición de Riesgo
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