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1.
ESMO Open ; 9(4): 102385, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38387111

RESUMEN

BACKGROUND: The FUTURE trial (UMIN000029294) demonstrated the safety and efficacy of adding palbociclib after fulvestrant resistance in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced and metastatic breast cancer (ABC/MBC). In this planned sub-study, cancer panel sequencing of cell-free DNA (cfDNA) was utilized to explore prognostic and predictive biomarkers for further palbociclib treatment following fulvestrant resistance. MATERIALS AND METHODS: Herein, 149 cfDNA samples from 65 patients with fulvestrant-resistant disease were analysed at the time of palbociclib addition after fulvestrant resistance (baseline), on day 15 of cycle 1, and at the end of treatment using the assay for identifying diverse mutations in 34 cancer-related genes. RESULTS: During the course of treatment, mutations in ESR1, PIK3CA, FOXA1, RUNX1, TBX3, and TP53 were the most common genomic alterations observed. Analysis of genomic mutations revealed that before fulvestrant introduction, baseline PIK3CA mutations were marginally lower in metastatic aromatase inhibitor (AI)-treated patients compared to adjuvant AI-treated patients (P = 0.063). Baseline PIK3CA mutations were associated with poorer progression-free survival [hazard ratio: 1.62, P = 0.04]. Comparative analysis between baseline and early-changing gene mutations identified poor prognostic factors including early-changing MAP3K1 mutations (hazard ratio: 4.66, P = 0.04), baseline AR mutations (hazard ratio: 3.53, P = 0.04), and baseline PIK3CA mutations (hazard ratio: 3.41, P = 0.02). Notably, the relationship between ESR1 mutations and mutations in PIK3CA, MAP3K1, and TP53 weakened as treatment progressed. Instead, PIK3CA mutations became correlated with TP53 and FOXA1 mutations. CONCLUSIONS: Cancer panel testing for cfDNA identified prognostic and predictive biomarkers for palbociclib add-on therapy after acquiring fulvestrant resistance in patients with HR+/HER2- ABC/MBC.


Asunto(s)
Biomarcadores de Tumor , Neoplasias de la Mama , Resistencia a Antineoplásicos , Fulvestrant , Piperazinas , Piridinas , Humanos , Fulvestrant/uso terapéutico , Fulvestrant/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Piperazinas/uso terapéutico , Piperazinas/farmacología , Femenino , Piridinas/uso terapéutico , Piridinas/farmacología , Resistencia a Antineoplásicos/genética , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Pronóstico , Anciano , Adulto , Ácidos Nucleicos Libres de Células , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Mutación
2.
Kyobu Geka ; 59(12): 1095-8, 2006 Nov.
Artículo en Japonés | MEDLINE | ID: mdl-17094548

RESUMEN

A 63-year-old female, who had undergone a modified radical mastectomy for breast cancer at the age of 45, was suffered from trachyphonia due to left recurrent nerve paralysis at the age of 53. She presented left phrenic nerve paralysis and dysphagia at the age of 61. Computed tomography (CT) revealed mediastinal fibrosis, stenosis of esophagus and superior vena cava, and slight lymph nodes swelling. Video-assisted thoracoscopic mediastinal biopsy was performed and the mediastinal fibrosis was diagnosed as recurrence of breast cancer 17 years after the breast cancer operation. She underwent mediastinal radiation and chemotherapy for mediastinal recurrence and stenting for esophageal stenosis.


Asunto(s)
Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/cirugía , Enfermedades del Mediastino/etiología , Enfermedades del Mediastino/patología , Mediastino/patología , Complicaciones Posoperatorias , Biopsia , Estenosis Esofágica/etiología , Estenosis Esofágica/terapia , Femenino , Fibrosis/etiología , Humanos , Escisión del Ganglio Linfático , Mastectomía Radical Modificada , Persona de Mediana Edad , Stents , Cirugía Torácica Asistida por Video
3.
Cancer Lett ; 193(1): 41-7, 2003 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-12691822

RESUMEN

Frequent observations of allelic loss in chromosomal band 17q25.1 in a variety of human cancers have suggested that one or more tumor suppressor genes are normally present in this region. Moreover, a locus responsible for hereditary focal non-epidermolytic palmoplantar keratoderma (tylosis oesophageal cancer; TOC), a condition associated with esophageal cancer, has been mapped to the same band. During efforts to sequence, by shot-gun methods, a 1 Mb target region that we had defined as the DNA segment harboring the putative tumor suppressor gene(s) involved in these events, we identified a novel cDNA, DRHC (down-regulated in human cancers), that showed reduced expression in 28 of 95 (29%) cell lines derived from a variety of human cancers. The full-length cDNA, 6275 bp long, was expressed predominantly in thymus and brain. The predicted 1942-amino-acid product exhibited significant sequence homology to yeast enzymes belonging to the DEAD-helicase superfamily, and appeared to be a Uvr/Rep helicase with a DEXDc consensus domain. Transfection of a DRHC expression vector inhibited growth of cancer cells in liquid medium or soft agar. The results suggest that loss of expression of DRHC may play a role in human carcinogenesis.


Asunto(s)
Cromosomas Humanos Par 17 , ADN Helicasas/biosíntesis , Regulación hacia Abajo , Neoplasias/genética , Neoplasias/metabolismo , Northern Blotting , Encéfalo/metabolismo , División Celular , Clonación Molecular , ADN/metabolismo , ADN Helicasas/genética , ADN Helicasas/metabolismo , ADN Complementario/metabolismo , Bases de Datos como Asunto , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Genes Supresores de Tumor , Vectores Genéticos , Humanos , Modelos Genéticos , Proteínas de Neoplasias , Polimorfismo Conformacional Retorcido-Simple , Estructura Terciaria de Proteína , ARN Helicasas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Timo/metabolismo , Factores de Tiempo , Transfección , Células Tumorales Cultivadas
4.
Clin Cancer Res ; 7(11): 3526-32, 2001 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11705872

RESUMEN

EBAG9, an estrogen-responsive gene located at 8q23 was identified in an effort to clone CpG-binding sites. Its product was later found to be identical to RCAS1, a cancer cell-surface antigen implicated in immune escape. We determined the sequence of the complete cDNA and the genomic structure for EBAG9. EBAG9 gene copy number in 21% (27 of 129) primary breast cancers we examined; EBAG9 mRNA was consistently expressed in cancer cell lines. Detailed physical mapping of the 8q arm, including polymorphic markers for EBAG9 and the CMYC loci, revealed allelic gain of either EBAG9, CMYC, or both, in 45% (58 of 129) of the breast cancers we examined. The EBAG9 gene was increased exclusively in 16 of the 27 tumors showing gain at that locus; the other 11 showed gain of a larger chromosomal region containing both EBAG9 and CMYC. Analysis of subsequent series of 144 primary breast cancers for allelic gain at EBAG9 and CMYC locus showed a similar degree of gain at EBAG9, CMYC, or both. When a total of 273 breast cancers from two series were combined and analyzed for clinicopathological correlation, almost all of the tumors with EBAG9 increased but not those with CMYC. Twenty-eight of 29 were T1/T2 stage carcinomas (<5 cm in diameter), whereas one third (21 of 61) of the tumors in which CMYC was increased but EBAG9 was not, were advanced T3-stage tumors (P = 0.0012). These data suggest that EBAG9 and CMYC gene are independent targets of gain and that overrepresentation of EBAG9 may play a specific role in early stages of breast carcinogenesis.


Asunto(s)
Antígenos de Neoplasias , Antígenos de Superficie/genética , Neoplasias de la Mama/genética , Cromosomas Humanos Par 8/genética , Alelos , Secuencia de Aminoácidos , Secuencia de Bases , Neoplasias de la Mama/patología , Clonación Molecular , ADN Complementario/química , ADN Complementario/genética , ADN de Neoplasias/química , ADN de Neoplasias/genética , Exones , Femenino , Amplificación de Genes , Regulación Neoplásica de la Expresión Génica , Genes/genética , Células HeLa , Humanos , Intrones , Datos de Secuencia Molecular , Estadificación de Neoplasias , Mapeo Físico de Cromosoma , Polimorfismo Conformacional Retorcido-Simple , Proteínas Proto-Oncogénicas c-myc/genética , Análisis de Secuencia de ADN , Células Tumorales Cultivadas
5.
Jpn J Cancer Res ; 92(4): 417-22, 2001 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11346464

RESUMEN

Frequent observations of allelic loss in chromosomal band 17q25.1 in a variety of human cancers have suggested that one or more tumor suppressor genes are present in that region. Moreover, a genetic locus for hereditary focal non-epidermolytic palmoplantar keratoderma, a condition associated with cancer of the esophagus (TOC; Tylosis with Oesophageal Cancer), lies in the same region. We screened cell lines derived from a variety of human cancers by reverse transcription-polymerase chain reaction (RT-PCR) to detect alterations in expression of genes within the region in question, by examining expressed sequence tags located there. These experiments identified an 1834-bp full-length cDNA encoding a novel, 441-amino acid integral membrane protein with seven putative transmembrane domains. This gene showed loss or extreme decrease of expression in 6 of 10 uterine cancer-cell lines, 2 of 11 hepatic cell carcinoma-cell lines, 2 of 7 lung cancer-cell lines, 1 of 6 gastric cancer-cell lines, and 1 of 10 breast cancer-cell lines. (We named it DMHC ("down-regulated in multiple human cancers").) Our results suggest that loss of expression of DMHC at 17q25.1 may play an important role in development of variety of human cancers.


Asunto(s)
Cromosomas Humanos Par 17/genética , Proteínas de la Membrana/genética , Neoplasias/genética , Secuencia de Aminoácidos , Secuencia de Bases , Clonación Molecular , ADN Complementario/genética , ADN de Neoplasias/genética , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de la Membrana/biosíntesis , Datos de Secuencia Molecular , Neoplasias/metabolismo , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas
6.
J Hum Genet ; 46(2): 70-5, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11281415

RESUMEN

Human cancers derived from breast, esophageal, or ovarian tissues frequently show allelic losses on chromosome band 17q25. Moreover, a locus responsible for hereditary focal nonepidermolytic palmoplantar keratoderma, a condition associated with esophageal cancer (TOC; tylosis with oesophageal cancer), has been mapped to the same band. During efforts to sequence, by shotgun methods, a 1-Mb target region that we had defined as the DNA segment harboring the putative tumor suppressor gene(s) involved in these events, we identified a novel cDNA. The full-length cDNA is 2495bp long and is expressed predominantly in skeletal muscle, heart, kidney, and placenta. The predicted product, a 627-amino-acid protein, exhibited significant sequence homology to the canine 68-kd subunit of the signal recognition particle that has been implicated in the transport of secreted and membrane proteins to the endoplasmic reticulum for proper processing. We confirmed the location of this gene at chromosome 17q25.1 by radiation-hybrid mapping and by fluorescence in situ hybridization.


Asunto(s)
Cromosomas Humanos Par 17 , Partícula de Reconocimiento de Señal/genética , Secuencia de Aminoácidos , Secuencia de Bases , Mapeo Cromosómico , Cromosomas Artificiales , Clonación Molecular , ADN Complementario , Humanos , Datos de Secuencia Molecular , Homología de Secuencia de Aminoácido
7.
J Hum Genet ; 46(2): 90-5, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11281419

RESUMEN

Frequent allelic losses within chromosomal band 17q25.1 in a variety of human cancers have suggested the presence of one or more tumor suppressor genes in this region. Furthermore, a genetic locus responsible for familial focal nonepidermolytic palmoplantar keratoderma, a condition associated with cancer of the esophagus, lies in the same region. This esophageal-cancer susceptibility locus, TOC (tylosis with oesophageal cancer), might be a target of deletions at 17q25.1 in multiple types of malignancy. Using the reverse transcriptase-polymerase chain reaction (RT-PCR) to examine cancer cell lines for alterations in the expression of transcripts from this portion of 17q, we identified a novel gene that we designated DMC1 (downregulated in multiple cancer-1). The full-length cDNA is 3293bp long. Its putative product is an integral membrane protein of 788 amino acids, belonging to the class of so-called 'inside-out" membrane proteins; it lacks a signal sequence but contains an N-terminal cytoplasmic domain, a single transmembrane peptide, and a C-terminal extracellular domain. We documented loss of expression of DMC1 in 2 of 10 breast-cancer cell lines, in 7 of 10 cervical-cancer lines, in 7 of 13 hepatocellular-cancer lines, in 3 of 7 lung-cancer lines, in 3 of 6 thyroid-cancer lines, in 2 of 6 gastric-cancer lines, and in 2 of 4 renal cell-cancer lines. Our results suggest that loss of expression of the DMC1 gene at 17q25.1 may play an important role in the development of cancers in a broad range of human tissues.


Asunto(s)
Proteínas de Ciclo Celular , Cromosomas Humanos Par 17 , Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Primarias Múltiples/genética , Secuencia de Aminoácidos , Secuencia de Bases , Clonación Molecular , ADN Complementario , Humanos , Pérdida de Heterocigocidad , Datos de Secuencia Molecular , Polimorfismo Conformacional Retorcido-Simple , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas
8.
Clin Cancer Res ; 7(4): 876-82, 2001 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11309336

RESUMEN

We previously defined 18 chromosomal regions in which frequent allelic losses were observed in breast cancers (T. Sato et al., Cancer RES:, 50: 7184-7189, 1990; Y. Harada et al., Cancer (PHILA:), 74: 2281-2286, 1994; I. Ito et al., BR: J. Cancer, 71: 438-441, 1995; K. Tsukamoto et al., Cancer (PHILA:), 78: 1929-1934, 1996; S. Matsumoto et al., Genes Chromosomes Cancer, 20: 268-274, 1997; T. Yokota et al., JPN: J. Cancer RES:, 88: 959-964, 1997; K. Tsukamoto et al., Cancer (PHILA:), 82: 317-322, 1998; A. Iida et al., Genes Chromosomes Cancer, 21: 108-112, 1998; K. Fukino et al., Genes Chromosomes Cancer, 24: 345-350, 1999; T. Yokota et al., Cancer (PHILA:), 85: 447-452, 1999; Y. Utada et al., JPN: J. Cancer RES:, 91: 293-300, 2000). To identify specific allelic losses that might correlate with postoperative recurrence, we examined tumors from a cohort of 504 breast cancer patients, who were followed clinically for 5 years postoperatively, for allelic losses of 18 microsatellite markers. Patients whose tumors had lost an allele at 3p25.1, 8p22, 13q12, 17p13.3, or 22q13 had significantly higher risks of recurrence than those whose tumors retained both alleles at those loci; at 3p25.1, the 5-year recurrence rate was 27% among patients with losses versus 18% with retention (P = 0.0131); at 8p22, 27% versus 14% (P = 0.0129); at 13q12, 28% versus 15% (P = 0.0109); at 17p13.3, 27% versus 20% (P = 0.0482); and at 22q13, 29% versus 20% (P = 0.0477). These data indicate that loss of heterozygosity at any one of these five specific loci is a significant predictor of postoperative recurrence among patients who have undergone surgery for breast cancer. These allelic losses can serve as negative prognostic indicators to guide postoperative management of patients.


Asunto(s)
Neoplasias de la Mama/genética , Cromosomas , Pérdida de Heterocigocidad/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/prevención & control , Cromosomas Humanos Par 13 , Cromosomas Humanos Par 17 , Cromosomas Humanos Par 22 , Cromosomas Humanos Par 3 , Cromosomas Humanos Par 8 , Supervivencia sin Enfermedad , Femenino , Marcadores Genéticos , Humanos , Persona de Mediana Edad , Recurrencia
9.
Biochem Biophys Res Commun ; 273(2): 654-60, 2000 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-10873660

RESUMEN

The human EBAG9 was previously identified as an estrogen responsive gene using CpG-genomic binding site cloning (Watanate et al., (1998) Mol. Cell. Biol. 18: 442-449). Recently it was revealed that the EBAG9 is identical with RCAS1 which is a cancer cell surface antigen implicated in immune escape. Here, we isolated and analyzed the 5'-flanking region of human EBAG9 gene. We determined transcription initiation site, which has a homology with an initiator element YYCAYYYY, and found that TATA motif was absent. Deletion analysis of the 5'-flanking region using MCF-7 breast cancer cells indicated that the sequences -86 to -36 containing the ERE had the basal level of promoter activity and the upstream GC-rich region positively regulated the activity. EBAG9 promoter luciferase reporters containing the ERE could respond to estrogen, and electrophoretic mobility shift assay showed that ERalpha bound to the ERE. Moreover, fluorescent in situ hybridization analysis has shown that the human EBAG9 gene is located at chromosome 8q23 which is frequently amplified in tumors. These findings suggest that the human EBAG9 might be involved in carcinogenesis as an estrogen responsive gene.


Asunto(s)
Cromosomas Humanos Par 8/genética , Estrógenos/metabolismo , Regiones Promotoras Genéticas , Secuencia de Bases , Sitios de Unión/genética , Mapeo Cromosómico , ADN/genética , ADN/metabolismo , Cartilla de ADN/genética , Receptor alfa de Estrógeno , Humanos , Hibridación Fluorescente in Situ , Datos de Secuencia Molecular , Receptores de Estrógenos/metabolismo
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