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1.
Cancer Immunol Immunother ; 73(10): 197, 2024 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-39105849

RESUMEN

BACKGROUND: Biomarkers for predicting response to the immunotherapy and chemotherapy combination in breast cancer patients are not established. In this study, we report exploratory genomic and transcriptomic analyses of pretreatment tumor tissues from patients enrolled in phase II clinical trial of a combination of eribulin and nivolumab for HER-2-negative metastatic breast cancer (MBC) (KORNELIA trial, NCT04061863). METHODS: We analyzed associations between tumor molecular profiles based on genomic (n = 76) and transcriptomic data (n = 58) and therapeutic efficacy. Patients who achieved progression-free survival (PFS) ≥ 6 months were defined as PFS6-responders and PFS6-nonresponders otherwise. FINDINGS: Analyses on tumor mutation burden (TMB) showed a tendency toward a favorable effect on efficacy, while several analyses related to homologous recombination deficiency (HRD) indicated a potentially negative impact on efficacy. Patients harboring TP53 mutations showed significantly poor PFS6 rate and PFS, which correlated with the enrichment of cell cycle-related signatures in PFS6-nonresponders. High antigen presentation gene set enrichment scores (≥ median) were significantly associated with longer PFS. Naïve B-cell and plasma cell proportions were considerably higher in long responders (≥ 18 months). INTERPRETATION: Genomic features including TMB, HRD, and TP53 mutations and transcriptomic features related to immune cell profiles and cell cycle may distinguish responders. Our findings provide insights for further exploring the combination regimen and its biomarkers in these tumors.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Furanos , Cetonas , Nivolumab , Receptor ErbB-2 , Transcriptoma , Humanos , Femenino , Cetonas/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Furanos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Nivolumab/uso terapéutico , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Persona de Mediana Edad , Genómica/métodos , Anciano , Biomarcadores de Tumor/genética , Adulto , Mutación , Metástasis de la Neoplasia , Perfilación de la Expresión Génica , Policétidos Poliéteres
2.
Int J Mol Sci ; 24(23)2023 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-38069324

RESUMEN

Tissue-specific gene expression generates fundamental differences in the function of each tissue and affects the characteristics of the tumors that are created as a result. However, it is unclear how much the tissue specificity is conserved during grafting of the primary tumor into an immune-compromised mouse model. Here, we performed a comparative RNA-seq analysis of four different primary-patient derived xenograft (PDX) tumors. The analysis revealed a conserved RNA biotype distribution of primary-PDX pairs, as revealed by previous works. Interestingly, we detected significant changes in the splicing pattern of PDX, which was mainly comprised of skipped exons. This was confirmed by splicing variant-specific RT-PCR analysis. On the other hand, the correlation analysis for the tissue-specific genes indicated overall strong positive correlations between the primary and PDX tumor pairs, with the exception of gastric cancer cases, which showed an inverse correlation. These data propose a tissue-specific change in splicing events during PDX formation as a variable factor that affects primary-PDX integrity.


Asunto(s)
Empalme Alternativo , Neoplasias Gástricas , Animales , Ratones , Humanos , Neoplasias Gástricas/patología , Empalme del ARN/genética , Análisis de Secuencia de ARN
3.
Sci Rep ; 13(1): 22482, 2023 12 18.
Artículo en Inglés | MEDLINE | ID: mdl-38110532

RESUMEN

Genomic hypomethylation has recently been identified as a determinant of therapeutic responses to immune checkpoint blockade (ICB). However, it remains unclear whether this approach can be applied to cell-free DNA (cfDNA) and whether it can address the issue of low tumor purity encountered in tissue-based methylation profiling. In this study, we developed an assay named iMethyl, designed to estimate the genomic hypomethylation status from cfDNA. This was achieved through deep targeted sequencing of young LINE-1 elements with > 400,000 reads per sample. iMethyl was applied to a total of 653 ICB samples encompassing lung cancer (cfDNA n = 167; tissue n = 137; cfDNA early during treatment n = 40), breast cancer (cfDNA n = 91; tissue n = 50; PBMC n = 50; cfDNA at progression n = 44), and ovarian cancer (tissue n = 74). iMethyl-liquid predicted ICB responses accurately regardless of the tumor purity of tissue samples. iMethyl-liquid was also able to monitor therapeutic responses early during treatment (3 or 6 weeks after initiation of ICB) and detect progressive hypomethylation accompanying tumor progression. iMethyl-tissue had better predictive power than tumor mutation burden and PD-L1 expression. In conclusion, our iMethyl-liquid method allows for reliable noninvasive prediction, early evaluation, and monitoring of clinical responses to ICB therapy.


Asunto(s)
Neoplasias de la Mama , Ácidos Nucleicos Libres de Células , Neoplasias Pulmonares , Humanos , Femenino , Ácidos Nucleicos Libres de Células/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Leucocitos Mononucleares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Genómica/métodos , Pulmón/patología , Biomarcadores de Tumor/genética
4.
Nat Genet ; 55(2): 221-231, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36624345

RESUMEN

Despite advances in predicting physical peptide-major histocompatibility complex I (pMHC I) binding, it remains challenging to identify functionally immunogenic neoepitopes, especially for MHC II. By using the results of >36,000 immunogenicity assay, we developed a method to identify pMHC whose structural alignment facilitates T cell reaction. Our method predicted neoepitopes for MHC II and MHC I that were responsive to checkpoint blockade when applied to >1,200 samples of various tumor types. To investigate selection by spontaneous immunity at the single epitope level, we analyzed the frequency spectrum of >25 million mutations in >9,000 treatment-naive tumors with >100 immune phenotypes. MHC II immunogenicity specifically lowered variant frequencies in tumors under high immune pressure, particularly with high TCR clonality and MHC II expression. A similar trend was shown for MHC I neoepitopes, but only in particular tissue types. In summary, we report immune selection imposed by MHC II-restricted natural or therapeutic T cell reactivity.


Asunto(s)
Neoplasias , Humanos , Neoplasias/genética , Neoplasias/terapia , Epítopos/genética , Linfocitos T , Péptidos/química , Péptidos/metabolismo
5.
J Atten Disord ; 25(2): 161-170, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-29781347

RESUMEN

Objective: We investigated the interaction effect between the methylation of dopamine receptor D4 (DRD4) and phthalate exposure in ADHD on continuous performance test (CPT) variables. Method: Urine concentrations of mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-n-butyl phthalate (MBP) were tested. The methylation status was analyzed for CpG sites of DRD4. Multivariable linear regression models were applied to investigate the interaction effects of methylation and phthalate levels. Results: There was a significant interaction effect of the methylation of CpG26 and CpG28 with the MEHHP level on omission errors in ADHD patients, but not in controls. The post hoc analysis revealed a significant correlation between the MEHHP concentration and omission errors in the methylated group, but not in the unmethylated group. Conclusion: The interaction between the methylation status of CpG sites of DRD4, particularly CpG26 and CpG28, and phthalate metabolite levels affects the attention level in ADHD patients.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Contaminantes Ambientales , Ácidos Ftálicos , Atención , Humanos , Metilación , Receptores de Dopamina D4/genética
6.
J Child Adolesc Psychopharmacol ; 28(8): 562-570, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-29905488

RESUMEN

OBJECTIVES: Environmental factors may interact with genetic factors via the epigenetic process, and this interaction can contribute to inter-individual variability in the treatment response. The purpose of this study was to investigate the interaction effects between dopamine receptor D4 (DRD4) methylation and prenatal maternal stress on the methylphenidate (MPH) response of youth with attention-deficit/hyperactivity disorder (ADHD). METHODS: This study was an 8-week open-label trial of MPH that included 74 ADHD youth. We investigated the associations between MPH treatment response, which was defined as a score ≤2 on the Clinical Global Impressions-Improvement (CGI-I) scale, and the methylation of 28 cytosine-guanine dinucleotide (CpG) sites of DRD4. Additionally, the interaction effects between DRD4 methylation and prenatal maternal stress on changes in Continuous Performance Test (CPT) scores after MPH treatment were investigated. RESULTS: Although there were no significant sites that showed significant association with treatment response, there was a significant interaction effect of the methylation of CpG7 and prenatal maternal stress on changes in omission errors of the CPT following treatment (p = 0.0001). CONCLUSIONS: The present findings indicate that the interaction between methylation of CpG7 of DRD4 and prenatal maternal stress may be predictive of the treatment response to MPH in youth with ADHD.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Estimulantes del Sistema Nervioso Central/uso terapéutico , Metilación , Metilfenidato/uso terapéutico , Receptores de Dopamina D4/genética , Estrés Psicológico/psicología , Niño , Femenino , Interacción Gen-Ambiente , Humanos , Masculino , Madres/psicología , Polimorfismo Genético
7.
Breast Cancer Res Treat ; 161(1): 95-102, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27783279

RESUMEN

PURPOSE: This study was performed to evaluate the frequency of mutations in CHEK2, PALB2, MRE11, and RAD50 among Korean patients at high risk for hereditary breast cancer. METHODS: A total of 235 Korean patients with hereditary breast cancer who tested negative for BRCA1/2 mutation were enrolled to this study. Entire coding regions of CHEK2, PALB2, MRE11, and RAD50 were analyzed using massively parallel sequencing (MPS). Sequence variants detected by MPS were confirmed by Sanger sequencing. RESULTS: Six patients (2.5 %) were found to have pathogenic variants in CHEK2 (n = 1), PALB2 (n = 2), MRE11 (n = 1), and RAD50 (n = 2). Among the pathogenic variants, PALB2 c.2257C>T was previously reported in other studies, while CHEK2 c.1245dupC, PALB2 c.1048C>T, MRE11 c.1773_1774delAA, RAD50 c.1276C>T, and RAD50 c.3811_3813delGAA were newly identified in this study. A total of 15 missense variants were found in the four genes among 26 patients; 7 patients had a variant in CHEK2, 11 in PALB2, 2 in MRE11, and 6 in RAD50. When in silico analyses were performed to the 15 missense variants, six variants (CHEK2 c.686A>G, PALB2 c.1492G>T, PALB2 c.3054G>C, MRE11 c.140C>T, RAD50 c.1456C>T, and RAD50 c.3790C>T) were predicted to be deleterious. CONCLUSIONS: Pathogenic variants in CHEK2, PALB2, MRE11, and RAD50 were detected in a small proportion of Korean patients with features of hereditary breast cancer.


Asunto(s)
Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Quinasa de Punto de Control 2/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Proteína del Grupo de Complementación N de la Anemia de Fanconi/genética , Mutación de Línea Germinal , Proteína Homóloga de MRE11/genética , Tasa de Mutación , Ácido Anhídrido Hidrolasas , Alelos , Sustitución de Aminoácidos , Biomarcadores de Tumor , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Riesgo
8.
Biosens Bioelectron ; 91: 122-127, 2017 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-28012317

RESUMEN

We herein describe a new mass spectrometry-based method for multiplex SNP genotyping by utilizing allele-specific ligation and strand displacement amplification (SDA) reaction. In this method, allele-specific ligation is first performed to discriminate base sequence variations at the SNP site within the PCR-amplified target DNA. The primary ligation probe is extended by a universal primer annealing site while the secondary ligation probe has base sequences as an overhang with a nicking enzyme recognition site and complementary mass marker sequence. The ligation probe pairs are ligated by DNA ligase only at specific allele in the target DNA and the resulting ligated product serves as a template to promote the SDA reaction using a universal primer. This process isothermally amplifies short DNA fragments, called mass markers, to be analyzed by mass spectrometry. By varying the sizes of the mass markers, we successfully demonstrated the multiplex SNP genotyping capability of this method by reliably identifying several BRCA mutations in a multiplex manner with mass spectrometry.


Asunto(s)
Neoplasias de la Mama/genética , Genes BRCA1 , Técnicas de Genotipaje/métodos , Polimorfismo de Nucleótido Simple , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Alelos , Técnicas Biosensibles/métodos , Femenino , Genotipo , Humanos , Técnicas de Amplificación de Ácido Nucleico/métodos
9.
Cancer Res Treat ; 48(3): 955-61, 2016 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26790966

RESUMEN

PURPOSE: The aim of the current study is to assess the spectrum of genetic variation in the BRIP1 gene among Korean high-risk breast cancer patients who tested negative for the BRCA1/2 mutation. MATERIALS AND METHODS: Overall, 235 Korean patientswith BRCA1/2 mutation-negative high-risk breast cancerwere screened for BRIP1 mutations. The entire BRIP1 gene was analyzed using fluorescent-conformation sensitive gel electrophoresis. In silico analysis of BRIP1 variants was performed using PolyPhen-2 and SIFT. RESULTS: A total of 20 sequence alterations including 12 exonic and eight intronic variantswere found. Among the 12 exonic variants, 10 were missense and two were silent mutations. No protein-truncating mutation was found among the tested patients. Among the 10 missense variants, four (p.L263F, p.L340F, p.L474P, and p.R848H) were predicted to be pathogenic by both PolyPhen-2 and SIFT, and these variants were found in five patients. Of the four missense variants, p.L263F, p.L474P, and p.R848H localize to regions between the helicase motifs, while p.L340F resides in an iron-sulfur domain of BRIP1. CONCLUSION: No protein-truncating mutation in BRIP1 was found among the tested patients. The contribution of BRIP1 variants is thought to be minor in Korean non-BRCA1/2 high-risk breast cancer.


Asunto(s)
Pueblo Asiatico/genética , Neoplasias de la Mama/genética , Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Predisposición Genética a la Enfermedad/genética , ARN Helicasas/genética , Adulto , Anciano , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/epidemiología , Análisis Mutacional de ADN/métodos , Exones/genética , Femenino , Humanos , Intrones/genética , Persona de Mediana Edad , Mutación Missense , Dominios Proteicos/genética , República de Corea/epidemiología , Mutación Silenciosa , Adulto Joven
10.
Fam Cancer ; 14(3): 365-71, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25712764

RESUMEN

The purpose of the present study was to analyze genetic variations in the NBS1 gene and to evaluate the contribution of heterozygous NBS1 mutation to the risk of breast cancer among Korean patients with high-risk breast cancer negative for BRCA1/2 mutation. We screened 235 non-BRCA1/2 Korean patients with high-risk breast cancer for NBS1 mutations. The entire NBS1 gene was sequenced using fluorescent conformation-sensitive capillary electrophoresis. In silico analysis of the NBS1 variants was performed using PolyPhen-2 and SIFT. The frequency of variants predicted to be deleterious by in silico analysis was compared between breast cancer patients and controls. Twenty-eight sequence variants in the NBS1 gene were identified: 9 exonic variants, including 5 missense mutations (p.R169C, p.I171V, p.E185Q, p.E564K, and p.F603L) and 4 silent mutations, and 19 variants within introns. Among the five missense variants, p.I171V (c.511A > G) was the only variant predicted to be deleterious by in silico analysis. Heterozygosity for p.I171V was found in 4/235 patients with breast cancer and 3/281 individuals in the control group. The frequency of p.I171V was not significantly different between the patient and control groups (1.7 vs. 1.06%, p = 0.7). Heterozygosity of p.I171V in the NBS1 gene was found in a small proportion of Korean patients with high-risk breast cancer. The contribution of the p.I171V variant to the development of breast cancer among Korean patients was not significant.


Asunto(s)
Neoplasias de la Mama/genética , Proteínas de Ciclo Celular/genética , Mutación de Línea Germinal , Proteínas Nucleares/genética , Adulto , Pueblo Asiatico/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama Masculina/genética , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Masculino , Mutación Missense
11.
Fam Cancer ; 13(2): 205-11, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24566764

RESUMEN

We screened large genomic rearrangements of the BRCA1 and BRCA2 genes in Korean, familial breast cancer patients. Multiplex ligation-dependent probe amplification assay was used to identify BRCA1 and BRCA2 genomic rearrangements in 226 Korean familial breast cancer patients with risk factors for BRCA1 and BRCA2 mutations, who previously tested negative for point mutations in the two genes. We identified only one large deletion (c.4186-1593_4676-1465del) in BRCA1. No large rearrangements were found in BRCA2. Our result indicates that large genomic rearrangement in the BRCA1 and BRCA2 genes does not seem like a major determinant of breast cancer susceptibility in the Korean population. A large-scale study needs to validate our result in Korea.


Asunto(s)
Neoplasias de la Mama/genética , Reordenamiento Génico , Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad/genética , Neoplasias Ováricas/genética , Eliminación de Secuencia , Pueblo Asiatico/genética , Secuencia de Bases , Exones , Femenino , Humanos , Reacción en Cadena de la Polimerasa Multiplex , República de Corea , Estudios Retrospectivos
12.
Breast Cancer Res Treat ; 134(3): 1315-26, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22798144

RESUMEN

This investigation is aimed at evaluating the epidemiologic characteristics of BRCA1/2 germline mutations in Korean patients with breast and ovarian cancer (BOC). We analyzed the entire mutational data of BRCA1/2 genes in BOC patients who were tested in Korea since the first Korean report of BRCA1 mutation in 1995 with the exception of the data covered in the Korean Hereditary Breast Cancer (KOHBRA) study, the project launched in 2007 for establishing BRCA1/2 carrier cohorts in Korea. In total, BRCA1/2 gene mutations of 3,922 Korean BOC patients were evaluated, including the unpublished data of 2,139 breast cancer patients examined by four Korean institutions and the data of 1,783 BOC patients covered in ten previous reports. Overall, 420 (150 distinct) pathogenic mutations were identified, 211 (73 distinct) in BRCA1 and 209 (77 distinct) in BRCA2. The majority (134 of 150) of the distinct mutations resulted in premature termination codon of the BRCA1/2 translation. BRCA1 c.4186-1593_4676-1465del was the only large genomic rearrangements mutation. Out of 150 distinct BRCA1/2 mutations, 84 (56 %) mutations were considered specific to Korean BOC. Eighty-five BRCA1/2 mutations were detected in at least two unrelated patients. These recurrent mutations account for 84.5 % (355 of 420) of mutations detected in the Korean population. In the pooled mutational data of BRCA1/2 genes, this study discovered the prevalence of BRCA1/2 mutations in the Korean BOC patients is similar to those found in other ethnic groups. Large genomic rearrangements in BRCA1/2 genes were infrequently detected among the Korean patients with BOC. There were several BRCA1/2 mutation candidates for founder mutations. To further establish a Korean cohort for BRCA1/2 mutations, the nationwide KOHBRA study is in progress.


Asunto(s)
Pueblo Asiatico/genética , Neoplasias de la Mama/genética , Genes BRCA1 , Genes BRCA2 , Mutación , Neoplasias Ováricas/genética , Neoplasias de la Mama/epidemiología , Femenino , Mutación de Línea Germinal , Humanos , Neoplasias Ováricas/epidemiología , Prevalencia , República de Corea/epidemiología
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