RESUMEN
BACKGROUND: The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) is a national precision medicine study incorporating centralized genomic testing to direct refractory cancer patients to molecularly targeted treatment subprotocols. This treatment subprotocol was designed to screen for potential signals of efficacy of ado-trastuzumab emtansine (T-DM1) in HER2-amplified histologies other than breast and gastroesophageal tumors. METHODS: Eligible patients had HER2 amplification at a copy number (CN) >7 based on targeted next-generation sequencing (NGS) with a custom Oncomine AmpliSeq™ (ThermoFisher Scientific) panel. Patients with prior trastuzumab, pertuzumab or T-DM1 treatment were excluded. Patients received T-DM1 at 3.6 mg/kg i.v. every 3 weeks until toxicity or disease progression. Tumor assessments occurred every three cycles. The primary end point was centrally assessed objective response rate (ORR). Exploratory end points included correlating response with HER2 CN by NGS. The impact of co-occurring genomic alterations and PTEN loss by immunohistochemistry were also assessed. RESULTS: Thirty-eight patients were enrolled and 36 included in efficacy analysis. Median prior therapies in the metastatic setting was 3 (range 0-9; unknown in one patient). Median HER2 CN was 17 (range 7-139). Partial responses were observed in two (5.6%) patients: one mucoepidermoid carcinoma of parotid gland and one parotid gland squamous cell cancer. Seventeen patients (47%) had stable disease including 8/10 (80%) with ovarian and uterine carcinomas, with median duration of 4.6 months. The 6-month progression-free survival rate was 23.6% [90% confidence interval 14.2% to 39.2%]. Common toxicities included fatigue, anemia, fever and thrombocytopenia with no new safety signals. There was a trend for tumor shrinkage with higher levels of gene CN as determined by the NGS assay. CONCLUSION: T-DM1 was well tolerated. While this subprotocol did not meet the primary end point for ORR in this heavily pre-treated diverse patient population, clinical activity was seen in salivary gland tumors warranting further study in this tumor type in dedicated trials.
Asunto(s)
Ado-Trastuzumab Emtansina/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias/tratamiento farmacológico , Receptor ErbB-2/genética , Ado-Trastuzumab Emtansina/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/farmacología , Resistencia a Antineoplásicos/genética , Femenino , Amplificación de Genes , Humanos , Persona de Mediana Edad , National Cancer Institute (U.S.) , Neoplasias/genética , Neoplasias/mortalidad , Neoplasias/patología , Medicina de Precisión/métodos , Supervivencia sin Progresión , Receptor ErbB-2/antagonistas & inhibidores , Estados Unidos/epidemiologíaRESUMEN
UNLABELLED: Our randomized controlled trial in prematurely menopausal breast cancer survivors showed that impact + resistance training prevented increases in percentage of body fat compared with controls and also improved BMD at the hip and prevented BMD loss at the spine among exercise-trained women who were menopausal for >1 year. INTRODUCTION: Cancer treatment-related menopause worsens bone health and body composition in breast cancer survivors (BCS). We investigated whether impact + resistance training could improve bone mineral density (BMD), reduce bone turnover, build muscle, and decrease fat mass in BCS with premature menopause. METHODS: We conducted a randomized controlled trial in 71 BCS (mean age, 46.5 years) within 5 years of treatment-related menopause. Women were randomly assigned to one of two groups: (1) impact + resistance training (prevent osteoporosis with impact + resistance (POWIR)) or (2) exercise placebo (FLEX) 3×/week for 1 year. Outcomes were hip and spine BMD (in grams per square centimeter) and body composition (percent body fat (%BF) and lean and fat mass (in kilograms)) by DXA and bone turnover markers (serum osteocalcin (in nanograms per milliliter) and urinary deoxypryrodinoline (in nanomoles per milliliter). RESULTS: There were no significant group × time interactions for bone outcomes when using an intent-to-treat approach on the full sample. In analyses restricted to BCS who were menopausal for ≥1 year, POWIR increased BMD at the hip and slowed BMD loss at the spine compared with FLEX (femoral neck-POWIR, 0.004 ± 0.093 g/cm(2) vs. FLEX, -0.010 ± 0.089 g/cm(2); p < 0.01; spine-POWIR, -0.003 ± 0.114 g/cm(2) vs. FLEX, -0.020 ± 0.110 g/cm(2); p = 0.03). POWIR prevented increases in %BF (POWIR, 0.01 % vs. FLEX, 1.3 %; p < 0.04). Women with attendance to POWIR at ≥64 % had better improvements in %BF than women attending less often (p < 0.03). CONCLUSION: Impact + resistance training may effectively combat bone loss and worsening body composition from premature menopause in BCS.
Asunto(s)
Densidad Ósea/fisiología , Neoplasias de la Mama/tratamiento farmacológico , Terapia por Ejercicio/métodos , Menopausia Prematura/fisiología , Osteoporosis Posmenopáusica/prevención & control , Adulto , Antineoplásicos/efectos adversos , Composición Corporal/fisiología , Neoplasias de la Mama/fisiopatología , Femenino , Cuello Femoral/fisiopatología , Humanos , Vértebras Lumbares/fisiopatología , Persona de Mediana Edad , Osteoporosis Posmenopáusica/etiología , Osteoporosis Posmenopáusica/fisiopatología , Cooperación del Paciente , Entrenamiento de Fuerza/métodos , Sobrevivientes , Resultado del TratamientoRESUMEN
The Zfy gene is located on the Y chromosome of placental mammals and encodes a zinc finger protein which may serve as the primary sex-determining signal. A related gene, Zfx, is similarly conserved on the X chromosome. Unlike that in most mammals, the mouse genome contains four homologous zinc finger loci: Zfy-1, Zfy-2, Zfx, and Zfa (on an autosome). We report that, in contrast to the mouse Zfy genes, Zfx is widely transcribed in embryos, newborns, and adults, both male and female. Moreover, Zfx transcripts contain long 3' untranslated sequences which are phylogenetically conserved. Zfa is a processed gene derived from Zfx. An analysis of cDNA clones demonstrated that Zfx encodes a 799-amino-acid protein that is 70% identical to the mouse Zfy-1 and Zfy-2 proteins. Zfx, Zfy-1, and Zfy-2 contain highly acidic amino-terminal domains and carboxy-terminal regions containing 13 zinc fingers. When fused to the DNA-binding domain of GAL4, the acidic domains of Zfx and Zfy-2 activated transcription in yeast cells.
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Proteínas de Unión al ADN/genética , Genes , Metaloproteínas/genética , Cromosoma Y , Zinc/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Clonación Molecular , Femenino , Humanos , Hígado/análisis , Masculino , Ratones , Ratones Endogámicos , Datos de Secuencia Molecular , Sondas de Oligonucleótidos , Especificidad de Órganos , Homología de Secuencia de Ácido Nucleico , Análisis para Determinación del Sexo , Especificidad de la Especie , Transcripción GenéticaRESUMEN
Genes homologous to mouse Zfx have been identified on the X and Y chromosomes of all placental mammals examined. The genes of this ZFX/ZFY family appear to encode proteins comprising an amino-terminal acidic domain, a putative nuclear localizing signal, and a carboxy-terminal domain of 13 zinc fingers. These proteins likely function as transcription activators. Although roles for these proteins in sex determination, Turner syndrome, and spermatogenesis have been proposed, the biological processes in which these proteins function are not known. No comprehensive studies of gene structure have been reported for any member of the ZFX/ZFY family. Here, we report that mouse Zfx spans 50 kb and contains at least 11 exons. Exons 1 through 4 contain 5' untranslated sequences, exons 5 through 10 encode the acidic domain, exon 10 also encodes the putative nuclear localizing signal, and exon 11 encodes 13 zinc fingers and contains the 3' untranslated sequences. The 5' untranslated exons exhibit complex patterns of differential splicing. At the 5' end of this widely expressed gene, a 1.5-kb CpG island encompasses multiple transcription initiation sites as well as the first and second exons. The 5' portion of the CpG island displays promoter activity. This knowledge of the Zfx gene structure allowed us to reconstruct the splicing and retroposition events by which the Zfa gene on mouse chromosome 10 arose from a Zfx transcript.
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Proteínas de Unión al ADN/genética , Genes , Ratones/genética , Cromosoma X , Animales , Secuencia de Bases , Evolución Biológica , Elementos Transponibles de ADN , Exones , Intrones , Factores de Transcripción de Tipo Kruppel , Mamíferos/genética , Datos de Secuencia Molecular , Regiones Promotoras Genéticas , Empalme del ARN , Alineación de Secuencia , Homología de Secuencia de Ácido Nucleico , Factores de Transcripción , Dedos de Zinc/genéticaRESUMEN
The ZFY gene in the sex-determining region of the human Y chromosome encodes a protein with 13 zinc fingers, and may determine whether an embryo develops as a male or female. ZFX, a related gene on the human X chromosome, may also function in sex determination; it encodes a protein with a very similar zinc-finger domain and escapes X inactivation. ZFY and ZFX diverged from a common ancestral gene before the radiation of placental mammals, and retain a similar genomic organization. Analysis of complementary DNAs from the mouse Y-chromosomal homologues of ZFY indicates that these genes encode probable transcription activators. Here, we report that ZFX encodes a protein composed of a highly acidic amino-terminal domain, a basic putative nuclear-localization signal, and a carboxy-terminal zinc-finger domain. This combination of features, also found in the ZFY gene product, is typical of transcription activators. Alternative splicing generates ZFX transcripts encoding isoforms of 575 and 804 amino acids. These ZFX protein isoforms differ in the length of their acidic domains and may be functionally distinct.
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Proteínas de Unión al ADN/genética , Cromosoma X , Secuencia de Aminoácidos , Secuencia de Bases , ADN/genética , ADN Polimerasa Dirigida por ADN , Femenino , Amplificación de Genes , Humanos , Factores de Transcripción de Tipo Kruppel , Masculino , Metaloproteínas/genética , Datos de Secuencia Molecular , Hibridación de Ácido Nucleico , Biosíntesis de Proteínas , Mapeo Restrictivo , Homología de Secuencia de Ácido Nucleico , Factores de Transcripción , Transcripción GenéticaRESUMEN
Several categories of human X-Y homologous DNA sequences have been recognized. We report that a locus (DXYS77) approximately 14 kb distal to the pseudoautosomal boundary (PAB) is 93% identical in nucleotide sequence to a locus (DYS148) on the long arm of the Y chromosome (Yq). Within this segment of pseudoautosomal/Yq homology we identified a member of a family of repeats that are concentrated in Xp22.3 and in the euchromatic portion of the Y chromosome. The repeat sequence structure--a dimer bounded by short terminal repeats--is reminiscent of retroposons derived from RNA polymerase III transcripts.
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Secuencias Repetitivas de Ácidos Nucleicos , Cromosoma X , Cromosoma Y , Secuencia de Bases , Humanos , Datos de Secuencia Molecular , Homología de Secuencia de Ácido NucleicoRESUMEN
The human ZFX, human ZFY, and mouse Zfx genes have CpG islands near their 5; ends. These islands are typical in that they span about 1.5 kb, contain transcription initiation sites, and encompass some 5' untranslated exons and introns. However, comparitive nucleotide sequencing of these human and mouse islands provided evidence of evolutionary conservation to a degree unprecedented among mammalian 5' CpG islands. In one stretch of 165 nucleotides containing 19 CpGs, mouse Zfx and human ZFX are identical to each other and differ from human ZFY at only 9 nucleotides. In contrast, we found no evidence of homologous CpG islands in the mouse Zfy genes, whose transcription is more circumscribed than that of human ZFX, human ZFY, and mouse Zfx. Using the isoschizomers HpaII and MspI to examine a highly conserved segment of the ZFX CpG island, we detected methylation on inactive mouse X chromosomes but not on inactive human X chromosomes. These observations parallel the previous findings that mouse Zfx undergoes X inactivation while human ZFX escapes it.
Asunto(s)
Evolución Biológica , Islas de CpG/genética , Proteínas de Unión al ADN/genética , Dedos de Zinc/genética , Animales , Secuencia de Bases , Secuencia Conservada , ADN/química , ADN/genética , ADN/metabolismo , Humanos , Factores de Transcripción de Tipo Kruppel , Masculino , Metilación , Ratones , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Homología de Secuencia de Ácido Nucleico , Especificidad de la Especie , Factores de Transcripción , Transcripción Genética , Cromosoma X , Cromosoma YRESUMEN
G2A is an orphan G protein-coupled receptor (GPCR), expressed predominantly in T and B cells and homologous to a small group of GPCRs of unknown function expressed in lymphoid tissues. G2A is transcriptionally induced in response to diverse stimuli, and its ectopic expression suppresses transformation of B lymphoid precursors by BCR-ABL. G2A induces morphological transformation of NIH 3T3 fibroblasts. Microinjection of constructs encoding G2A into Swiss 3T3 fibroblasts induces actin reorganization into stress fibers that depends on RhoA, but not CDC42 or RAC. G2A elicits RhoA-dependent transcriptional activation of serum response factor. Direct evaluation of RhoA activity demonstrates elevated levels of RhoA-GTP in G2A-expressing cells. Microinjection of embryonic fibroblasts derived from various G alpha knockout mice establishes a requirement for G alpha 13 but not G alpha 12 or G alpha q/11 in G2A-induced actin rearrangement. In conclusion, G2A represents a family of GPCRs expressed in lymphocytes that may link diverse stimuli to cytoskeletal reorganization and transcriptional activation through a pathway involving G alpha 13 and RhoA.
Asunto(s)
Actinas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Unión al GTP/metabolismo , Receptores de Superficie Celular/metabolismo , Receptores Acoplados a Proteínas G , Proteína de Unión al GTP rhoA/metabolismo , Animales , Línea Celular , Citoesqueleto/metabolismo , Humanos , Ratones , Activación TranscripcionalRESUMEN
The zinc-finger proteins ZFX and ZFY, encoded by genes on the mammalian X and Y chromosomes, have been speculated to function in sex differentiation, spermatogenesis, and Turner syndrome. We derived Zfx mutant mice by targeted mutagenesis. Mutant mice (both males and females) were smaller, less viable, and had fewer germ cells than wild-type mice, features also found in human females with an XO karyotype (Turner syndrome). Mutant XY animals were fully masculinized, with testes and male genitalia, and were fertile, but sperm counts were reduced by one half. Homozygous mutant XX animals were fully feminized, with ovaries and female genitalia, but showed a shortage of oocytes resulting in diminished fertility and shortened reproductive lifespan, as in premature ovarian failure in humans. The number of primordial germ cells was reduced in both XX and XY mutant animals at embryonic day 11.5, prior to gonadal sex differentiation. Zfx mutant animals exhibited a growth deficit evident at embryonic day 12.5, which persisted throughout postnatal life and was not complemented by the Zfy genes. These phenotypes provide the first direct evidence for a role of Zfx in growth and reproductive development.